Textbook of Endocrine Surgery, Second Edition

ELSEVIER SAUNDERS 1600 John F. Kennedy Blvd., Ste 1800 Philadelphia, PA 19103-2899 TEXTBOOK OF ENDOCRINE SURGERY ISBN 0-7216-0139-1

Copyright© 2005, 1997 Elsevier Inc.

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NOTICE Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the EditorslAuthors assumes any liability for any injury and/or damage to persons or property arising out or related to any use of the material contained in this book.

Textbook of endocrine surgery / [edited by] Orlo H. Clark, Quan-Yang Duh, Electron Kebebew. - 2nd ed. p. . crn. Includes bibliographical references and index. ISBN 0-7216-0139-1 I. Endocrine glands-Surgery. 2. Endocrine glands-Diseases. I. Clark, Orlo H. II. Duh, Quan-Yang. III. Kebebew, Electron. [DNLM: 1. Endocrine System Diseases-surgery. 2. Endocrine Glands-surgery. WK 140 T355 2006] RD599.T492006 2005042824 617.4' 4-dc22

Acquisitions Editor: Judith Fletcher Publishing Services Manager: Tina Rebane Project Manager: Norm Stellander Design Manager: Gene Harris

Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1

Dedication We would like to dedicate this book to our wives, Carol, Ann, and Tida, and families, and to Ms. Kate Poole. Their wonderful support helped to make this book possible.

Claudette Abela-Forman EK, MD Assistant Professor, Department of Ophthalmology, Medical University of Vienna; Senior Resident, General Hospital of Vienna, Vienna, Austria Metabolic Complications of Primary Hyperparathyroidism Bo Ahren, MD, PhD Professor, Department of Medicine, Lund University, Lund, Sweden Pancreatic Endocrine Physiology Goran Akerstrom, MD, PhD Professor of Surgery, Uppsala University; Professor of Surgery and Chief of Endocrine Surgery, Department of Surgical Sciences, University Hospital, Uppsala, Sweden Natural History of Untreated Primary Hyperparathyroidism Maha AI-Fehaily, MD Associate Consultant, Breast and Endocrine Surgery, King Faisal Specialist Hospital and Research Centre, Department of Surgery, Riyadh, Saudi Arabia Sporadic Nontoxic Goiter Saif AI-Sobhi, MD, FRCS (Glas), ABIS Chairman, Department of Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Parathyroid Hyperplasia: Parathyroidectomy Ahmad Assalia, MD Deputy Director, Department of Surgery, Rambam Medical Center, Haifa, Israel Laparoscopic Adrenalectomy Jon Armstrong, MD Clinical Instructor, University of Perth, Royal Perth Hospital; Senior Surgeon, General and Endocrine Surgery, Royal Perth Hospital, Perth, Western Australia, Australia Adrenocortical Carcinoma: Nonfunctioning and Functioning Sylvia L. Asa, MD, PhD Professor, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto; Pathologist-in-Chief, University Health Network, and Medical Director, Toronto Medical Laboratories, Toronto, Ontario, Canada Anaplastic Carcinoma of the Thyroid Gland

Anders O. J. Bergenfelz, MD, PhD Associate Professor, Lund University; Consultant Surgeon, Department of Surgery, University Hospital, Lund, Sweden Surgical Approach to Primary Hyperparathyroidism (Unilateral Approach) Piero Berti, MD Professor of Surgery, University of Pisa; Assistant, S. Chiara Hospital, Pisa, Italy Minimally Invasive Parathyroid Surgery Michael Sean Boger, MD, PharmD House Officer, Department of Internal Medicine, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina Graves' and Plummer's Diseases: Medical and Surgical Management H. Jaap Bonjer, MD, PhD Professor of Surgery, Dalhousie University; Director of Minimally Invasive Surgery, Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada Technique of Parathyroidectomy Bert A. Bonsing, MD, PhD Staff Surgeon, Department of Surgery, Leiden University Medical Center, Leiden, Germany Occurrence and Prevention of Complications in Thyroid Surgery Michael Brauckhoff, MD Department of General, Visceral, and Vascular Surgery, University of Halle, Halle, Germany Surgical Management ofAdvanced Thyroid Cancer Invading the Aerodigestive Tract James D. Brierley, MB BS, MRCP, FRCP, FRCP (C) Associate Professor, Department of Radiation Oncology, University of Toronto, Toronto; Staff Radiation Oncologist, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada Anaplastic Carcinoma of the Thyroid Gland Hajo A. Bruining, MD, PhD Emeritus Professor of Surgery, Erasmus University, Rotterdam, The Netherlands Technique of Parathyroidectomy

v

vi - - Contributors Laurent Brunaud, MD, PhD Professor of Surgery, University of Nancy; Staff Surgeon, Department of General and Endocrine Surgery, Chu Nancy-Brabois, Nancy, France Comparative Genomic Hybridization in Thyroid Neoplasms; Neuroendocrine Tumors Blake Cady, MD Professor of Surgery, Brown Medical School; Interim Director, Comprehensive Breast Center, Rhode Island Hospital, Providence, Rhode Island Predictors of Thyroid Tumor Aggressiveness Denise M. Carneiro-Pia, MD Fellow, Department of Endocrine Surgery, University of Miami/Jackson Memorial Center, Miami, Florida Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism Herbert Chen, MD, FACS Chief of Endocrine Surgery, and Assistant Professor of Surgery, University of Wisconsin, Madison, Wisconsin Hiirthle Cell Adenoma and Carcinoma Polly S-Y Cheung, MB BS (HK) Consultant Surgeon, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong Medical and Surgical Treatment of Endemic Goiter Orlo H. Clark, MD Professor of Surgery, Department of Surgery, University of California, San Francisco, School of Medicine, San Francisco, California Sporadic Nontoxic Goiter; Thyroiditis; Papillary Thyroid Carcinoma: Rationale for Total Thyroidectomy; Potentially New Therapies in Thyroid Cancer; Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy; Parathyroid Hyperplasia: Parathyroidectomy Roderick Clifton-Bligh, MBBS, PhD, FRACP Honorary Senior Lecturer in Medicine, University of Sydney; Staff Specialist in Endocrinology, Royal North Shore Hospital, Sydney, New South Wales, Australia Thyroid Physiology Alan P. B. Dackiw, MD, PhD Assistant Professor of Surgery, Johns Hopkins University, Baltimore, Maryland Transplantation of Endocrine Cells and Tissues Leigh Delbridge, MD, FRACS Professor of Surgery, University of Sydney; Head, Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia Thyroid Physiology

Michael J. Demeure, MD Chief, Section of General Surgery, Professor of Surgery, Arizona Health Sciences Center, Tucson, Arizona Mechanisms and Regulation of Invasion in Thyroid Cancer Gerard M. Doherty, MD M. W. Thompson Professor of Surgery, University of Michigan, Ann Arbor, Michigan Follicular Neoplasms of the Thyroid Henning Dralle MD Head, Department of General, Visceral, and Vascular Surgery, University of Halle, Halle, Germany Surgical Management ofAdvanced Thyroid Cancer Invading the Aerodigestive Tract Quan-Yang Duh, MD Professor of Surgery, University of California, San Francisco, School of Medicine, San Francisco, California Potentially New Therapies in Thyroid Cancer; Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) Erol Duren, MD Professor Emeritus, Department of Surgery, University of Istanbul, Cerrahpasa Medical School; Medical Director and Chief of Surgery, Istanbul German Hospital, Istanbul, Turkey Recurrent Thyroid Cancer Mete Duren, MD Professor, Department of Surgery, University of Istanbul, Cerrahpasa Medical School, Istanbul, Turkey Recurrent Thyroid Cancer Kathryn L. Edmiston, MD Assistant Professor of Medicine, Associate Director, Breast Center, University of Massachusetts Medical Center, Boston, Massachusetts Chemotherapy for Unresectable Endcorine Neoplasms E. Christopher Ellison, MD Professor and Chair, Department of Surgery, The Ohio State University College of Medicine and Public Health, Columbus, Ohio Multiple Endocrine Neoplasia Type 2B Gennaro Favia, MD Professor of Surgery and Head, Endocrine Surgery Unit, Department of Surgical and Gastroenterological Sciences, University of Padua, School of Medicine, Padova, Italy Cushing's Syndrome

Contributors - - vii

Volker Fendrich, MD Resident in Surgery, Philipps University; Resident in the Department of Visceral, Thoracic, and Vascular Surgery, Klinikum Der Philipps-Universitat, Marburg, Germany Localization of Endocrine Pancreatic Tumors

Oliver Gimm, MD Department of General, Visceral, and Vascular Surgery, Martin Luther University of Halle-Wittenberg, Halle, Germany Surgical Management ofAdvanced Thyroid Cancer Invading the Aerodigestive Tract

Douglas L. Fraker, MD Jonathan Rhoads Associate Professor of Surgery; Vice Chairman, Clinical Affairs, and Director, General Surgery, University of Pennsylvania, Philadelphia, Pennsylvania Factors That Predispose to Thyroid Neoplasia

Victor Gorelev, MD Professor of Surgery, Heinrich Heine University, DUsseldorf, Germany Oncogenes in Thyroid Tumors

John R. Frandon, BSc, MD, FRCSt Formerly Professor of Surgery, University of Bristol, United Kingdom Surgical Embryology and Anatomy of the Adrenal Glands Yoshihide Fujimoto, MD, PhD Former Professor of Surgery, Department of Endocrine Surgery, Tokyo Women's Medical University, Tokyo; Adviser of the Hospital and Director, Division of Thyroid-Endocrine Surgery, Cancer Institute Hospital, Tokyo, Japan Papillary Thyroid Carcinoma: Rationale for Hemithyroidectomy Shuji Fukata, MD Chief of Internal Medicine, Kuma Hospital, Kobe, Japan Hypothyroidism Michel Gagner, MD, FRCS, FACS Professor of Surgery, Weill Medical College of Cornell University; Chief, Laparoscopy and Bariatric Surgery, Department of Surgery, New York-Presbyterian Hospital, New York, New York Laparoscopic Adrenalectomy Armando Gamboa-Dominguez, MD, PhD Associate Professor of Pathology, Facultad de Medicina, Universidad Nacional Aut6noma de Mexico; Senior Pathologist, Instituto Nacional de Ciencias Medicas y Nutrici6n Salvador Zubiran, Mexico City, Mexico Parathyroid Embryology, Anatomy, and Pathology Helene Gilbelin, MD Consultant Surgeon, Endocrine Surgery, Jean Bernard Hospital, Poitiers, France Familial Hyperparathyroidism in Multiple Endocrine Neoplasia Syndromes Glenn Gibson, BA Senior Scientist, Pfizer Global Research and Development, Ann Arbor; Michigan Cryopreservation of Parathyroid Tissue

tDeceased

Peter E. Goretzki, MD Professor of Surgery, Heinrich Heine University, DUsseldorf, Germany Oncogenes in Thyroid Tumors Clive S. Grant, MD Professor of Surgery, Mayo Clinic, Rochester, Minnesota Pheochromocytoma Staffan Grandal, MD, PhD Associate Professor of Surgery, Karolinska Institutet; Consultant, Department of Surgery, Danderyds Hospital, Stockholm, Sweden Adrenal Physiology Bertil Hamberger, MD, PhD Professor of Surgery, Department of Surgical Sciences, Karolinska Institutet; Consultant; Department of Surgery, Karolinska Hospital, Stockholm, Sweden Adrenal Physiology J. F. Hamming, MD, PhD Surgeon, St. Elisabeth Hospital, Tilburg; The Netherlands Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer Jay K. Harness, MD Medical Director, St. Joseph Hospital Comprehensive Breast Center, Orange, California Childhood Thyroid Carcinoma Susannah E. Harte, MD, MRCPI University College, Dublin, Ireland Use and Abuse of Thyroid-Stimulating Hormone Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms Nils-Erik Heldin, PhD Associate Professor in Experimental Pathology, University, Hospital, Uppsala, Sweden Growth Factor, Thyroid Hyperplasia, and Neoplasia Jean-Francois Henry, MD Professor of Surgery, University of Marseilles; Chief, Department of General and Endocrine Surgery, University Hospital La Timone, Marseilles, France Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands and Recurrent and External Laryngeal Nerves; Endoscopic Parathyroidectomy

viii - - Contributors

Miguel F. Herrera, MD, PhD Associate Professor of Surgery, Facultad de Medicina, Universidad Veracruzana; Staff Surgeon, Instituto Nacional de Ciencias Medicas y Nutrici6n Salvador Zubiran, Mexico City, Mexico Parathyroid Embryology, Anatomy, and Pathology Shih-ming Huang, MD Professor, Department of Surgery, Buddhist Tzu-Chi University; Professor and Consultant Surgeon, Buddhist Tzu-Chi General Hospital, Hualien, Taiwan Familial Hyperparathyroidism

Electron Kebebew, MD Assistant Professor of Surgery, University of California, San Francisco/Mt, Zion Medical Center, San Francisco, California Thyroid Oncogenesis Rachel R. Kelz, MD Assistant Professor of Clinical Surgery, University of Pennsylvania, Philadelphia, Pennsylvania Factors that Predispose to Thyroid Neoplasia

Maurizio Iacobone, MD Assistant Professor, Clinical Research, University of Padua, School of Medicine; Endocrine Surgery Unit, Department of General and Gastroenterological Sciences, University of Padua, Italy Cushing's Syndrome

Job Kievit, MD, PhD Professor of Clinical Decision Analysis and Associate Professor of Surgery, Leiden University Medical Center; Chief, Section of EndocrinelHead and Neck Surgery, Department of Surgery, Leiden University Medical Center, Leiden, Germany Occurrence and Prevention of Complications in Thyroid Surgery

Masatoshi Iihara, MD Assistant Professor, Department of Endocrine Surgery, Tokyo Women's Medical University; Assistant Professor, Department of Endocrine Surgery, Tokyo Women's Medical University Hospital, Shinjuku-ku, Tokyo, Japan Hyperaldosteronism

Barbara K. Kinder, MD William H. Carmalt Professor of Surgery, Yale University, School of Medicine; Attending Surgeon, Yale-New Haven Hospital, New Haven, Connecticut Endocrine Emergencies: Hypoglycemic and Hyperglycemic Crises

Silvio E. Inzucchi, MD Professor of Medicine, Section of Endocrinology, Yale University School of Medicine; Director, Yale Diabetes Center, Yale-New Haven Hospital, New Haven, Connecticut Endocrine Emergencies: Hypoglycemic and Hyperglycemic Crises

Jean-Louis Kraimps, MD Professor, Poitiers University Medical School; Professor of General Surgery, Jean Bernard Hospital, Poitiers, France Familial Hyperparathyroidism in Multiple Endocrine Neoplasia Syndromes

George L. Irvin III, MD Professor of Surgery, University of Miami School of Medicine, Miami, Florida Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism Yukio Ito, MD Associate Professor, Department of Endocrine Surgery, Tokyo Women's Medical University; Associate Professor, Department of Endocrine Surgery, Tokyo Women's Medical University Hospital, Shinjuku-ku, Tokyo, Japan Hyperaldosteronism Suzanne Jan de Beur, MD Director, Division of Endocrinology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Hypoparathyroidism and Pseudohypoparathyroidism Edwin L. Kaplan, MD Professor of Surgery, The University of Chicago, Pritzker School of Medicine; Attending Physician, The University of Chicago Hospitals, Chicago, Illinois Insulinomas

Kanji Kuma, MD Honorary Director, Kuma Hospital, Kobe, Japan Hypothyroidism Geeta Lal, MD, MSc, FRCS(C) Assistant Professor of Surgery, University of Iowa; Staff Surgeon, Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa Thyroiditis; Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy Anne C. Larkin, MD Director of Undergraduate Surgical Education, Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts Chemotherapy for Unresectable Endocrine Neoplasms Chen-Hsen Lee, MD Professor of Surgery, National Yang-Ming University; Team Leader of Endocrine Surgery and Vice Superintendent, Taipei Veterans General Hospital, Taipei, Taiwan Thyroid Emergencies: Thyroid Storm and Myxedema Coma Sten Lennquist, MD, PhD Professor Emeritus, University of Linkoping; Former Chairman, Department of Surgery, University Hospital, Linkoping, Sweden Thyroidectomy

Contributors - - ix

Hong-Da Lin, MD Clinical Professor, Taipei Medical University, School of Medicine; Chief, Division of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taipei, Taiwan Thyroid Emergencies: Thyroid Storm and Myxedema Coma

Christopher R. McHenry, MD Professor of Surgery, Case Western Reserve University School of Medicine; Vice Chairman, Department of Surgery, and Director, Division of General Surgery, MetroHealth Medical Center, Cleveland, Ohio Anatomy and Embryology of the Pancreas

Dimitrios A. Linos, MD Associate Professor of Surgery, Athens Medical School, and Director of First Surgical Clinic, Hygeia Hospital Athens, Greece; Lecturer in Surgery, Harvard Medical School, and Consultant in Surgery, Massachusetts General Hospital, Boston, Massachusetts Clinically Inapparent Adrenal Mass (Incidentaloma or Adrenaloma)

Paolo Miccoli, MD Professor of Surgery, and Chairman, Department of Surgery, Universita Studi di Pisa, Pisa, Italy Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases; Minimally Invasive Parathyroid Surgery

Chung Yau Lo, MB BS(HK), MS(HK), FRCS(Edin), FACS Associate Professor, Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital; Associate Professor and Chief of Endocrine Surgery, Department of Surgery, University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong Parathyroid Reoperations Franco Lumachi, MD Assistant Professor, Clinical Research, University of Padua, School of Medicine; Endocrine Surgery Unit, Department of Surgical and Gastroenterological Sciences, University of Padua, School of Medicine, Padova, Italy Cushing's Syndrome Ewa Lundgren, MD, PhD Associate Professor, Uppsala University, Medical Faculty; Consultant and Head of the Surgery Department, Institution of Surgical Sciences, University Hospital, Uppsala, Sweden Natural History of Untreated Primary Hyperparathyroidism Andreas Machens, MD Department of General, Visceral, and Vascular Surgery, University of Halle, Halle, Germany Surgical Management ofAdvanced Thyroid Cancer Invading the Aerodigestive Tract Lloyd A. Mack, MD, FRCSC Assistant Professor, Department of Surgery and Oncology, Division of General Surgery, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid Paul R. Maddox, BSc, MCh, FRCS(Ed), FRCS(Eng) Consultant Surgeon, Royal United Hospital, Bath, England, United Kingdom Approach to Thyroid Nodules

Raducu Mihai, MD, PhD, MRCS Lecturer in Surgery, University of Bristol; Specialist Registrar in Endocrine Surgery, Bristol Royal Infirmary, Bristol, United Kingdom Surgical Embryology and Anatomy of the Adrenal Glands Craig A. Miller, MD Director of Vascular Services, St. Joseph Hospital, Kokomo, Indiana Multiple Endocrine Neoplasia Type 2B Daishu Miura, MD Staff, Department of Endocrine Surgery, Toranomon Hospital, Tokyo, Japan Comparative Genomic Hybridization in Thyroid Neoplasms Jeffery F. Moley, MD Associate Professor of Surgery, Washington University School of Medicine; Associate Chief of Surgery, St. Louis Veterans Administration Medical Center, St. Louis, Missouri Medullary Thyroid Carcinoma Jack M. Monchik; MD, FACS Clinical Professor of Surgery, Brown University School of Medicine, Chief, Endocrine Surgery, Rhode Island Hospital, Providence, Rhode Island Normocalcemic Hyperparathyroidism Bruno Niederle, MD Professor of Surgery, Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, Medical University of Vienna; Chief, Endocrine Surgery, General Hospital of Vienna, Vienna, Austria Metabolic Complications of Primary Hyperparathyroidism Ronald H. Nishiyama, MD Chief Emeritus, Department of Pathology, Maine Medical Center, Portland, Maine Pathology of Tumors of the Thyroid Gland Shiro Noguchi, MD, PhD, FJCS, FACE Chief Executive Officer, Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Oita, Japan Localization Tests in Patients with Thyroid Cancer

x - - Contributors

Jeffrey A. Norton, MD Professor of Surgery, Stanford University Medical Center; Chief of Surgical Oncology, Stanford University, Department of Surgery, Stanford, California Somatostatinoma and Rare Pancreatic Endocrine Tumors Patricia J. Numann, MD The Lloyd S. Rogers Professor of Surgery, SUNY Distinguished Teaching Professor, and SUNY Distinguished Service Professor, State University of New York, Upstate Medical University; Medical Director, University Hospital, Syracuse, New York Addison's Disease and Acute Adrenal Hemorrhage Takao Obara, MD, PhD Professor and Chief, Department of Endocrine Surgery, Tokyo Women's Medical University, Tokyo; Director, Institute of Clinical Endocrinology, Tokyo Women's Medical University Hospital, Tokyo, Japan Papillary Thyroid Carcinoma: Rationale for Hemithyroidectomy; Hyperaldosteronism Niall O'Higgins, MCh, FRCSI, FRCS(Edin), FRCS(Eng) Professor and Head, Department of Surgery, University College, Dublin; Professor of Surgery, St. Vincent's University Hospital, Dublin, Ireland Use and Abuse of Thyroid-Stimulating Hormone Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms Takahiro Okamoto, MD, PhD Assistant Professor, Department of Endocrine Surgery, Tokyo Women's Medical University, Tokyo, Japan Papillary Thyroid Carcinoma: Rationale for Hemithyroidectomy Furio Pacini, MD Professor of Endocrinology, Universita di Siena, Siena Italy Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases Kevin Packman, MD Department of Surgery, Froedtert Memorial Lutheran Hospital and Medical College of Wisconsin, Milwaukee, Wisconsin Mechanisms and Regulation of Invasion in Thyroid Cancer P. Parrilla, MD Professor of Surgery, Department of Surgery, School of Medicine, University of Murcia; Chairman, Department of General Surgery, Virgen de la Arrixaca University Hospital, Murcia, Spain Localization Studies in Persistent or Recurrent Hyperparathyroidism Jin-Woo Park, MD, PhD Associate Professor, College of Medicine, Chungbuk National University, Cheongju, Korea Potentially New Therapies in Thyroid Cancer

Janice L. Pasieka, MD Clinical Professor of Surgery and Oncology, Faculty of Medicine, Department of Surgery, University of Calgary; Regional Division Chief, Division of General Surgery, Calgary Health Region and University of Calgary, Foothills Medical Center, Calgary, Alberta, Canada Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid; Asymptomatic Primary Hyperparathyroidism Fran~ois N. Pattou, MD Associate Professor of Surgery, Medical School of Lille; Senior Surgeon, Department of General and Endocrine Surgery, Lille University Hospital-Huriez, Lille, France Advenocortical Carcinoma: Nonfunctioning and Functioning

Nilima A. Patwardhan, MD Professor of Surgery, University of Massachusetts Medical Center, Worcester, Massachusetts Chemotherapy for Unresectable Endocrine Neoplasms Nancy Dugal Perrier, MD FACS Associate Professor of Surgery, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Graves' and Plummer's Diseases: Medical and Surgical Management Gerhard Prager, MD Assistant Professor, Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, Medical University of Vienna; Senior Resident, General Hospital of Vienna, Vienna, Australia Metabolic Complications of Primary Hyperparathyroidism Richard A. Prinz, MD Helen Shedd Keith Professor and Chairman, Department of General Surgery, Rush University; Chairman, Department of General Surgery, Rush University Medical Center, Chicago, Illinois Open Operative Approaches to the Adrenal Gland Charles A. G. Proye, MD Professor and Chairman of Surgery, Medical School of Lille; Head of the Department of General and Endocrine Surgery, Lille University Hospital-Huriez, Lille, France Adenocortical Carcinoma: Nonfunctioning and Functioning Roderick M. Quiros, MD General Surgery Resident, Rush University Medical Center, Chicago, Illinois Open Operative Approaches to the Adrenal Gland Jonas Rastad, MD, PhD Associate Professor, Department of Surgery, Uppsala University Hospital, Uppsala, Sweden Parathyroid Hormone: Regulation of Secretion and Laboratory Determination

Contributors - - xi

Peter Ridefelt, MD, PhD Associate Professor, Department of Surgery, Uppsala University Hospital, Uppsala, Sweden Parathyroid Hormone: Regulation of Secretion and Laboratory Determination

Andrew Saxe, MD Associate Program Director, Michigan State University, East Lansing; Director, Surgical Education, McLaren Regional Medical Center, Flint, Michigan Cryopreservation of Parathyroid Tissue

Jose M. Rodriguez, MD Professor of Surgery, Department of Surgery, School of Medicine, University of Murcia; Endocrine Surgery Unit, Department of Surgery, Virgen de la Arrixaca, II University Hospital, Murcia, Spain Localization Studies in Persistent or Recurrent Hyperparathyroidism

Frederic Sebag, MD Medical School, Mediterranean University; Attending Surgeon in Endocrine Surgery, Department of Endocrine Surgery, University Hospitalla Timone, Marseilles, France Endoscopic Parathyroidectomy

Hans-Dietrich Roeher, MD Professor of Surgery, Heinrich Heine University, Dusseldorf, Germany Oncogenes in Thyroid Tumors; Neuroendocrine Tumors

Wen T. Shen, MD Fellow, Endocrine Surgical Oncology Program, Department of Surgery, University of California, San Francisco, San Francisco, California Parathyroid Hormone: Regulation of Secretion and Laboratory Determination

Irving B. Rosen, MD, FRCS(C) Professor, Department of Surgery, University of Toronto, Toronto; Attending Surgeon, Mt. Sinai Hospital, Toronto, Ontario, Canada Anaplastic Carcinoma of the Thyroid Gland

Nina Shervin, MD Resident in Surgery, Harvard Combined Orthopaedic Residency Program, Massachusetts General Hospital, Boston, Massachusetts Medullary Thyroid Carcinoma

Matthias Rothmund, MD Professor of Surgery, Philipps University; Professor of Surgery and Chairman of the Department of Visceral, Thoracic, and Vascular Surgery, Klinikum der Philipps-Universitat, Marburg, Germany Adrenal Imaging Procedures; Localization of Endocrine Pancreatic Tumors

Mauricio Sierra, MD Fellow in Endocrine Surgery, Jean Bernard Hospital, Poitiers, France Familial Hyperparathyroidism in Multiple Endocrine Neoplasia Syndromes

J. A. Roukema, MD, PhD Surgeon, St. Elisabeth Hospital, Tilburg, The Netherlands Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer

Dietmar Simon, MD Professor of Surgery, Heinrich Heine University, Dusseldorf, Germany Neuroendocrine Tumors; Oncogenes in Thyroid Tumors

Mary Ruppe, MD Senior Fellow, Division of Endocrinology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Hypoparathyroidism and Pseudohypoparathyroidism

Antonio Sitges-Serra, MD Professor of Surgery, Universedad Aut6noma de Barcelona; Head, Department of Surgery, Hospital del Mar, Barcelona, Spain Surgical Management of Recurrent and Intrathoracic Goiters; Metabolic Complications of Secondary Hyperparathyroidism; Surgical Approach to Secondary Hyperparathyroidism

David E. Sahar, MD Resident, University of California San Francisco-East Bay Program, San Francisco, California Childhood Thyroid Carcinoma Juan J. Sancho, MD Associate Professor, Universidad Aut6noma de Barcelona; Staff Surgeon; Hospital del Mar, Barcelona, Spain Surgical Management ofRecurrent and Intrathoracic Goiters; Metabolic Complications of Secondary Hyperparathyroidism; Surgical Approach to Secondary Hyperparathyroidism Kerstin Sandelin, MD, PhD Associate Professor of Surgery, Department of Surgical Sciences, Korolinska Institutet, Stockholm; Senior Staff Surgeon, Karolinska University Hospital, Solna, Stockholm, Sweden Parathyroid Carcinoma

Allan E. Siperstein, MD Professor of Surgery and Section Head, Endocrine Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio Signal Transduction in Thyroid Neoplasms Staffan Smeds, MD, PhD Professor of Surgery, University Hospital, Linkoping, Sweden Growth Factor, Thyroid Hyperplasia, and Neoplasia Ilfet Songun, MD, PhD Surgeon, University Hospital, Maastricht, The Netherlands Occurrence and Prevention of Complications in Thyroid Surgery

xii - - Contributors

Maria Sorhede-Winzell, PhD Department of Medicine, Lund University, Lund, Sweden Pancreatic Endocrine Physiology Gordon J. Strewler, MD Professor of Medicine, Harvard Medical School; Vice Chairman, Department of Medicine, Brigham and Women's Hospital; Chief of Medical Service, Brockton/ West Roxburg, Veterans Administration Medical Center, Boston, Massachusetts Hypercalcemia of Malignancy and Parathyroid Hormone-Related Protein Masahiro Sugawara, MD Professor of Medicine, University of California, Los Angeles, School of Medicine; Staff Physician, Greater Los Angeles VA Medical Center, Los Angeles, California Hypothyroidism Hiroshi Takami, MD Professor of Surgery, Teiko University School of Medicine, Tokyo,Japan Hypercalcemic Crisis Serdar T. Tezelman, MD Professor of Surgery, Department of Surgery, Istanbul Faculty of Medicine, Istanbul University; Attending Surgeon, International Hospital, Istanbul, Turkey Signal Transduction in Thyroid Neoplasms Geoffrey B. Thompson, MD Professor of Surgery, Mayo Graduate School; Consultant, Department of Surgery, Division of Gastroenterologic and General Surgery, Mayo Clinic, Saint Mary's and Rochester Methodist Hospitals, Rochester, Minnesota Multiple Endocrine Neoplasia Type 1 Norman W. Thompson, MD Emeritus Professor of Surgery, University of Michigan, Ann Arbor, Michigan Pancreatic Surgery for Endocrine Tumors Sten A. G. Tibblin, MD, PhDt Formerly Associate Professor and Consultant Surgeon, Department of Surgery, University Hospital, Lund, Sweden Surgical Approach to Primary Hyperthyroidism (Unilateral Approach) Lars-Erik Tisell, MD, PhD Retired Chief of Endocrine Surgery, Department of Surgery, Sahlgrenska University Hospital, Sahlgrenska, Sweden Natural History of Treated Primary Hyperparathyroidism Robert Udelsman, MD, MBA, FACS Lampman Professor of Surgery and Oncology, and Chairman, Department of Surgery, Yale University School of Medicine; Chief of Surgery, Yale New Haven Hospital, New Haven, Connecticut Hiirthle Cell Adenoma and Carcinoma

tDeceased

John A. van Heerden, MB, ChB, MS(Surg) (Minn), FRCS (C), FACS, Hon FCM(SA), Hon FRCS(Edin), FRCPS (Glasg) Fred C. Anderson Professor of Surgery, Mayo Graduate School; Consultant in General Surgery, Mayo Clinic, Rochester, Minnesota Parathyroid Reoperations Cornelis J. H. van de Velde, MD, PhD Professor of Surgery, Leiden University Medical Center, Leiden, Germany Occurrence and Prevention of Complications in Thyroid Surgery Nobuyuki Wada, MD, PhD Assistant Professor, Department of Surgery, Yokohama City University School of Medicine, Yokohama City, Japan Comparative Genomic Hybridization in Thyroid Neoplasms Jeffrey D. Wayne, MD Assistant Professor of Surgery, Northwestern University, Feinberg School of Medicine; Attending Physician, Northwestern Memorial Hospital, Chicago, Illinois Insulinomas Malcolm H. Wheeler, MD, FRCS Professor of Surgery, University Hospital of Wales, Cardiff, Wales, United Kingdom Approach to Thyroid Nodules Scott M. Wilhelm, MD Assistant Professor of Surgery, University Hospital of Cleveland, Case Western Reserve University; Staff Surgeon, University Hospitals of Cleveland, Cleveland, Ohio Open Operative Approaches to the Adrenal Gland Stuart D. Wilson, MD Professor and Chief, Division of PancreatobiliarylEndocrine Surgery, Medical College of Wisconsin; Senior Attending Surgeon, Froedtert Memorial Lutheran Hospital, Milwaukee, Wisconsin Gastrinoma Michael W. Yeh, MD Fellow, University of California, San Francisco, San Francisco, California; Endocrine Surgical Unit, Royal North Shore Hospital, St. Leonards, New South Wales, Australia Mechanisms and Regulation of Invasion in Thyroid Cancer William F. Young, Jr, MD, MSc Professor of Medicine, Mayo Clinic College of Medicine; Consultant, Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota Multiple Endocrine Neoplasia Type 1 Rasa Zarnegar, MS Surgical Resident, Case Western Reserve University Cleveland, Ohio Sodium-Iodide Symporter and Radioactive Iodine Therapy

Contributors - - xiii

Andrew P. Zbar, MB, BS University of the West Indies, Queen Elizabeth Hospital, St. Michael, Barbados Use and Abuse of Thyroid-Stimulating Hormone Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms Martha A. Zeiger, MD Associate Professor of Surgery, Division of Endocrine and Oncologic Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland Hypoparathyroidism and Pseudohypoparathyroidism; Transplantation of Endocrine Cells and Tissues

Andreas Zielke, MD Department of Surgery, Endocrine Research Group, Philipps University, Marburg, Germany Adrenal Imaging Procedures

Since the first edition of the Textbook of Endocrine Surgery there have been considerable changes in the clinical management of patients with endocrine surgical problems, as well as advances in basic science regarding endocrine neoplasms. Many colleagues have asked Drs. Duh and Clark whether another edition will be published because of numerous recent changes in endocrine surgery. Major changes have occurred regarding the indications for parathyroidectomy in patients with primary hyperparathyroidism based on the natural history of the disease. The surgical approach for patients with primary hyperparathyroidism has also changed as more surgeonsare now recommending a selective approach rather than a bilateral approach. Much of this change is due to better preoperative localization studies and the use of intraoperative parathyroid hormone assays to determine when all abnormal parathyroid tissue has been removed. Some experts are also recommending a minimally invasive approach via small == 2.S-cm incisions or by using an endoscopic approach with I.S-cm incisions for patients with primary hyperparathyroidism. Substantial changes have also occurred regarding indications for adrenalectomy for patients with incidentally discovered adrenal neoplasms. More accurate localization studies and improved testing have made the diagnosis easier and tumor identification more precise. Most endocrine surgeons are now recommending laparoscopic removal of non-malignant-appearing adrenal tumors under 6 em in maximal diameter. Such treatment has dramatically reduced the duration of hospitalization and has also increased the referral of such patients to endocrine surgical units that are proficient in laparoscopic operations. There have been numerous other advances in using genetic testing to diagnose patients with multiple endocrine neoplasia types I and II. Children who are ret oncogene positive usually receive prophylactic thyroidectomy before age 6 and before they develop medullary thyroid cancer. More information is also available regarding genotype-phenotype relationships in predicting tumor behavior. Familial nonmedullary thyroid cancer with or without other syndromes has recently become a recognized clinical syndrome, and the thyroid cancers in these patients are somewhat more aggressive than are sporadic thyroid cancers. Papillary thyroid cancer in children and after radiation are frequently

associated with ret/PTC rearrangements and other papillary thyroid cancers with BRAF mutations, whereas follicular cancers are more often associated with PAX-S/PPARy and ras mutations. Since the Chemobyl nuclear accident in 1986, considerably more information has become available relating to the association of radiation exposure and thyroid cancer. Many other advances or consensus of opinion have also become available regarding the diagnosis, localization, and treatment of endocrine neoplasms, including endocrine tumors of the pancreas. New or revised areas in the second edition of Textbook of Endocrine Surgery include: (l) recent advances in the etiology and molecular biology of endocrine neoplasms; (2) methods used to diagnose patients with sporadic and familial thyroid cancers and the risks and benefits of prophylactic operations; (3) the association of low-dose therapeutic radiation, RET/PTC rearrangements, and surgical management of thyroid tumors; (4) current information regarding the adverse effects of primary hyperparathyroidism and related symptoms, associated conditions, and survival, as well as the indications for parathyroidectomy (this will include the usefulness of the follow-up information regarding the NIH consensus criteria and newer studies regarding quality of life improvement after parathyroidectomy); (5) the changing selective surgical approach for patients with primary hyperparathyroidism based on preoperative localization tests and intraoperative PTH testing; (6) the indications for operations for patients with incidentally discovered adrenal neoplasms; and (7) the use of laparoscopic adrenalectomy to remove most adrenal tumors under 6 em in maximal diameter. In summary, during the past several years there have been improved methods for diagnosing and treating patients with endocrine neoplasms, including screening for familial disease, more precise diagnostic tests, better preoperative localization studies, and new surgical instrumentation, as well as a better understanding of the natural history of many of these disorders. Orlo H. Clark, MD

Quan- Yang Duh, MD Electron Kebebew, MD

xv

Table of Contents 1

Thyroid physiology

3

2

Surgical anatomy and embryology of the thyroid and parathyroid glands and recurrent and external laryngeal nerves

9

3

Medical and surgical treatment of endemic goiter

16

4

Sporadic nontoxic goiter

24

5

Thyroiditis

34

6

Hypothyroidism

44

7

Graves' and Plummer's diseases : medical and surgical management

54

8

Use and abuse of thyroid-stimulating hormone suppressive therapy in patients with nodular goiter and benign or malignant thyroid 68 neoplasms

9

Approach to thyroid nodules

85

10

Childhood thyroid carcinoma

93

11

Papillary thyroid carcinoma : rationale for hemithyroidectomy

102

12

Papillary thyroid carcinoma : rationale for total thyroidectomy

110

13

Follicular neoplasms of the thyroid

115

14

Hurthle cell adenoma and carcinoma

123

15

Medullary thyroid carcinoma

129

16

Localization tests in patients with thyroid cancer

142

17

Papillary and follicular carcinoma : surgical and radioiodine treatment 152 of distant metastases

18

Anaplastic carcinoma of the thyroid gland

159

19

Unusual thyroid cancers, lymphoma, and metastases to the thyroid

168

20

Recurrent thyroid cancer

181

21

Thyroidectomy

188

22

Management of regional lymph nodes in papillary, follicular, and medullary thyroid cancer

195

23

Occurrence and prevention of complications in thyroid surgery

207

24

Thyroid emergencies : thyroid storm and myxedema coma

216

25

Pathology of tumors of the thyroid gland

223

26

Factors that predispose to thyroid neoplasia

240

27

Predictors of thyroid tumor aggressiveness

248

28

Growth factor, thyroid hyperplasia, and neoplasia

256

29

Signal transduction in thyroid neoplasms

265

30

Oncogenes in thyroid tumors

280

31

Thyroid oncogenesis

288

32

Mechanisms and regulation of invasion in thyroid cancer

295

33

Surgical management of recurrent and intrathoracic goiters

304

34

Surgical management of advanced thyroid cancer invading the aerodigestive tract

318

35

Potentially new therapies in thyroid cancer

334

36

Comparative genomic hybridization in thyroid neoplasms

344

37

Sodium-iodide symporter and radioactive iodine therapy

355

38

Parathyroid embryology, anatomy, and pathology

365

39

Parathyroid hormone : regulation of secretion and laboratory determination

372

40

Diagnosis of primary hyperparathyroidism and indications for parathyroidectomy

384

41

Natural history of untreated primary hyperparathyroidism

393

42

Metabolic complications of primary hyperparathyroidism

402

43

Natural history of treated primary hyperparathyroidism

413

44

Asymptomatic primary hyperparathyroidism

419

45

Normocalcemic hyperparathyroidism

424

46

Localization studies in persistent or recurrent hyperparathyroidism

430

47

Technique of parathyroidectomy

439

48

Surgical approach to primary hyperparathyroidism (bilateral approach)

449

49

Surgical approach to primary hyperparathyroidism (unilateral approach)

456

50

Minimally invasive parathyroid surgery

462

51

Endoscopic parathyroidectomy

467

52

Intraoperative parathyroid hormone assay as a surgical adjunct in patients with sporadic primary hyperparathyroidism

472

53

Parathyroid hyperplasia : parathyroidectomy

481

54

Familial hyperparathyroidism in multiple endocrine neoplasia syndromes

489

55

Familial hyperparathyroidism

493

56

Metabolic complications of secondary hyperparathyroidism

502

57

Surgical approach to secondary hyperparathyroidism

510

58

Parathyroid reoperations

518

59

Hypoparathyroidism and pseudohypoparathyroidism

527

60

Cryopreservation of parathyroid tissue

530

61

Hypercalcemia of malignancy and parathyroid hormone-related protein

536

62

Hypercalcemic crisis

543

63

Parathyroid carcinoma

549

64

Surgical embryology and anatomy of the adrenal glands

557

65

Adrenal physiology

571

66

Adrenal imaging procedures

576

67

Clinically inapparent adrenal mass (incidentaloma or adrenaloma)

586

68

Hyperaldosteronism

595

69

Adrenocortical carcinoma : nonfunctioning and functioning

604

70

Cushing's syndrome

612

71

Pheochromocytoma

621

72

Addison's disease and acute adrenal hemorrhage

634

73

Open operative approaches to the adrenal gland

641

74

Laparoscopic adrenalectomy

647

75

Anatomy and embryology of the pancreas

665

76

Multiple endocrine neoplasia type 1

673

77

Transplantation of endocrine cells and tissues

691

78

Pancreatic endocrine physiology

701

79

Insulinomas

715

80

Localization of endocrine pancreatic tumors

730

81

Pancreatic surgery for endocrine tumors

737

82

Gastrinoma

745

83

Multiple endocrine neoplasia type 2B

757

84

Somatostatinoma and rare pancreatic endocrine tumors

764

85

Non-multiple endocrine neoplasia endocrine syndromes

773

86

Neuroendocrine tumors

780

87

Endocrine emergencies : hypoglycemic and hyperglycemic crises

789

88

Chemotherapy for unresectable endocrine neoplasms

800

Thyroid Physiology Roderick Clifton-Bligh, MB, BS, PhD • Leigh Delbridge, MD, FRCS

The thyroid gland contains two separate physiologic endocrine systems: one responsible for the production of the thyroid hormones thyroxine (T4 ) and triiodothyronine (T3) , and the other responsible for the production of the hormone calcitonin. The functional unit for thyroid hormone production is the thyroid follicle. This is composed of a single layer of cuboidal follicular cells surrounding a central space filled with colloid. The average size of a follicle varies from 100 to 300 urn, each of which is surrounded by a network of capillaries. The primary function of the thyroid follicle is to make and store thyroid hormones. Calcitonin is produced by C cells within the thyroid. These cells, of neural crest origin, lie in a parafollicular position in direct contact with the follicular basement membrane.

Thyroid Embryogenesis Thyroid primordial cells develop from pharyngeal ectoderm, forming a visible medial anlage by human gestational days 16 to 17.1 The thyroid diverticulum then migrates caudally to reach its final position in the thyroid primordial body anterior to the cricoid cartilage (Fig. 1-1). Subsequently, these cells begin to express markers of mature thyrocyte differentiation, including proteins that are intrinsic to thyroid secretory function (thyroglobulin, thyroperoxidase, and the sodiumiodide symporter [NIS]), and the thyroid-stimulating hormone (TSH) receptor that controls both thyroid growth and secretory function. The foramen caecum, at the junction between the anterior two thirds and posterior third of the tongue base, remains as an embryologic reminder of thyroid origin. Thyrocytes form thyroid follicles, while intervening cells derived from the ultimobranchial body within the fourth pharyngeal pouch develop into calcitonin-secreting C cells (see Fig. 1-1). The parathyroid glands develop from the third and fourth pharyngeal pouches and migrate to the posterior surface of the thyroid gland. The thyroid gland begins to trap iodide between gestational weeks 10 and 12.1 Several transcription factors involved in the development of the thyroid gland have been identified. Three such factors-thyroid transcription factors (TTFs)-1 2•3 and _24 and the paired homeodomain factor Pax-85.6-were identified and isolated by their binding to specific regulatory elements

within the promoters of thyroid-specific genes (e.g., thyroperoxidase and thyroglobulin). Mutation of any of these transcription factors leads to thyroid dysgenesis, together with other phenotypic features specific to each transcription factor (TTF-l, pulmonary disease; Pax-8, renal hemiagenesis; TTF-2, cleft palate).7-9 The transcription factor GATA3 has been shown to be important in parathyroid gland development since mutations in this gene are associated with HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal aplasia).'? Failure of parathyroid gland development is also a feature of DiGeorge syndrome, in which parathyroid and thymic aplasia are variably accompanied by cardiac defects and facial malformations owing to microdeletion or rearrangement of the short arm of chromosome 22. 11 Several transcription factors involved in the development of the parathyroid glands in mouse models have been identified," including Gcm2 and Hoxa3.

Thyroid Hormone Physiology Iodide Metabolism and Uptake Iodine usually enters the body as the result of dietary and water uptake, but it can also be found in various drugs, such as cough medicines, and in diagnostic agents. Dietary iodine intake varies widely throughout various parts of the world. The relationship between iodine intake and thyroid disease was first demonstrated by Chatin in 1852, but the practice of iodine supplementation of food and water, which he recommended, fell into disrepute and was not revived until the large-scale experiments of Marine and Kimball in Ohio in 1917.14 Even in areas where endemic goiter is not a problem, iodine intake and excretion vary considerably with urinary excretion, ranging from as little as 40 ug/day up to 400 ug/day." Iodine deficiency is associated with nodular goiter, hypothyroidism, and cretinism" as well as the development of follicular thyroid carcinoma.!? In areas of the world where iodine deficiency is still a problem, a variety of measures are being introduced to increase iodine intake, such as iodination of salt, bread, and water to treat entire population groups and injections of iodized oil for target groups such as pregnant women.P Iodine excess, on the other hand, is associated

3

4 - - Thyroid Gland

FIGURE 1-1. Thyroid embryogenesis. Left, Coronal section through the pharyngeal arch region in a late-somite embryo. The thyroid diverticulum forms from a thickening in the midline of the anterior pharyngeal floor. The two lateral anlagen (ultimobranchialbodies) are derived from the fourth or fifth pharyngeal pouch; the thymus and inferior parathyroids are derived from the third pouch, whereas the superior parathyroid glands form from the fourth pharyngeal pouch (not shown). Right, Ventral view of the pharyngeal organ derivatives following migration toward their ultimate positions.The thyroid diverticulumhas caudally migrated anterior to the cricoid cartilage, where it is infiltrated by cells from the ultimobranchial bodies that will form parafollicular C cells. The superior and inferior parathyroid glands are positioned on the posterolateral surface of the thyroid gland. The two thymic primordia will fuse to become a single gland anterior to the trachea. (Adapted from Manley NR, Capecchi MR. The role of Hoxa-3 in mouse thymus and thyroid development. Development 1995;12l:l989.)

with an increased incidence of autoimmune thyroid disease such as Graves' disease and Hashimoto's thyroiditis'S" as well as papillary thyroid carcinoma. I? Iodine, in the form of inorganic iodide, is rapidly and efficiently absorbed from the gastrointestinal tract and enters the extracellular iodide pool, where it is joined by iodide derived from the breakdown of previously formed thyroid hormone. Less than 10% of total body iodide is contained in the extracellular pool; the remaining 90% is stored in the thyroid gland as either preformed thyroid hormone or iodinated amino acids.'? Iodide is taken up from the extracellular space into the follicular cells by an active transport process. The major source of loss of iodide from the extracellular space, in addition to uptake by the thyroid gland, is renal excretion. Small quantities of iodide are also lost through the skin, through the saliva, or in expired air. The active transport of iodide into the cells results in a significant intrathyroidal iodide gradient. The NIS is part of a family of membrane-associated transport glycoproteins that probably contain 12 membranespanning domains. 2o•21 Iodide is actively transported using energy from the coupled inward sodium transport. Mutations in the NIS gene are associated with goitrous congenital hypothyroidism.P Iodide transport into the follicular cells is influenced by TSH levels as well as by the glandular content of iodide.

Synthesis of Thyroid Hormone After uptake into the follicular cells through the basal membrane (Fig. 1-2), inorganic iodide is rapidly oxidized. Thyroid hormones are then synthesized by the combination of iodine with tyrosyl residues within the protein thyroglobulin. This reaction is catalyzed by thyroperoxidase in two principal steps. In the first reaction, iodide reacts with

FIGURE 1-2. Uptake of iodide into the follicular cell by active transport, with subsequent iodide oxidation, tyrosine iodination, and iodotyrosine coupling occurring at the apical membrane, catalyzed by thyroid peroxidase. DIT = diiodotyrosine; MIT = monoiodotyrosine; T3 = triiodothyronine; T4 = thyroxine.

Thyroid Physiology - -

tyrosyl residues in thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). In the second reaction, MIT and DIT condense to form 3,5,3'-triiodothyronine (T 3) or the inactive 3,3',5'-triiodothyronine (rT3) , whereas two molecules of DIT condense to form T 4 • T 3 and rT 3 are also formed by intrathyroidal deiodination of thyroxine, catalyzed by deiodinase enzymes.P In conditions of iodine-sufficient intake, the predominant iodothyronine synthesized by the thyroid gland is T 4 •24 Once formed, the thyroid hormones, covalently bound to thyroglobulin, are stored in colloid within the center of the follicle. The thyroid gland contains a very large store of thyroid hormone, which lasts for several weeks in the absence of the formation of new hormone. 19 Thyroid peroxidase (TPO) is a membrane-bound glycoprotein that is localized to the apical membrane of the follicular cell; the peroxidase reactions occur at the cell-colloid interface.f TPO has now been cloned and has been shown to have a hydrophobic signal peptide at its aminoterminus and a hydrophobic region with the characteristics of a transmembrane domain near the carboxylterminus.P This structure is consistent with TPO being a membrane-associated protein. The synthesis of thyroglobulin occurs exclusively in the thyroid gland, where homodimers are formed in the endoplasmic reticulum before being transported into the apical lumen of thyroid follicles.P Defects in thyroglobulin synthesis usually cause moderate to severe hypothyroidism in association with low circulating thyroglobulin levels." A partial organification defect and goiter (with or without overt hypothyroidism) is associated with sensorineural deafness in Pendred's syndrome. Mutations in a putative sulfate transporter gene (PDS) have recently been associated with this disorder," Although the precise mechanisms by which the pendrin protein causes the phenotype is unclear, it is proposed that defective sulfation of thyroglobulin impairs its subsequent iodination." Release of thyroid hormone into the peripheral blood occurs as the result of lysosomal hydrolysis within the follicular cells (Fig. 1-3). Pseudopodia form at the apical membrane

5

of the thyroid cell, and multiple vesicles containing thyroglobulin are incorporated into the follicular cell by endocytosis. Lysosomal hydrolysis of the thyroglobulin, with reduction of disulfide bonds, leads to release of both T3 and T 4 through the basement membrane into the circulation. The ratio of the levels of these two hormones released into the peripheral blood approximates their levels in stored thyroglobulin (T3:T4 is "" 1:13). Very little thyroglobulin reaches the peripheral circulation; however, when sensitive immunoassay procedures are used, small quantities can be detected in normal individuals.P Iodotyrosines released from thyroglobulin undergo deiodination and are recycled, with the iodide so released available for new thyroid hormone synthesis.

Peripheral Transport and Metabolism of Thyroid Hormones More than 99% of circulating thyroid hormones are bound to serum proteins, including thyroxine-binding globulin (TBG), transthyretin, and albumin." TBG is a glycoprotein that contains only one binding site per molecule. TBG is responsible for the transport of more than three fourths of thyroid hormone in the blood, and its levels are significantly increased by elevated levels of estrogens, as occurs in pregnancy. Dissociation of the free hormone from its binding proteins is rapid and efficient. Thyroid hormones are lipophilic and are capable of passive diffusion into cells, although specific transporters may also regulate intracellular thyroid hormone content." T 3 synthesized directly by the thyroid forms a relatively small proportion of the effective T 3 concentration in tissues, which is mainly derived from peripheral deiodination of T4 . This reaction is catalyzed by two deiodinases with characteristic tissue distributions. Type I deiodinase (5'DI) is predominant in liver, kidney, and thyroid, whereas type II deiodinase (5'DII) is present in the central nervous system, pituitary, placenta, brown adipose tissue, cardiac and skeletal muscle, and thyroid.'? A third deiodinase (5'DIII) catalyzes deiodination of T 4 to rT 3 or T 3 to diiodothyronine (T 2) and is found in the placenta and central nervous system." These differences in distribution and regulation may explain some tissue-specific variation in thyroid hormone action. Peripheral conversion of T 4 to T 3 may be impaired in a number of situations, including systemic illness, malnutrition, and trauma or by various drugs. The thyroid hormones generally have slow turnover times in the peripheral circulation. In adults, the half-life of T 4 is about 7 days, presumably because of the high degree of binding of T4 to its carrier proteins, whereas the half-life of T, is approximately 8 to 12 hours.

Peripheral Action of Thyroid Hormones

FIGURE 1-3. Lysosomal hydrolysis of pinocytotic vesicles containing stored colloid, with subsequent release of thyroid hormone into the peripheral circulation. T 3 = triiodothyronine; T4 = thyroxine.

The major effects of thyroid hormone action occur through the intranuclear action of Tj, with T4 being largely a prohormone." It remains controversial as to whether T 4 might also regulate non-nuclear biologic responses in some contexts, for instance, the activation of certain mitochondrial or cellmembrane enzymes." In the 1960s, Tata and associates observed that T3 treatment resulted in the rapid synthesis of nuclear RNA, which preceded increases in protein synthesis

6 - - Thyroid Gland and mitochondrial oxygen consumption." Subsequently, subcellular fractionation demonstrated specific nuclear binding sites for T 3 and identified the anterior pituitary, liver, brain, and heart as having high binding capacity for T 3.3! Thus, the current concept of thyroid hormone action is that its nuclear receptor binds to specific regulatory regions in target genes and regulates gene transcription in response to T 3.32-34 Thyroid hormone receptors (TRs) are members of the steroid hormone receptor superfamily. There are two TR genes, a and ~, located on chromosomes 17 and 3, respectively, and differential splicing of both these genes yields a total of four isoforms, denoted as TRal, TRa2, TRf3I, and TRf32 (Fig. 1_4).32 The expression of the various TR isoforms is both developmentally regulated and tissue specific, such that TRa is widely expressed at all stages of development, preceding the appearance of endogenous thyroid hormone, whereas TR~ begins to be expressed as thyroid hormone-dependent processes occur," An aminoterminal is specifically splice variant of the TR~ receptor, TR~2 expressed in the hypothalamus and pituitary and may therefore be the critical subtype involved in negative-feedback effects of T 3.32 In the adult, TRal may be the predominant isoform in myocardium, skeletal muscle, and fat, whereas TR~l and TR~2 predominate in the pituitary and liver." TRa2 does not bind ligand and its function is poorly understood, although it may function as an inhibitor of thyroid hormone action in some contexts.F TRs bind to specific regulatory DNA sequences usually within gene promoters.P A consensus regulatory binding site, termed the thyroid hormone response element (TRE), consists of a pair of hexanucleotide half-sites. Natural TREs present in gene promoters are commonly degenerate variations of these consensus sequences. Biochemical evidence suggests that on many TREs, the receptor complex is most active when bound to DNA as a heterodimer with the retinoid X receptor."

FIGURE 1-4. Multiple human thyroid hormone receptor (TR) isoforms, TRa and TR~ receptors are transcribed from different genes on chromosomes 17 and 3, respectively. Different isofonns are then generated from differential splicing of the primary messenger RNA transcripts in each case, such that TRal and TRa2 isofonns and TR~2 isofonns differ in their carboxytennini, whereas TR~I differ in their aminotermini, as shown. (Adapted from Lazar MA. Thyroid hormone receptors: Multiple forms, multiple possibilities. Endocr Rev 1993;14:184.)

The clinical manifestations of thyroid hormone action are the net result of the actions of the products of the various genes whose expression is regulated by T 3. For example, thyroid hormones affect cardiac contractility by affecting the transcription of, and subsequent relative proportions of, the various myosin heavy chains in cardiac muscle.P'" In the pituitary, T 3 regulates the transcription of the genes for both ex and ~ subunits of TSH, thus affecting the level of TSH secretion.'?

Thyroid Hormone Regulation Thyroid hormone production and release are under the control of the hypothalamic-pituitary-thyroid axis (Fig. 1-5), acting in a negative-feedback cycle. TSH is the major regulator of thyroid gland activity. Increased levels of TSH lead to hypertrophy and increased vascularity of the gland, whereas decreased levels of TSH lead to gland atrophy. A glycoprotein secreted by the anterior pituitary, TSH is composed of an a subunit and a ~ subunit. The ex subunit is common to a family of glycoprotein hormones, including

FIGURE 1-5. Negative-feedback regulation of thyroid hormone production. TRH = thyrotropin-releasing hormone; TSH = thyroidstimulating hormone; T 3 = triiodothyronine; T 4 = thyroxine.

Thyroid Physiology - - 7

follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin (hCG). TSH binds to a specific receptor on the surface of the thyroid cell. The TSH receptor is a G protein-coupled receptor. After activation by TSH, the receptor interacts with a guanine nucleotide-binding protein (G protein), which induces the production of cyclic adenosine monophosphate (cAMP).4o This cAMP then stimulates the synthesis and secretion of thyroid hormones. Receptors that are linked to G proteins are characterized by the presence of seven transmembranespanning domains linked by cytoplasmic and extracellular loops. The first cytoplasmic loop, as well as the carboxylterrninal residues in the second and third cytoplasmic loops, are important in mediating a TSH-dependent increase in intracellular cAMP production." The TSH receptor has been cloned.f and specific mutations have been identified in association with hyperfunctioning follicular thyroid neoplasms.tv" TSH is secreted from the anterior pituitary in response to thyrotropin-releasing hormone (TRH) and to reduced pituitary levels of T; TRH acts to directly stimulate the thyrotropic cells to increase both the synthesis and the release of TSH. TRH is a tripeptide synthesized in the paraventricular nucleus of the hypothalamus, and, after synthesis, it passes to the median eminence and down the pituitary stalk in the hypophysial portal system. It is thought that the principal function of TRH is to set the ambient level of regulatory control whereby thyroid hormone levels are mediated by negative feedback. TRH secretion itself is also under negative-feedback control in response to peripheral thyroid hormone levels. T 3, on the other hand, derived principally from the local deiodination of peripheral T 4 in the pituitary, directly inhibits the release and synthesis of TSH. It is also thought that peripheral thyroid hormone levels may regulate TRH receptor numbers on the surface of the pituitary thyrotropic cells, thus decreasing their responsiveness to TRH. A number of other factors affect thyroid hormone synthesis in addition to the hypothalamic-pituitary feedback cycle. Other hormones can have a direct effect on the thyroid gland. Catecholamines are thought to have a direct stimulatory effect on thyroid hormone release. hCG also stimulates thyroid hormone production, with free levels of thyroid hormone increasing during pregnancy and in the presence of hydatidiform moles." Glucocorticoids, on the other hand, act to reduce thyroid hormone production by suppressing pituitary TSH secretion. The thyroid also obtains direct adrenergic innervation, and there is some evidence that sympathetic stimulation can increase thyroid hormone synthesis. Other external factors that can affect thyroid regulation include nonthyroidal illness, starvation, and temperature changes. A variety of disorders, especially severe illness, lead to reduced levels of peripheral thyroid hormone in the absence of a compensatory rise in TSH (the so-called sick euthyroid syndrome). Starvation also leads to markedly reduced levels of both T 4 and T 3 , as does exposure to high temperatures.

Autoregulatory Mechanisms The thyroid can also control its own stores of thyroid hormone by intrinsic autoregulatory mechanisms. These mechanisms are principally seen in response to alterations in

iodide availability. For example, an excess of dietary iodide leads to autoregulated inhibition of iodide uptake into the follicular cells, whereas iodide deficiency results in increased iodide transport and uptake. Large doses of iodide have more complex effects, including an initial increase followed by a decrease in organification, the so-called Wolff-Chaikoff effect." Excess iodide also inhibits, at least initially, the release of stored thyroid hormone from the thyroid follicle.

Calcitonin Physiology Calcitonin Secretion Calcitonin is secreted by the parafollicular C cells located in the lateral lobes of the thyroid. This hormone is a 32-amino acid polypeptide with an NH-terminal 7-member disulfide ring."? Calcitonin acts to lower serum calcium concentration, principally by inhibition of bone resorption. Secretion of the hormone is increased in the presence of elevated levels of serum calcium. In the clinical context, calcitonin secretion can be stimulated by a number of techniques, including calcium infusion, pentagastrin infusion, and alcohol.t''

Peripheral Action of Calcitonin Calcitonin acts via specific cell surface receptors located predominantly on the surface of osteoclasts." These receptors have also been found in renal tubular epithelium, neural tissue, and lymphocytes.t" The predominant action of calcitonin is to inhibit osteoclast action, although in the physiologic situation calcitonin does not actually cause a lowering of s~rum calcium levels. Indeed, in patients with medullary carcinoma of the thyroid, in which calcitonin levels may be many thousands of times the normal level, hypocalcemia is not seen. Similarly, patients who have had a total thyroidectomy, with removal of all known C cells, maintain normal calcium metabolism.

Summary In summary, the thyroid gland contains two separate functioning units. The follicular cells produce T 4 and T 3, which regulate growth and metabolism, whereas the parafollicular cells produce the antihypercalcemia hormone calcitonin. Iodine is required for the synthesis of thyroid hormone, and iodine deficiency can result in endemic goiter and cretinism. Circulating levels of thyroid hormone depend on a negative feedback between T 3 and T 4 and TSH secretion as well as a positive action of TSH. Thus, medications and other factors can influence ambient thyroid hormone levels and, consequently, the metabolic state.

REFERENCES 1. Pintar JE. Normal development of the hypothalamic-pituitary-thyroid

axis. In: Braverman LE, Utiger RD (eds), Werner and Ingbar's The Thyroid, 7th ed. Philadelphia, Lippincott-Raven, 1996, p 6. 2. Guazzi S, Price M, De Felice M, et al. Thyroid nuclear factor I (ITF-I) contains a homeodomain and displays a novel DNA-binding specificity. EMBO J 1990;9:3631.

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Thyroid Gland

3. Mizuno K, Gonzalez FJ, Kimura S. Thyroid-specific enhancer-binding protein (TIEBP): cDNA cloning, functional characterization, and structural identity with thyroid transcription factor TTF-1. Mol Cell Bioi 1991;11:4927. 4. Zannini M, Avantaggiato V, Biffali E, et al. TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation. EMBO J 1997;16:3185. 5. Plachov D, Chowdhury K, Walther C, et al. Pax-8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development 1990;110:643. 6. Zannini M, Francis-Lang H, Plachov D, Di Lauro R. Pax-8, a paired domain-containing protein, binds to a sequence overlapping the recognition site of a homeodomain and activates transcription from two thyroid-specific promoters. Mol Cell Bioi 1992;12:4230. 7. Devriendt K, Vanhole C, Matthijs G, de Zegher F. Deletion of thyroid transcription factor 1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. N Engl J Med 1998;338: 1317. 8. Macchia PE, Lapi P, Krude H, et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet 1997;19:83. 9. Clifton-Bligh RJ, Wentworth JM, Heinz P, et al. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate, and choanal atresia. Nat Genet 1998;19:399. 10. Van Esch H, Groenen P, Nesbit MA, et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature 2000;406:419. 11. Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343:1863. 12. Gunther T, Chen Z-F, Kim J, et al. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature 2000;406: 199. 13. Manley NR, Capecchi MR. The role of Hoxa-3 in mouse thymus and thyroid development. Development 1995;121:1989. 14. Medvei Vc. The birth of endocrinology: Part I. In: Medvei VC (ed), A History of Endocrinology. Hingham, MA, MTP Press, 1982, p 213. 15. Laurence P. Iodine intake: What are we aiming at? [Editorial] J Clin Endocrinol Metab 1994;79: 17. 16. Boyages Sc. Iodine deficiency disorders. J Clin Endocrinol Metab 1993;77:587. 17. Livoisi VA, Asa SL. The demise of follicular carcinoma of the thyroid gland. Thyroid 1994;4:233. 18. Braverman LE. Iodine and the thyroid: 33 years of study. Thyroid 1994;4:351. 19. Larsen PR, Ingbar SH. The thyroid gland. In: Wilson DJ, Foster DW (eds), Williams Textbook of Endocrinology, 8th ed. Philadelphia, WB Saunders, 1992, p 357. 20. Dai G, Levy 0, Carrasco N. Cloning and characterization of the thyroid iodide transporter. Nature 1996;379:458. 21. Smanik PA, Liu Q, Furminger TL, et al. Cloning of the human sodiumiodide symporter. Biochem Biophys Res Commun 1996;226:339. 22. Fujiwara H, Tatsumi K-I, Miki K, et al. Congenital hypothyroidism caused by a mutation in the Na+/I- symporter. Nat Genet 1997;16:PI24. 23. McLachlan SM, Rapoport B. The molecular biology of thyroid peroxidase: Cloning, expression, and role as autoantigen in autoimmune thyroid disease. Endocr Rev 1992;13:192. 24. Bjorkman U, Ekholm R, Denef F. Cytochemical localization of hydrogen peroxide in isolated thyroid follicles. J Ultrastruct Res 1981; 74:105. 25. Taurog A. Hormone synthesis. In: Braverman LE, Utiger RD (eds), Werner and Ingbar's The Thyroid, 7th ed. Philadelphia, LippincottRaven, 1996, p 47. 26. Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 1997;17:411.

27. Refetoff S, Nicoloff JT. Thyroid hormone transport and metabolism. In: DeGroot LJ, Besser M, Burger HG, et al (eds), Endocrinology, 3rd ed. Philadelphia, WB Saunders, 1995, p 560. 28. Freake HC, Mooradian AD, Schwartz HL, Oppenheimer JH. Stereospecific transport of triiodothyronine to cytoplasm and nucleus in GHI cells. Mol Cell Endocrinol 1986;44:25. 29. Oppenheimer JH, Schwartz HL, Strait KA. The molecular basis of thyroid hormone actions. In: Braverman LE, Utiger RD (eds), Werner and Ingbar's The Thyroid, 7th ed. Philadelphia, Lippincott-Raven, 1996, p162. 30. Tata JR, Ernster L, Lindberg 0, et al. The action of thyroid hormones at the cell level. Biochem J 1963;86:408. 31. Oppenheimer JH, Schwartz HL, Surks MI. Tissue differences in the concentration of triiodothyronine nuclear binding sites in the rat: Liver, kidney, pituitary, heart, brain, spleen, and testis. Endocrinology 1974; 95:897. 32. Lazar MA. Thyroid hormone receptors: Multiple forms, multiple possibilities. Endocr Rev 1993;14:184. 33. Brent GA. The molecular basis of thyroid hormone action. N Engl J Med 1994;331:847. 34. Chin WW. Molecular mechanisms of thyroid hormone action. Thyroid 1994;4:389. 35. Glass CK. Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. Endocr Rev 1994;15:391. 36. Yu VC, Delsert C, Andersen B, et al. RXR~: A coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell 1991;67:1251. 37. Dillman WHo Biochemical basis of thyroid hormone action in the heart. Am J Med 1990;88:626. 38. Morkin E. Regulation of myosin heavy chain genes in the heart. Circulation 1993;87: 1451. 39. Chin WW, Can FE, Burnside J, et al. Thyroid hormone regulation of thyrotropin gene expression. Rec Prog Horm Res 1993;48:393. 40. Wess J. Mutational analysis of muscarinic acetylcholine receptors: Structural basis of ligandlreceptor/G protein interactions. Life Sci 1993;53: 1447. 41. Chazenbalk GD, Nagayama Y, Russo D, et al. Functional analysis of the cytoplasmic domains of the human thyrotropin receptor by site directed mutagenesis. J Bioi Chern 1990;265:20970. 42. Parmentier M, Libert F, Maenjhaut C, et al. Molecular cloning of the thyrotropin receptor. Science 1989;246: 1620. 43. Parma J, Duprez L, Van Sande J, et al. Somatic mutations in the thyrotropin receptor gene causing hyperfunctioning thyroid adenomas. Nature 1993;365:649. 44. Porcellini A, Ciullo I, Laviola L, et al. Novel mutations of thyrotropin receptor gene in thyroid hyperfunctioning adenomas. J Clin Endocrinol Metab 1994;79:657. 45. Yoshikawa N, Nishikawa N, Horimoto M, et al. Thyroid-stimulating activity in sera of normal pregnant women. J Clin Endocrinol Metab 1989;69:74. 46. Wolff J. Physiological aspects of iodide excess in relation to radiation protection. J Mol Med 1980;4:151. 47. Aurbach GD, Marx J, Spiegel AM. Parathyroid hormone, calcitonin, and the calciferols. In: Wilson OJ, Foster DW (eds), Williams Textbook of Endocrinology, 8th ed. Philadelphia, WB Saunders, 1992, p 1397. 48. Ewins DL, McGregor AM. Medical aspects of thyroid disease. In: Lynn J, Bloom SR (eds), Surgical Endocrinology. Oxford, England, Butterworth Heinemann, 1993, p 294. 49. Takahashi N, Akatsu T, Sasaki T, et al. Induction of calcitonin receptors by l-o, 25-dihydroxyvitamin D3 in osteoclast-like multinucleated cells formed from mouse bone marrow cells. Endocrinology 1988; 123:1504. 50. Body JJ, Gilbert F, Nejal S, et al. Calcitonin receptors on circulating normal human lymphocytes. J Clin Endocrinol Metab 1990;71:675.

Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands and Recurrent and External Laryngeal Nerves Jean-Francois Henry, MD

The surgical anatomy of the thyroid, parathyroid glands, and recurrent and external laryngeal nerves should be considered as a whole. A thorough knowledge of the anatomy and an understanding of the embryonic development of the thyroid and parathyroid glands are the keys to successful surgery.

Thyroid Embryology and Developmental Abnormalities The thyroid gland has a double origin from the primitive pharynx and the neural crest. The main body of the thyroid gland is derived from epithelial cells of the endoderm of the primitive pharynx. These cells will form the greater portion of the follicular elements of the thyroid tissue. They arise as a diverticulum from the midline of the pharyngeal floor. It soon develops as a bilobed, encapsulated structure that descends in the midline of the neck. With further development, this diverticulum remains attached to the buccal cavity by a narrow tract-the thyroglossal duct. Its distal end may become the pyramidal lobe. The neural crest is the source of the parafollicular cells, or C cells, which secrete calcitonin. 1,2 These C cells migrate from the neural crest of the ultimobranchial bodies of the fourth branchial pouch (P IV) and the fifth branchial pouch. The incorporation of the fifth pouch with the P IV leads to the formation of the caudal-pharyngeal complex, which includes not only the ultimobranchial bodies (lateral thyroids) but also the parathyroid glands arising from the endoderm of the P IV. Eventually, C cells populate the thyroid tissue by way of its lateral lobes, which join the main body on each side (Fig. 2-1).

The normal adult thyroid gland is composed of two lateral lobes connected by an isthmus. Anomalies of embryonic development of the two lobes result in a large variety of shapes and sizes. Rarely, in fewer than 0.1 % of cases, the isthmus or one lobe may not develop. The thyroglossal duct may persist or may differentiate into thyroid tissue at any level. Normally, the epithelium of the thyroglossal duct disappears. Occasionally, the epithelium and the duct may form thyroglossal cysts or fistulas, which usually present above the hyoid bone but may occur at any site along the duct between the base of the tongue and the suprasternal notch. These are essentially midline structures. Because the duct passes through or anterior or posterior to the hyoid bone, excision of the midsection of the hyoid bone is necessary for complete excision of the entire cyst and thyroglossal duct up to the foramen cecum. Midline ectopic thyroid rests are the result of the failure of or incomplete descent of the thyroglossal duct and of abnormal development of its epithelium. The most common example is the pyramidal lobe, which extends upward from the isthmus or from either lateral lobe in about 30% of patients. It may be considerably enlarged in patients with endemic goiters and in Graves' disease. In the latter case, if overlooked, it may be responsible for recurrent hyperthyroidism. Complete failure of descent of the thyroglossal duct results in a lingual thyroid, located at the base of the tongue. A lingual thyroid may be the only functioning tissue and may be responsible for lingual goiter; symptoms depend on its size. Other midline ectopic thyroid rests of the thyroglossal duct may be found below or above the hyoid bone. Usually asymptomatic, they are demonstrated on radioiodine scanning after total thyroidectomy. Carcinomas may rarely arise in median ectopic thyroid tissue.

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Thyroid Gland

FIGURE 2-1. Schematic view of embryonic migrations of parafolIicular andparathyroid tissues. At the 13- to l4-mm stage, the P III and P IV migrate together with the thymus and ultimobranchial

bodies, respectively.

About I % of thyroglossal cysts contain papillary thyroid cancers. Aberrant thyroid tissue has also been identified lateral or inferior to the main body of the thyroid gland and in the superior anterior mediastinum. When aberrant thyroid tissue is situated lateral to the jugular vein and is unassociated with lymph node tissue, it may rarely be a developmental anomaly deriving from the fourth pouch. Ectopic intrathoracic thyroid tissue may also be found in the periaortic region and the pericardium. It is the result of the displacement of thyroid rests into the mediastinum by the descent of the heart and great vessels. Because their blood supply is from intrathoracic vessels, tumors arising from these thyroid remnants usually cannot be removed by cervicotomy and require a sternum-splitting incision. In contrast with the former rare situations, what appears on histologic examination to be normal thyroid tissue within lymph nodes lateral to the jugular vein in fact represents metastatic papillary thyroid carcinoma. On the other hand, on rare occasions, a few follicles of normal thyroid tissue are observed within the capsule of medially located lymph nodes. They do not necessarily represent metastases, provided that the follicular cells appear normal and the follicles are limited to the periphery of the lymph node. It has been demonstrated that in these rare cases, the thyroid gland is entirely normal at meticulous histologic examination.' Thyroid tissue may also rarely be found in ovarian teratomas. In rare instances, when thyroid tissue is the main component, struma ovarii may arise and be responsible for thyrotoxicosis or malignancy with peritoneal metastases.

it as the origin of the thymus IV (rudimentary thymus IV), which rapidly undergoes involution. The fatty lobules sometimes found at the site of the upper parathyroid (P IV) may well constitute the vestigial remnants of this thymus IV. At the 13- to 14-mm stage, the P III and P IV migrate together with the thymus and ultimobranchial bodies, respectively. The P III-thymus complex separates from the pharyngeal wall and moves toward the caudal and medial regions. Because of the extension of the cervical spine and the descent of the heart and great vessels, the thymus and the P III are drawn toward the superior mediastinum. At the 20-mm stage, the cephalic regression of the thymus brings about its separation from the P III, which are thus abandoned at the level of the anterior or posterolateral region of the inferior poles of the thyroid lobes or at the level of thyrothymic ligaments, vestigial structures indicative of their former connections. This embryologic migration results in an extensive area of dispersal of the normal P III. In 61% of cases, they are situated at the level of the inferior poles of the thyroid lobes on the posterior, lateral, or anterior aspects. In 26% of cases, they are situated in the thyrothymic ligaments or on the upper cervical portion of the thymus. More rarely, in 7% of cases, they are situated higher up, at the level of the middle third of the posterior aspect of the thyroid lobes, and may then be confused with P IV (Fig. 2-2). The P IV follow the thyroid migration of the ultimobranchial bodies, which travel toward the lateral part of the main median thyroid rudiment. Their descent in the neck is thus relatively limited. They remain in contact with the posterior part of the middle third of the thyroid lobes. The short course of embryonic migration of P IV explains why they remain relatively stable in their topography when they are not pathologic. Thus, in 85% of cases, they are grouped at the posterior aspect of the thyroid lobes, in an area 2 em in diameter, whose center is situated about 1 em above the

Parathyroid Embryology and Developmental Abnormalities The inferior parathyroid glands arise from the dorsal part of the P III. The thymus arises from the ventral portion of the same pouch. This common origin justifies labeling P III and thymus as parathymus. The dorsal part of the P IV gives rise to the superior parathyroids. The fate of the ventral portion of the P IV is little understood in humans. Gilmour" regarded

FIGURE 2-2. The embryonic migration of the third branchial

pouch (P III)-thymus complex results in an extensive area of the normal P III from the angleof the mandible to pericardium.

Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands - -

FIGURE 2-3. The short course of embryonic migration of the fourth branchial pouches explains why they remain relatively stable in the topography when they are not pathologic. In 85% of cases, they are grouped at the junction of the middle and superior thirds of the posterior aspect of the thyroid lobe.

crossing of the inferior thyroid artery and the recurrent nerve (Fig. 2_3).4.6 Thus, the P IV are crossed by the P III during the descent of the parathymus. This embryonic crossing of P III and P IV explains why their grouping at the level of the inferior thyroid artery, at the junction of the middle and inferior thirds of the thyroid lobe, is more or less close, depending on the migration of P III. Because the area of dispersal of the P IV is limited by their short migratory course, a congenital ectopic position of P IV is unusual. In 12% to 13% of cases, the glands are on the posterior aspect of the superior pole of the thyroid lobe in a laterocricoid, lateropharyngeal, or intercricothyroid position, and, exceptionally, in less than 1% of cases, they are above the upper pole of the lobe. In 1% to 4% of cases, they are frankly posterior behind the pharynx or esophagus. Because the embryonic descent of the thymus extends from the angle of the mandible to the pericardium, anomalies of migration of the parathymus, whether excessive or defective, are responsible for high or low ectopias of P III. The incidence of high ectopias, along the carotid sheath, from the angle of the mandible to the lower pole of the thyroid, does not seem to exceed 1% to 2%.5.8 Conversely, if their separation from the thymus is delayed, the P III may be dragged down into the anterior mediastinum to a varying degree. They are then usually in the thymus, at the posterior aspect of its capsule, or still in contact with the great mediastinal vessels. These low ectopias are found in 3.9% to 5% of cases.v" Parathyroid glands found in the posterosuperior mediastinum are usually tumoral P IV that have migrated subsequently because of gravity." The strictly intrathyroid localization of some parathyroids is explicable only on embryologic grounds. According to Wang,1O the P IV may become included within the thyroid at the time of fusion of the ultimobranchial bodies with the median thyroid rudiment. Although the P III do not arise from the P IV, undeniable cases of a normal or pathologic P III included in the lower poles of the thyroid lobes have been reported.t'! According to Gilmour," intrathyroid inclusion of parathyroid tissue may be found with the same incidence as inclusions of thymic tissue. Overall, the incidence of intrathyroid ectopias that seem to involve both P III and P IV is between 0.5% and 3.5%.4,8-11 Other embryologic cervical or mediastinal ectopic glands are more rare and usually related to supernumerary glands. 13, 14 These develop from accessory parathyroid debris

11

arising from fragmentation of the pharyngotracheal duct when the pharyngeal pouches separate from the pharynx. The incidence of these supernumerary glands is relatively high at 13%.5 Akerstrom and colleagues' distinguish between accessory parathyroid glands containing simple tissue debris and weighing less than 5 mg, found very close to the main glands, and true supernumerary glands weighing more than 5 mg (average weight, 24 mg) situated apart from the other glands. Ectopic or supernumerary parathyroids may also be situated in quite exceptional positions. They are then revealed by tumoral formations developing from them and are responsible for hyperparathyroidism: in the middle mediastinum (0.3%) at the level of the aortopulmonary window," lateral to the jugulocarotid axis." The migration of pathologic parathyroid tissue seems highly improbable in such cases. In both cases, the embryologic hypotheses suggest a precocious fragmentation of P Iy' 15.16 Parathyroid tissue'? and parathyroid adenomas" have also been described within the vagus nerve. In the latter case, it has been hypothesized that parathyroid tissue arises from the P III, which is closely related to the vagus nerve during embryogenesis.'? A case of a parathyroid located in the mucosa of the piriform sinus has even been reported. 19

Surgical Anatomy of the Thyroid and Parathyroid Glands The normal adult thyroid gland weighs about 17 g. It is wrapped around the anterolateral portion of the upper tracheal rings and larynx. Each lobe occupies a bed between the trachea and the esophagus medially; the carotid sheath posteriorly; and the sternocleidomastoid, the sternohyoid, and the sternothyroid muscles laterally and anteriorly. If the sternothyroid and sternohyoid muscles are to be divided transversely, they must be transected high, at the cricoid level, to preserve their motor nerve, the ansa hypoglossi. Section of the strap muscles has no clinical functional consequence. The normal thyroid is soft, dark wine-red in color, and covered with a thin capsule. It is loosely attached to neighboring structures. The variations in fixation of the gland may arouse suspicion of pathologic change, particularly when the history suggests acute thyroiditis or cancer. Normally, the gland adheres only to the cricoid cartilage and the upper tracheal rings. This is the posterior suspensory, or Berry's, ligament. The superior and inferior thyroid arteries are derived from the external carotid arteries and the thyrocervical trunks, respectively. Occasionally, a branch from the innominate artery or aorta, the arteria thyroidea ima, may be present. It passes directly upward in front of the trachea to enter the lower border of the isthmus. Its frequency of occurrence has been greatly overemphasized. The superior thyroid artery is the first branch of the external carotid artery. It arises just above the thyroid cartilage. It gives off the superior laryngeal artery and then descends on the surface of the inferior constrictor of the pharynx, deep to the sternothyroid muscle. It enters the upper pole of the thyroid on its anterosuperior surface. It gives off a relatively

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Thyroid Gland

FIGURE 2-4. Relation between the external branchof the superior laryngeal nerve and the thyroid artery. The nerve may run partly to or around the artery or its branches.

large branch to the pyramidal lobe and isthmus. The superior thyroid artery, via its posterior branch, feeds the superior parathyroid or P IV. There is an extremely close relationship between the superior thyroid artery and the external branch of the superior laryngeal nerve (Fig. 2_4).20.2\ This nerve is the motor nerve to the cricothyroid muscle, which produces tension of the vocal cord and makes possible the production of high-pitched voice sounds. Injuries to the nerve, in particular bilateral injuries, are easily overlooked at postoperative laryngoscopy. In 6% to 18% of cases, the external branch of the superior laryngeal nerve runs with or around the superior thyroid artery or its branches. Therefore, the nerve is highly vulnerable during ligation of the superior thyroid artery. Nevertheless, routine identification of the nerve during thyroid surgery is usually not advocated. Indeed, in 20% of cases, the nerve is not located in the surgically accessible area around the superior thyroid pole. It cannot be identified without dissection into or through the fibers of the pharyngeal constrictor muscle. To avoid nerve injury when ligating the superior thyroid vascular pedicle, one may recommend first identifying the branches of the artery to avoid ligation of its main trunk. This identification is particularly recommended during excision of pathologically enlarged thyroid glands. The superior thyroid arteries should be ligated as low as possible on the thyroid gland. Second, it is advisable to dissect the superior thyroid vessels away from the nerve by opening up a space between the cricothyroid muscle and the upper pole of the thyroid. This dissection requires strong downward and outward traction on the upper pole of the gland. During this traction, the nerve should be sought more or less transversely between the superior thyroid vessels and the pharyngeal constrictor muscle or the cricothyroid muscle. Finally, the dissection must be performed from medial to lateral. Moreover, small vessels run from the superior thyroid artery into the pharyngeal constrictor and the cricothyroid muscles. As the nerve slips under these muscles, there is a risk of heat injury to the nerve during cauterization of these little muscular vascular branches. The inferior thyroid artery arises from the thyrocervical trunk. It runs upward behind the carotid sheath to about the

level of the cricoid cartilage, loops medially and downward to a level above the inferior pole of the thyroid, crossing the sympathetic trunk or its branches, and then runs upward again to reach the gland at its midportion. For the surgeon, the inferior thyroid artery appears from beneath the carotid artery only when the thyroid gland is retracted medially and the jugular vein laterally. This maneuver puts tension on the artery and makes it easier to identify. Before entering the thyroid, the artery usually divides into three branches: inferior, posterior, and internal. One branch or sometimes the trunk itself supplies the inferior parathyroid or P III. The inferior thyroid artery and its terminal branches are intimately associated with the recurrent laryngeal nerve at about the level of the junctions of the lower and middle thirds of the thyroid gland (Fig. 2-5). The left recurrent laryngeal nerve ascends at the depth of the tracheoesophageal groove or just lateral to it at the lower pole of the thyroid. Usually it crosses deep to the inferior thyroid artery, sometimes between the terminal branches of the artery, rarely superficially. The right recurrent laryngeal nerve courses more obliquely, being somewhat more lateral in position caudally. It rarely crosses deep to the artery, usually between its terminal branches. Innumerable variations have been described.F This is one of the most vulnerable areas for injury to the recurrent laryngeal nerve. From a practical point of view, it is safer to search for the nerve below the artery. Identification of the inferior thyroid artery and careful ligation of its branches close to the gland is an excellent means of preserving the nerve and the inferior parathyroid. The recurrent nerve may be mistaken for one branch of the artery and especially for the inferior laryngeal artery. The nerve is somewhat less regular, rounded, and elastic than the artery. A small, red, sinuous vessel, a vasa nervorum, is always observed on it. The tortuousity of this small vessel is reduced when retraction of the thyroid puts the nerve under tension. Rarely, the nerve branches below the inferior thyroid artery. In any case, the surgeon must consider each extralaryngeal branch of the recurrent nerve as the possible motor branch and make every attempt to preserve them all.

FIGURE 2-5. Recurrent laryngeal nerve and its relationship to the

inferior thyroid arteryandto Berry's ligament. The nerve is embedded in the posterior portion of Berry's ligament. It is accompanied by the inferiorlaryngeal artery, whichgivesoff a small branch that crosses the nerve internally.

Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands - -

The recurrent laryngeal nerve continues upward and medially at the posterolateral aspect of the middle third of the thyroid gland. It is extremely close to the capsule of the gland. In a few cases, particularly in pathologically enlarged glands, it may appear to penetrate or may actually penetrate the thyroid gland itself before entering the larynx. At the two upper tracheal rings, the nerve is embedded in the posterior portion of Berry's ligament (see Fig. 2-5). This ligament extends posteriorly behind the recurrent nerve and loosely attaches the thyroid to the esophagus. Vessels and connective tissue are more condensed anteriorly at the level of the tracheal rings. The nerve commonly divides before the point at which it enters the larynx, posterior to the cricothyroid muscle. The nerve is accompanied by the inferior laryngeal artery. At the site of Berry's ligament, this artery, usually just posterior to the recurrent nerve, gives off a small branch that crosses the nerve to enter the thyroid glands. Therefore, bleeding vessels in this portion of the ligament should never be clamped until the nerve has been identified. It is in this area that the recurrent nerve is most vulnerable to injury. Medial retraction on the thyroid lobe makes the nerve more vulnerable to injury during lobectomy. Indeed, this maneuver puts tension on the inferior thyroid artery and its branches and on Berry's ligament; consequently, the nerve is displaced anteriorly on the lateral aspect of the trachea. Moreover, the posterior fibers of Berry's ligament press the nerve against the lateral aspect of the tracheal rings, increasing the difficulties of dissection. Instead of medial retraction, it is preferable to retract the lobe upward after complete dissection of its lower pole. With this maneuver, it is easier to follow the nerve until its entry in the larynx at the level of the cricoid cartilage. The recurrent laryngeal nerve is the motor nerve to the intrinsic muscles of the larynx." Injury to the motor trunk causes paralysis of the vocal cord on the ipsilateral side. The other extralaryngeal branches are sensory. On rare occasions (0.63%), the right inferior laryngeal nerve does not recur'" On the left side, this anomaly is quite exceptional (0.04%). As a rule, the origin of the nonrecurrent laryngeal nerve is cervical. Depending on its level of origin, the nerve runs more or less down along the vagus nerve and more or less across the jugulocarotid groove, making a downward curve. It always passes behind the common carotid artery. In one third of cases, it is in close contact with the trunk or the branches of the inferior thyroid artery; it enters the larynx at the usual level. Nonrecurrence of the inferior laryngeal nerve results from a vascular anomaly during embryonic development of the aortic arches: no innominate artery, but an aberrant subclavian artery (arteria lusoria). Nerve anomaly on the left side requires, in addition, a right aortic arch associated with situs inversus viscerum. A nonrecurrent laryngeal nerve has been also reported in association with an ipsilateral recurrent laryngeal nerve.25-28 Curiously, in some cases, no vascular anomaly has been demonstrated." The supposed coexistence of a recurrent and a nonrecurrent laryngeal nerve is questionable. First, an enlarged anastomotic branch between the cervical sympathetic system and the recurrent laryngeal nerve may be mistaken for nonrecurrent laryngeal nerve." Second, in the reported cases, it has never been demonstrated that the recurrent branch originated from the vagus nerve.

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The nervous branch has only been described running in the usual pathway of a recurrent laryngeal nerve and having a small caliber. Whether this branch really originates from the vagus nerve and not from the sympathetic system, for example, the stellate ganglion, has not been proved." During thyroid lobectomy, if the nerve is not found at its usual place, before it crosses the inferior thyroid artery, it should be sought more or less transversely between the laterally retracted carotid sheath and the medially retracted thyroid in a plane that, in the case of nerve anomaly, cannot be cleaved as easily as usual, because the nonrecurrent inferior laryngeal nerve links the two structures. Other aberrant pathways for the recurrent laryngeal nerve are observed only with pathologically enlarged thyroids and particularly with large posterior nodules and in substernal multinodular goiters. In these cases, if it is not possible to search for the nerve at its usual place, below the inferior thyroid artery, it should be located superiorly near to where it enters the larynx at the level of the cricoid cartilage. This maneuver requires previous dissection of the upper pole of the gland, or an "inside-out" approach, after section of the isthmus. Then the nerve should be dissected in a downward direction. The venous drainage is more variable than the arterial supply. The capsular veins vary in size and may be enormous in pathologic glands. These are thin-walled structures that intercommunicate freely among themselves, forming a characteristic capsular network. The vessels within the gland itself are relatively small. Consequently, hemorrhage from capsular vessels may be important, but, provided that the vessels are clamped, subtotal resection of a lobe is a relatively bloodless procedure. The capsular network is schematically drained by three pedicles. The superior thyroid veins, just anterior and lateral to the superior thyroid artery, empty directly or indirectly into the internal jugular vein. The lateral or middle veins vary greatly in number. They pass directly from the anterolateral border of the lobe into the internal jugular vein. Careful lateral retraction of the carotid sheath facilitates their identification and their ligation, especially in enlarged glands where they may be mistaken for capsular veins. The inferior thyroid veins leave the lower pole and the isthmus in several trunks, frequently forming a plexus. They empty into the internal jugular vein and directly into the innominate vein. Ligation of the most lateral inferior thyroid veins requires previous identification of the recurrent nerve. The nerve may be anterior and, particularly when the thyroid lobe is medially retracted, could be mistaken for a vein. Follicular carcinomas, because of their high tendency for vascular invasion, may spread directly through veins into the internal jugular veins and sometimes downward into the innominate vein. In such cases, previous distal control of these veins is mandatory before thyroidectomy. Lymphatic drainage of the thyroid is extensive and may flow practically in all directions. Capsular lymph channels, draining the intraglandular capillaries, may even crosscommunicate with the isthmus and opposite lobe. Therefore, it is technically impossible to remove all the potential lymph node metastases in thyroid cancers. Nevertheless, and from a practical point of view, the surgeon must consider two zones of lymphatic drainage for the

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Thyroid Gland

FIGURE 2-6. The two sites of lymphatic drainage of the thyroid. The first site is the visceral compartment of the neck. The second site is the lateral cervical region. The boundary between the two sites is the carotid sheath.

thyroid (Fig. 2-6). The first site is the paraglandular space or middle or visceral compartment of the neck. The second site is the lateralcervical region. The boundary between the two sites is the carotid sheath. In the visceral compartment, there are two groups: (l) the prelaryngeal and pretracheal and (2) the paratracheoesophageal. The prelaryngeallymphatic vessels lie anterior to and above the isthmus and merge superiorly and laterally with the lymphatic vessels of the superior pole of the thyroid along the superior thyroid vessels to drain into the nodes of the lateral neck. The pretracheal lymphatic vessels lie below the isthmus and merge inferiorly with the lymphatic vessels of the anterior and superior mediastinum. The anterior boundary of the visceral compartment is the posterior surface of the prethyroid muscles, but sometimes node metastases may be found very anteriorly in the midline, particularly just above the isthmus (Delphian lymph nodes). The paratracheoesophageal lymphatic vessels lie along the lateral and posterior aspects of the thyroid gland and along the course of the recurrent laryngeal nerves. They communicate laterally with the lymphatic vessels in the supraclavicular triangles and posteriorly with those around and behind the trachea, the larynx, the pharynx, and the esophagus. Lymphatic drainage of the isthmus flows down into the mediastinal nodes and upward into the paralaryngeal nodes. The normal flow direction from the central and lower parts of the lateral lobes is toward the tracheoesophageal nodes. Only lymphatic drainage of the superior poles of the lobes may flow directly into the lateral neck nodes. This may explain why papillary thyroid carcinomas revealed by metastatic laterocervical lymph nodes are located in the upper pole of thyroid lobes in nearly two thirds of cases.'? Therefore, the central neck area is the primary zone of lymphatic drainage for all thyroid cancers except those located in upper poles of the glands. Lateral neck areas (internaljugular chains and posterior triangles) are secondary

zones of lymphatic drainage. Some of the involvement probably is brought about by retrograde extension resulting from obstruction of the lymph flow route in the central neck area." Because the visceral or central compartment of the neck is the primary zone of involvement, many surgeons advocate prophylactic neck dissection in this area in cases of papillary and medullary thyroid carcinomas. Indeed, even if metastatic nodal recurrences are rare, reoperations in the central neck area are difficult and increase the risk of injury to the recurrent laryngeal nerve and parathyroid glands. Just as embryology helps the surgeon understand where the parathyroid glands are positioned, their gross appearance makes it possible to identify them and to differentiate them from other structures. The parathyroid glands vary in shape but remain compact in 94% to 98% of cases.' Their color depends on their adipocyte content and vascularization: light brown or coffee colored when the gland is very fatty, and darker, buff, or reddish brown when the gland is more cellular or has a richer blood supply. They are soft and supple and retain their original shape during dissection. If flattened by the development of a thyroid nodule, they can become rounded again when detached from its surface. Their average size varies from 5.25 x 3 x 1.28 mm to 5 x 3 x 1 mm, as reported by Gilmour and Martin'? and Wang,6 respectively. The average weight of a normal gland is 40 mg (range, 10 to 78 mg). They are encapsulated and have sharp outlines and a smooth, glistening surface. Parathyroid glands have a particular affinity for fat and are often found completely or partially embedded in a fatty globule. They often have a fatty capsule over their surface like the crest of a helmet. Characteristically, they can be separated easily from the adjacent fatty structures. Whatever their size, shape, or color, the parathyroid glands always share an encapsulated appearance, which gives them a proper shape, an ocher tint, and a soft elastic consistency. Fat is softer, paler, and straw colored, with no definite shape. Thyroid tissue is firmer, less homogeneous, darker wine-red in color with bluish-gray tints, and often embedded in "padding." Lymph nodes are firmer, more rounded, less homogeneous, and white, dirty gray, or putty colored, with black dots. Nodes are separated from the adjacent fat with greater difficulty. Lymph nodes are usually multiple. Thymic tissue is paler, grayish yellow or grayish pink, granular, and adherent to the fat. The arterial supply of the parathyroid glands is terminal in type; the artery is solitary in two thirds of cases. The length of the artery varies (l to 40 mm), but in cases of thyroidectomy, even if the parathyroid is pedicled, its preservation depends primarily on the distance between the origin of its artery and the thyroid capsule. The vascularization of P III depends primarily on the inferior thyroid artery. The P IV are supplied by the inferior thyroid artery, by the posterior branch of the superior thyroid artery, or by the posterior marginal arch of Evans. Both P III and P IV may be entirely dependent on the inferior thyroid artery. Therefore, during thyroid lobectomy, the inferior thyroid artery must never be ligated at the level of its main trunk. Similarly, the preservation of P IV requires separate ligation of the branches of the superior thyroid artery so as to preserve the posterior branch. At the lower poles of the thyroid lobes, the preservation of P III is ensured by the technique of ultraligation

Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands - - 15

advised by Halsted and Evans." When the lower parathyroid glands (P III) are situated in the thyrothymic ligaments or in the upper poles of the thymus, they are supplied by the inferior thyroid artery. Venous drainage occurs by three methods: (1) by the capsular network of the thyroid, (2) by the venous pedicles of the thyroid body, or (3) by a combination. Thyroid lobectomy may render the ipsilateral parathyroid glands ischemic. Hemostasis of a parathyroid vein generally should be avoided because of the risk of glandular infarction. Parathyroid ischemia is often evidenced by progressive darkening of the gland. Incision of the capsule and superficial parenchyma may prevent venous stasis and allow the gland to recover its normal color.

Summary The thyroid gland is made up of follicular and parafollicular cells of endoderm and neural crest origin, respectively. The lower parathyroid glands and thymus arise from the dorsal part of the P III, and the upper parathyroid glands arise from the P IV. The lower parathyroid glands are usually situated caudal to where the inferior thyroid artery and recurrent laryngeal nerve cross. If not situated here, they are usually in the thymus. The upper parathyroid glands are more dorsal or posterior, more consistent in position at the level of the cricoid cartilage. When not situated here, they may descend along the esophagus into the posterior mediastinum. An understanding of the embryonic formation of the thyroid and parathyroid glands as well as experience helps the surgeon recognize not only the normal relationship of the thyroid and parathyroid glands with the adjacent structures but also the aberrant development or position of these glands. This knowledge is of paramount importance for successful operations.

REFERENCES I. Le Douarin N, Le Lievre c. Embryologie experimentale: Demonstration de I'origine neurale des cellules a calcitonine du corps uItimobranchial chez I'embryon de poulet. Comptes rendus de l'Academie des Sciences 1970;270:2857. 2. Pearse AGE, Cavalheira AE Cytochemical evidence for an ultimobranchial origin of rodent thyroid C cells. Nature 1967;214:929. 3. Meyer JS, Steinberg LS. Microscopically benign thyroid follicles in cervical lymph nodes. Cancer 1969;24:302. 4. Gilmour JR. The gross anatomy of the parathyroid glands. J Pathol Bact 1938;46:133. 5. Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95:14. 6. Wang CA. The anatomic basis of parathyroid surgery. Ann Surg 1976; 183:271. 7. Fraker DL, Doppman JL, Shawker TH, et al. Undescended parathyroid adenoma: An important etiology for failed operations for primary hyperparathyroidism. World J Surg 1990;14:342.

8. Henry JF, Denizot A. Anatomic and embryologic aspects of primary hyperparathyroidism. In: Barbier J, Henry JF (eds), Primary Hyperparathyroidism. Paris, Springer-Verlag, 1992, p 5. 9. Thompson NW. Surgical anatomy of hyperparathyroidism. In: Rothmund M, Wells SA Jr (eds), Parathyroid Surgery. Basel, Switzerland, Karger, 1986, p 59. 10. Wang CA. Hyperfunctioning intra-thyroid parathyroid gland: A potential cause of failure in parathyroid surgery. J R Soc Med 1981;74:49. I I. Wheeler MH, Williams ED, Wade JSH. The hyperfunctioning intrathyroid parathyroid gland: A potential pitfall in parathyroid surgery. World J Surg 1987;11:110. 12. Gilmour JR. The embryology of the parathyroid glands, the thymus, and certain associated rudiments. J Pathol Bact 1937;45:507. 13. Numano M, Tominaga Y, Uchida K, et al. Surgical significance of supernumerary parathyroid glands in renal hyperparathyroidism, World J Surg 1998;22:1098. 14. Pattou NF, Pelissier LC, Noel C, et al. Supernumerary parathyroid glands: Frequency and surgical significance in treatment of renal hyperparathyroidism. World J Surg 2000;24: I330. 15. Curley IR, Wheeler MH, Thompson NW, Grant CS. The challenge of the middle mediastinal parathyroid. World J Surg 1988;I2:8 I8. 16. Udekwu AG, Kaplan EL, Wu TC, et al. Ectopic parathyroid adenoma of the lateral triangle of the neck: Report of two cases. Surgery 1987;101:114. 17. Lack EE, Delay S, Linnoila RI. Ectopic parathyroid tissue within the vagus nerve. Arch Pathol Lab Med 1988;112:304. 18. Raffaelli M, Defechereux T, Lubrano D, et al. Intravagal ectopic parathyroid gland. Ann Chir 2000;125:961. 19. Joseph MP, Nadol JB, Goodman ML. Ectopic parathyroid tissue in the hypopharyngeal mucosa (pyriform sinus). Head Neck Surg 1982;5:70. 20. Lennquist S, Cahlin C, Smeds S. The superior laryngeal nerve in thyroid surgery. Surgery 1987;102:999. 21. Cernea CR, Ferraz AR, Cordeiro AC. Surgical anatomy of the superior laryngeal nerve. In: Randolf GW (ed), Surgery of the Thyroid and Parathyroid Glands. Philadelphia, WB Saunders, 2003, p 293. 22. Reed AE Relations of inferior laryngeal nerve to inferior thyroid artery. Anat Rec 1943;85:17. 23. Randolf WR. Surgical anatomy of the recurrent laryngeal nerve. In: Randolf GW (ed), Surgery of the Thyroid and Parathyroid Glands. Philadelphia, WB Saunders, 2003, p 300. 24. Henry JF, Audiffret J, Denizot A. The nonrecurrent inferior laryngeal nerve: Review of 33 cases, including two on the left side. Surgery 1988;104:977. 25. Katz AD, Nemiroff P. Anastomoses and bifurcations of the recurrent laryngeal nerve: Report of II 77 nerves visualized. Am Surg 1993; 59:188. 26. Thompson NW. In discussion of article Reference 24. Surgery 1988;104:983. 27. Proye CAG, Carnaille BM, Goropoulos A. Nonrecurrent and recurrent inferior laryngeal nerve: A surgical pitfall in cervical exploration. Am J Surg 1991;162:495. 28. Sanders G, Uyeda RY, Karlan MS. Nonrecurrent inferior laryngeal nerves and their association with a recurrent branch. Am J Surg 1983;146:501. 29. Raffaelli M, Iacobone M, Henry JE The false nonrecurrent inferior laryngeal nerve. Surgery 2000; I28: 1082. 30. Henry JF, Denizot A, Bellus JE Papillary thyroid carcinomas revealed by metastatic cervical lymph nodes. Endocr Surg 1992;9:349. 31. Noguchi S, Noguchi A, Murakami N. Papillary carcinoma of the thyroid: I. Developing pattern of metastasis. Cancer 1970;2:1053. 32. Gilmour JR, Martin WJ. The weight of the parathyroid glands. J Pathol Bact 1987;34;431. 33. Halsted WS, Evans HM. The parathyroid glandules: Their blood supply and preservation. Ann Surg 1907;46:489.

Medical and Surgical Treatment of Endemic Goiter Polly S-Y Cheung, MBBS(HK)

Endemic goiter is a preventable disease caused by iodine deficiency. According to statistics from the World Health Organization (WHO) in 1999, a total of 740 million people-about 13% of the world's population-are affected by endemic goiter alone. ' Clinically, the individual with endemic goiter may present with a diffuse to multinodular goiter. Biochemically, the urinary iodine excretion level is low, and the serum thyroxine (T4) level may be low or normal with an elevated thyroidstimulating hormone (TSH) level. Long-standing goiters may become autonomous in function and produce toxicity. Mechanical obstruction to the trachea and the thoracic inlet and malignant changes are possible sequelae of endemic goiters. The occurrence of endemic goiter is preventable by an adequate supply of iodine in the diet. Universal salt iodination is the goal of WHO in an attempt to eliminate the disease by the year 2000. Data from WHO in 1999 showed that 68% of the total population in countries affected by iodine deficiency disorders (IDDs) have access to iodized salt. Existing endemic goiters are currently treated with iodine supplementation to reverse hypothyroidism and to reduce the size of the goiters. For long-standing goiters, the treatment is the same as that for sporadic goiter: T4 therapy and thyroidectomy are used for treatment; radioiodine therapy is used selectively. Goiter, an enlargement of the thyroid gland, is conventionally called an endemic goiter when it occurs in more than 10% of the population in a defined geographic area; the area is called an endemic area? A total goiter rate of 5% or higher is now recommended as the cut-off point to indicate a public health problem, following a decision made by the WHOlUnited Nations International Children's Emergency Fund (UNICEF)/lnternational Council for the Control of Iodine Deficiency Disorders (ICCIDD) Consultation on IDD Prevalence in November 1992.3 This recommendation is based on the observation that goiter prevalence rates between 5% and 10% may be associated with a range of abnormalities, including inadequate urinary iodine excretion or subnormal levels of T4 among adults, children, and neonates. Epidemiologic studies are usually carried out in school-age children (6 to 12 years of age) because of their high physiologic vulnerability and their accessibility

16

through school for studies on baseline health parameters and results of public health programs. Endemic goiter is the chief consequence of iodine deficiency, resulting from either low iodine intake or ingestion of goitrogens. The effects of iodine deficiency on human growth and development are denoted collectively as IDDs (Table 3-1). 4 It affects all stages of development from fetus and neonate to infant, child, and adolescent. Severe iodine deficiency affects the developing central nervous system. In the fetus, it causes abortion, stillbirth, congenital anomalies, or cretinism. In children and adolescents, it produces problems ranging from mild intellectual impairment to mental retardation to full-blown endemic cretinism. It is well recognized that a marginal iodine intake is associated with some degree of motor deficit or developmental delays, such as poor hand-eye coordination and impaired intellectual performance exemplified by a reduction in IQ scores by as much as 10 to 15 points in tests of mental development.'

Prevalence According to a global review in 1999, more than 2 billion people are at risk for iodine deficiency, this number representing 38% of the world's population. Approximately 741 million people from 130 countries have endemic goiter, representing 13% of the world population (Table 3-2).' Most of the world's natural supply of iodine exists in the ocean as iodide. In high, mountainous areas and inland waters, the soil becomes leached of iodine by snow water and glaciation. Lowlands with heavy rainfall or flooding can also become iodine deficient. The most important goitrous areas historically include the northern and southern slopes of the Himalayas, the Andean region of South America, the European Alps, and the mountainous areas of China. Goiters also occur in lowlands far from the oceans, such as the central part of Africa and, to a lesser extent, in the coastal areas of Europe." The global prevalence of goiter has hardly increased at the global level from 1990 to 1998 (Table 3-3),1 This figure was thought to reflect the vigorous efforts in survey and

Medical and Surgical Treatment of Endemic Goiter - - 17

increased data, especially in countries in the Eastern Mediterranean, Africa, and Europe, where the total goiter rate is high. The Eastern Mediterranean region has the highest goiter prevalence rate, with 74% of the population at risk for iodine deficiency. On the other hand, IDD prevalence has decreased slightly in the Americas, Southeast Asia, and the Western Pacific, reflecting the impact of IDD control programs, especially salt iodization, on the population. Southeast Asia and the Western Pacific (including China) together account for more than 50% of the world's total population at risk for IDD (Fig. 3-1). Countries in this region, including India, Pakistan, Bangladesh, Nepal, Myanmar (Burma), Vietnam, and Thailand, share a large rate of prevalence of IDD; 599 million people are at risk and 172 million are goitrous. China alone has 300 million people at risk of IDD because of the extensive mountainous areas in that country, with 109 million suffering from goiter.8 Iodine deficiency persists mostly in developing countries despite the established benefits of iodine supplementation in the prevention of endemic goiter. In decreasing order of magnitude, the number of people at risk of IDD is largest in the Eastern Mediterranean, followed by Africa, Southeast Asia, Europe, Western Pacific, and the Americas (see Table 3-2).

18 - - Thyroid Gland

FIGURE 3-1. Prevalence of iodine deficiency disorders (IDDs)-global distribution. TGR = total goiter rate. (From WHOIUNICEFI International Council for the Control of Iodine Deficiency Disorders. Global Prevalence of Iodine Deficiency Disorders. Geneva, Switzerland, World Health Organization, 1996.)

Mild to moderate iodine deficiency still persists in a number of European regions, namely Italy, Spain, Germany, Greece, Romania, Hungary, Poland, and the former Yugoslavia." Continuous measures to provide iodine are required to overcome the socioeconomic and cultural limitations in different regions. The prevalence of endemic goiter is influenced by age and gender. In severely iodine-deficient areas, goiter appears at an early age, and the prevalence increases markedly during childhood and attains its peak during puberty. From the age of 10 years, the prevalence is higher in girls than in boys, probably because of the difference in metabolism of iodine during adolescent growth. In both sexes, goiter prevalence decreases during adulthood, but the decline is sharper in men than in women. 10

Etiology of Iodine Deficiency Iodine is an essential substrate in the synthesis of the thyroid hormones i.-thyroxine (T4) and t-triiodothyronine (T 3) . The normal human thyroid gland releases about 65 ug of hormonal iodine to the circulation per day, which represents the minimum daily requirement of iodine. Iodine requirements increase during puberty, pregnancy, and lactation.

Iodine intake is considered adequate when it is between 100 and 200 ug/day (Table 3-4). The principal source of iodine intake is from diet or pharmaceuticals. I I The highest amounts of iodine in food are found in fish, seafood, and seaweed. Iodine is also found to a lesser extent in milk, eggs, and meat from animals whose diet contained sufficient amounts of iodine. Fruits and vegetables, except spinach, generally have very low iodine contents. The iodine content of drinking water is too low to serve as a consistent contributor to iodine supply.12 In an iodine-deficient environment, the locally grown food will also have a low iodine content. Some foods, beverages, and drugs, such as multivitamins, minerals, and antacids, have coating or coloring agents that contain iodine.

Medical and Surgical Treatment of Endemic Goiter - - 19 Low supply of dietary iodine is the main cause of development of endemic goiter. Because it is difficult to measure the iodine content of foods, the adequacy of dietary iodine is usually determined by the measurement of urinary excretion of iodine. This measurement represents the ratio between concentrations of iodine and creatinine in casual urine samples. 13 Two or more casual urine samples from the same individual taken on consecutive days are recommended to allow for variation in creatinine content." Experience has shown that the iodine concentration in early-morning urine specimens adequately reflects an individual's iodine status. In addition, iodine concentration per liter of urine bears a 1:I relationship with iodine per gram of creatinine and is now adopted as the standard in field studies by WHO.3 Measuring iodine concentration per liter of urine helps avoid the cumbersome measurement and calculation of the iodinecreatinine ratio. In nonendemic areas, the urinary iodine measurement is at least 100 ug/L. Severe iodine deficiency is considered to occur with a daily iodine excretion of less than 20 IlgIL; moderate deficiency, 20 to 49 IlglL; and mild deficiency, 50 to 99 IlgIL.15.16 The prevalence of endemic goiter varies with the severity of iodine deficiency (Table 3-5). Increasing iodine consumption in endemic areas has resulted in a reduction in goiter prevalence. The persistence of goiter in some areas with adequate iodine prophylaxis and the unequal geographic distribution of goiter in iodine-deficient areas suggest the existence of other goitrogenic factors. Natural goitrogens were first found in vegetables of the Brassica family, including cabbage, turnips, and rutabagas. Their antithyroid action is related to the presence of thioglucosides, which, after digestion, release thiocyanate and isothiocyanate. These compounds have goitrogenic actions by inhibiting iodide transport in the thyroid gland. A particular thioglucoside, goitrin, is also found in the weeds growing in pastures in Finland and Tasmania. 17 Cyanoglucosides are another important group of naturally ?ccurring goitrogens found in several staple foods in the tropICS, namely cassava, maize, bamboo shoots, and sweet potatoes. They are converted to the goitrogen thiocyanate after digestion. Flavonoids from millet, a staple food in Sudan, are also known to have antithyroid activity. IS The consumption of millet in Sudan and cassava in Zaire was found to aggravate the severity of the goiter endemism in these places.'? Protein malnutrition coexists frequently with endemic goiter. Studies of malnourished individuals in endemic areas show alterations in thyroid morphology and functions, suggesting that malnutrition has a goitrogenic effect.P

Pathophysiology of Endemic Goiter Endemic goiter is the end result of the physiologic and morphologic changes in the thyroid gland as an adaptation to an insufficient supply of dietary iodine. When iodine intake is low, thyroid hormone synthesis is impaired. This impairment leads to an increased thyroidal clearance of iodide from the plasma and decreased urinary excretion of iodide, an adaptation toward iodine conservation. T3, being three to four times more potent than T 4 but containing only three fourths as much iodine as T 4, is preferentially synthesized over T 4 . There is also increased peripheral conversion of T 4 to T321 Clinical euthyroidism is thus maintained, but biochemically the pattern of low serum T4, elevated TSH, and normal or supranormal T 3 is often found. 22 . 24 In severe thyroid failure, such as that in endemic cretinism, serum T3and T 4 concentrations are low and serum TSH concentration is markedly elevated. In less severe thyroid endemism, serum T3 and T 4 concentrations may remain normal. The serum TSH level may also be normal or moderately elevated, and there may be an exaggerated TSH response to thyrotropin-releasing hormone (TRH) simulation, implying an increase in the pituitary reserve of TSH and subclinical hypothyroidism. Such changes are thought to be mediated through an elevation in the serum TSH level. However, a wide variation in the level of TSH has been observed in normal and goitrous individuals in endemic areas.P Such dissociation between goiter size and biochemical findings suggests the po~sible role of circulating thyroid growth factors, such as epidermal growth factors, or an autoimmune process in the pathogenesis of goiter." Activity of thyroid growth-promoting i~unoglo~ulin (TGI) has been demonstrated in patients With sporadic and endemic goiter.'? However, conflicting results were obtained, and the methods of detection of such activity have been criticized, with this uncertainty leaving an unsettled role of TGI in goitrogenesis.P-"

Morphologic Changes in Endemic Goiter An increase in thyroid gland mass often accompanies the physiologic changes in response to iodine deficiency. Generalized epithelial hyperplasia occurs, with cellular

20 - - Thyroid Gland hypertrophy and reduction in follicular spaces. In chronic iodine deficiency, the follicles become inactive and distended with colloid accumulation. These changes persist into adult life, and focal nodular hyperplasia may develop, leading to nodule formation." Some nodules retain the ability to secrete thyroid hormone and form hot nodules. Others do not retain this ability, become inactive, and form cold nodules. Necrosis and scarring result in fibrous septa, which contribute to the formation of multinodular goiter.

Clinical Presentation and Diagnosis Goiter is classified according to the size of the thyroid gland on inspection and palpation, and the following grading system was proposed by WHO in 196032 : Stage 0: no goiter Stage Ia: goiter detectable only by palpation and not visible even when the neck is fully extended Stabe Ib: goiter palpable but visible only when the neck is fully extended Stage II: goiter visible with the neck in the normal position; palpation is not needed for diagnosis

FIGURE 3-2. Classification of goiter size. 1, Stage Ia: goiter palpable but not visible. 2, Stage Ib: goiter visible when neck extended. 3, Stage II: goiter visible in normal neck extension. 4, Stage III: goiter visible at a distance. (From Perez C, Scrimshaw NS, Munoz JA. Technique of endemic goitre surveys. In: Endemic Goiter, Monograph Series No. 44. Geneva, Switzerland, World Health Organization, 1960, p 369.)

Stage III: very large goiter that can be recognized at a considerable distance (Fig. 3-2) Because of observer variation in the measurement of goiter by inspection and palpation, the WHOIUNICEFI ICCIDD Consultation on IDD indicators in November 1992 recommended a simplified classification of goiter by combining the previous stages la and Ib into a single grade (grade 1) and combining stages II and III into grade 2. 3 The sum of grades 1 and 2 is taken as the total goiter rate. The simplicity of this assessment allows for easy training of field staff in public health surveys. • Grade 0: no palpable or visible goiter • Grade 1: a mass in the neck that is consistent with an enlarged thyroid that is palpable but not visible when the neck is in the neutral position; it also moves upward in the neck as the subject swallows • Grade 2: a swelling in the neck that is visible when the neck is in a neutral position and is consistent with an enlarged thyroid when the neck is palpated In areas of mild endemicity where the goiter rate is low and goiters are generally small (i.e., grade 1 or bordering on either grade 0 or 2), interobserver variations can be as high as 40%. Ultrasonography is therefore recommended by WHO as a safe, noninvasive method for providing a more precise and objective measurement of thyroid volume than inspection and palpation." The most common form of goiter in children is a diffuse thyroid enlargement. Nodularity may occur at a young age, and the finding of a small, solitary, palpable nodule in adolescence is common. Some diffuse goiters persist into adulthood, or the main bulk of the goiter may be replaced by multiple nodules that form a multinodular goiter, simulating a bag of marbles on palpation. Functionally, the individual often remains clinically euthyroid despite biochemical evidence of hypothyroidism, with low or normal serum T4 concentrations and minimally elevated serum TSH levels. Scintigraphy of the thyroid in endemic areas may show marked heterogeneity in the uptake of radioiodine and formation of hot or cold nodules. Autonomous function of the nodules leads to failure of 1311 or 1231 suppression with T 3 and absence of TSH response to TRH. Hyperthyroidism in older patients with endemic goiter may be precipitated by iodination and cause Jodbasedow hyperthyroidism.>' Endemic cretinism is a sequela of severe iodine deficiency in which intrauterine growth is affected by deficiencies of maternal T4 and dietary iodine. The infant is born with mental retardation and either (1) a predominantly neurologic syndrome of hearing and speech defects and varying degrees of characteristic stance and gait disorders or (2) predominant hypothyroidism and stunted growth. These changes are preventable with iodine prophylaxis but are not curable once they have occurred. Mechanical problems often arise in patients with huge goiters that cause tracheal deviation and compression. Large, substernal, or retrosternal goiter can cause venous congestion and the development of collateral venous circulation on the chest wall (Fig. 3-3). Surgical treatment is indicated in such patients. The presence of hard nodules suggests possible malignant disease, although an increase in the number of thyroid cancers in endemic goiter remains controversial.v-"

Medical and SurgicalTreatment of Endemic Goiter - - 21

FIGURE 3-3. Large goiter with thoracic inlet obstruction. (From

DeSmetMP. Pathological anatomy of endemic goiter. In: Endemic Goiter, Monograph Series No. 44. Geneva, Switzerland, World Health Organization, 1960, p 338.)

Follicular and anaplastic carcinoma are more common in areas of endemic goiter. The diagnosis is often delayed in such patients because goiters are so common in iodine-deficient areas. Fine-needle aspiration biopsy helps select patients for

thyroidectomy.'?

Treatment and Prophylaxis The occurrence of endemic goiter can be prevented by supplying an adequate amount of iodine in the diet and eliminating goitrogens and malnutrition. Iodination of salt is the preferred method of prophylaxis because salt consumption is consistent and universal, the technology of iodination is simple, and its production is easy to regulate. It was first successfully introduced in Switzerland and in the state of Michigan in 1921.38 Iodine in the form of potassium iodide is added to table salt in varying amounts ranging from 1 to 10,000 parts of salt to 1 to 200,000 depending on local factors such as customary consumption of salt. Potassium iodate is preferred in humans because of its increased stability." Epidemiologic surveys have confirmed that there is a dramatic reduction in the prevalence of goiter and progressive disappearance of endemic cretinism within several years after introduction of salt iodination programs."

Countries such as the United States, the United Kingdom, New Zealand, Australia, the Netherlands, Norway, and Sweden have completely eliminated IDDs.41 Difficulties in implementation occur in countries where locally inexpensive noniodized salt is available and government programs to increase iodine consumption are lacking. Iodination of vegetable oil is the principal alternative used in developing countries and in areas where salt is not customarily used, such as the New Guinea highlands.f It is also used as a short-term intervention while an iodized-salt program is being established. One intramuscular injection containing 480 mg of iodine provides adequate amounts of iodine for up to 3 years. Oral administration of iodized oil has the advantage of avoiding injections, but its duration of action is shorter and more variable, depending on absorption of iodine through the gastrointestinal tract." An oral dose of 1 mL (containing 480 mg of iodine) provides adequate iodine for 1 to 2 years after a single administration. An increased incidence of thyrotoxicosis occurs after increased iodine consumption. This increase was observed in Tasmania after bread iodination in 1966 and was most evident in older people." The thyrotoxicosis was attributed to the presence of autonomous nodules or underlying hyperthyroidism in persons with long-standing endemic goiters. Overall, however, the long-term correction of iodine deficiency not only abolishes endemic goiter but also reduces the incidence of toxic nodular goiters. Therefore, the occurrence of thyrotoxicosis does not outweigh the enormous benefits of iodine prophylaxis in endemic regions. However, iodination does have some risk in individuals older than 45 years with goiter, because hyperthyroidism may develop. At the World Summit for Children in 1990, which was attended by 71 heads of state and government, WHO, UNICEF, and ICCIDD established the target of virtual elimination of IDDs by the year 2000 and universal salt iodination in affected countries by the end of 1995.45 Efforts have been made to reduce the cost of salt iodination by reducing the price of potassium iodate and the manufacturing cost of the spray-mixing equipment for salt iodination. At present, the cost of salt iodination is approximately $0.05 per person per year. Campaigns have been launched in affected countries to analyze the existence and the severity of the problem and to convince governments, salt producers, and other relevant bodies of the costeffectiveness and benefits of salt iodination. Funds have been raised to help developing countries start programs of salt iodination.i" A 1998 global survey by WHO reported that 85% of the total number of countries affected by IDD have either formed legislation on salt iodization to start implementing national plans for iodination of all salt and introducing legislation to prohibit the sale of uniodized salt'? or have plans of action for controlling IDD. Data also showed that of the 5 billion people living in countries with IDD, 68% have access to iodized salt and 65% of these countries have laboratory facilities to monitor urinary iodine status and salt iodine levels. America is the region that is closest to virtual elimination of IDD, with more than 90% of the total population consuming iodized salt. For the patient with hypothyroidism and endemic goiter, the functional and neurologic changes are irreversible.

22 - - Thyroid Gland Iodine supplementation during the first 6 months of life, however, has been shown to prevent some of the neurologic problems and also to cause regression in the size of endemic goiter in young children and adolescents.f In adults with large, diffuse, or nodular goiters, T4 therapy suppresses TSH secretion and in 50% to 87% of patients causes involution of the hyperplastic tissue and a 20% decrease in goiter size." Surgical treatment is indicated in diffuse or nodular goiters in the following situations: (1) large size or increase in size while the individual is receiving TSH suppression treatment; (2) mechanical obstruction to the trachea, esophagus, or thoracic inlet, such as in retrostemal or intrathoracic goiter; (3) toxic change; (4) suspected or proven malignant change; and (5) cosmetic reasons. Subtotal thyroidectomy, near-total, and total thyroidectomy are acceptable operations, and the indications are the same as those for patients with sporadic goiters.P Radioiodine therapy has been used to reduce the size of euthyroid goiters and to control toxicity in the presence of autonomously functioning tissue in multinodular goiters.51•52 However, large doses of radioiodine are usually required because of the low levels of uptake in these large multinodular goiters, which are also more radioresistant than diffuse toxic goiters." Surgical treatment is preferred for most patients because it eliminates the bulk of the goiter, corrects the functional abnormality, removes possible malignant neoplasms, and avoids long-term complications of radioiodine therapy.

Conclusion In conclusion, endemic goiter is preventable and is a public health problem worldwide, affecting 13% of the world's population. Iodination is cost-effective, and although it results in a transient increase in hyperthyroidism, overall the benefits greatly outweigh the risks. Significant progress has been achieved in a global effort in eliminating IDD in the last decade, with 68% of the 5 billion people living in countries with IDD having access to iodized salt. The global rates of goiter, mental retardation, and cretinism are falling. For established goiters, treatment with thyroid hormone is helpful in some patients in stabilizing or decreasing goiter size. Thyroidectomy becomes indicated for mechanical and cosmetic reasons or because of possible or documented malignancy.

Acknowledgment The author is grateful to Mrs. Pat Soong for providing technical assistance in the preparation of the chapter and Ms. Veronica Chan for typing the manuscript.

REFERENCES I. WHOfUNICEFIICCIDD. Progress Towards the Elimination of Iodine Deficiency Disorders (lDD). Document WHOINHD/99.4. Geneva, Switzerland, World Health Organization, 1999. 2. Delange F, Bastani S, Benmiloud M, et aI. Definitions of endemic goiter and cretinism, classification of goiter size and severity of endemias, and survey techniques. In: Dunn IT, Pretell EA, Daza CH, et aI (eds), Towards the Eradication of Endemic Goiter, Cretinism, and Iodine Deficiency, No. 502. Washington,DC, Pan American Health Organization, 1986,p 373.

3. WHOfUNICEFIICCIDD. Indicators for assessing iodine deficiency disorders and their control through salt iodization. Document WHOI NUT/94.6. Geneva, Switzerland, World Health Organization, 1994. 4. Hetzel BS, Dunn IT, Stanbury 18 (eds), The Prevention and Control of Iodine Deficiency Disorders. Amsterdam, Elsevier, 1987. 5. Fierro-Benitez R, et al. Long-term effects of correction of iodine deficiency on psychomotor and intellectual developments. In: Dunn IT, Pretell EA, Daza CH, et al (eds), Towards the Eradication of Endemic Goiter, Cretinism, and Iodine Deficiency. Washington DC, Pan American Health Organization, 1986, p 182. 6. Kelly FC, Snedden WW. Prevalence and geographical distribution of endemic goiter. In: Endemic Goiter, Monograph Series No. 44. Geneva, Switzerland, World Health Organization, 1960, p 27. 7. WHOfUNICEFIICCIDD. Global Prevalence of Iodine Deficiency Disorders. In: Micronutrient Deficiency Information System (MDIS), No.1. Geneva, Switzerland, World Health Organization, 1993. 8. Ma T, et al. The present status of endemic goiter and endemic cretinism in China. Food Nutr Bull 1982;4:13. 9. Gaitan E, Nelson NC, Poole GV. Endemic goiter and endemic thyroid disorders. World 1 Surg 1991;15:205. 10. Clements FW. Health significance of endemic goiter and related conditions. In: Endemic Goiter, Monograph Series No. 44. Geneva, Switzerland, World Health Organization, 1960, p 235. II. World Health Organization. Trace Elements in Human Nutrition and Health. Geneva, Switzerland, World Health Organization, 1996. 12. Koutras DA, Papapetrou PD, Yataganas X, et al. Dietary sources of iodine in areas with and without iodine deficiency goiter. Am 1 Clin Nutr 1970;23:870. 13. Bourdoux P, Thilly C, Delange F, et al. A new look at old concepts in laboratory evaluation of endemic goiter. In: Dunn IT, Pretell EA, Daza CH, et aI (eds), Towards the Eradication of Endemic Goiter, Cretinism, and Iodine Deficiency, No. 502. Washington, DC, Pan American Health Organization, 1986, p 115. 14. Furnee CA, van der Haar F, West CE, et al. A critical appraisal of goiter assessment and the ratio of urinary iodine to creatinine for evaluating iodine status. Am 1 Clin Nutr 1994;59: 1415. 15. Stanbury IB, Hetzel B. Endemic Goiter and Endemic Cretinism. New York, Wiley, 1980. 16. Gaitan E. Iodine deficiency and toxicity. In: White PL, Selvey N (eds), Proceedings of the Western Hemisphere Nutrition Congress IV. Acton, MA, Publishing Sciences, 1975, p 56. 17. Gaitan E. Environmental Goitrogenesis. Boca Raton, FL, CRC Press, 1989. 18. Gaitan E, Lindsay RH, Reichert RD, et al. Antithyroid and goitrogenic effects of millet: Role of C-glycosylflavones. 1 Clin Endocrinol Metab 1989;68:707. 19. Vanderpas 1, Bourdoux P, Lagasse R, et al. Endemic infantile hypothyroidism in a severe endemic goiter area of Central Africa. Clin Endocrinol 1984;20:327. 20. Ingenbleek Y, Luypaert B, De Nayer P. Nutritional status and endemic goiter. Lancet 1980;I :388. 21. Greer MA, Grimm Y, Studer H. Qualitative changes in the secretion of thyroid hormones induced by iodine deficiency. Endocrinology 1968;83:1193. 22. Delange F, Camus M, Ermans AM. Circulating thyroid hormones in endemic goiter. 1 Clin Endocrinol Metab 1972;34:891. 23. Pharoah POD, Lawton NF, Ellis SM, et al. The role of triiodothyronine (T3 ) in the maintenance of euthyroidism in endemic goiter. Clin Endocrinol 1973;2:193. 24. Bachtarzi H, Benmiloud M. TSH regulation and goitrogenesis in severe iodine deficiency. Acta Endocrinol (Copenh) 1983;103:21. 25. Weber P, Krause U, Gaffga G, et al. Unilateral pulsatile and circadian TSH release in euthyroid patients with endemic goiter. Acta Endocrinol (Copenh) 1991;124:386. 26. Tseng YC, Burman KD, Schaudies RP, et al. Effects of epidermal growth factor on thyroglobulin and adenosine 3',5'-monophosphate production by cultured human thyrocytes. 1 Clin Endocrinol Metab 1989;69:771. 27. Medeiros-Neto GA, Halpern A, Cozzi ZS, et al. Thyroid growth immunoglobulins in large multinodular endemic goiters: Effect of iodized oil. 1 Clin Endocrinol Metab 1986;63:644. 28. Vitti P, Chiovato L, Tonacchera M, et al. Failure to detect thyroid growth-promoting activity in immunoglobulin G of patients with endemic goiter. 1 Clin Endocrinol Metab 1994;78:1020. 29. Zakarija M, McKenzie 1M. Do thyroid growth-promoting immunoglobulins exist? 1 Clin Endocrinol Metab 1990;70:308.

Medical and Surgical Treatment of Endemic Goiter - - 23 30. Weetman AP. Is endemic goiter an autoimmune disease? J Clin Endocrinol Metab 1994;78:1017. 31. Studer H, Peter HJ, Gerber H. Natural heterogeneity of thyroid cells: The basis for understanding thyroid function and nodular goiter growth. Endocr Rev 1989;10:125. 32. Perez C, Scrimshaw NS, Munoz JA. Technique of endemic goiter surveys. In: Endemic Goiter, Monograph Series No. 44. Geneva, Switzerland, World Health Organization, 1960, p 369. 33. World Health OrganizationlInternational Council for Control of Iodine Deficiency Disorders. Recommended normative values for thyroid volume in children aged 6-15 years. Bull WHO 1997;75:95. 34. Steward JC, Vidor GI, Butterfield IH, et al. Epidemic thyrotoxicosis in northern Tasmania. Aust N Z J Med 1972;3:203. 35. Wahner HW, Cuello C, Correa P, et al. Thyroid carcinoma in an endemic goiter area--Cali, Columbia. Am J Med 1966;40:58. 36. Harach HR, Escalante DA, Onativia A, et al. Thyroid carcinoma and thyroiditis in an endemic goiter region before and after iodine prophylaxis. Acta Endocrinol (Copenh) 1985;108:55. 37. Lowhagen T, Granberg PO, Lundell G, et aI. Aspiration biopsy cytology (ABC) in nodules of the thyroid gland suspected to be malignant. Surg Clin North Am 1979;59:3. 38. Marine D, Kimball OP. Prevention of simple goiter in man. JAMA 1921;77: I 068. 39. Sooch SS, Deo MG, Karmarkar MG, et al. Prevention of endemic goiter with iodized salt. Bull WHO 1973;49:307. 40. Aykroyd WR. Endemic goiter. In: Conquest of Deficiency Disease: Achievements and Prospects. Geneva, Switzerland, World Health Organization, 1970, p 78. 41. UNICEF. Nutrition. In: Adamson P (ed), The Progress of Nations1994. New York, UNICEF, 1994, P 8. 42. Hetzel BS, Thilly CH, Fierro-Benitez R, et al. Iodized oil in the

43. 44. 45. 46. 47. 48.

49.

50. 51. 52. 53.

prevention of endemic goiter and cretinism. In: Stanbury JB, Hetzel BS (eds), Endemic Goiter and Endemic Cretinism. New York, Wiley, 1980, p 513. Bautista S, Barker PA, Dunn JT, et al. The effects of oral iodized oil on intelligence, thyroid status, and somatic growth in school-aged children from an area of endemic goiter. Am J Clin Nutr 1982;35:127. Connolly RJ, Vidor GI, Stewart JC. Increase in thyrotoxicosis in endemic goiter area after iodination of bread. Lancet 1970; 1:500. United Nations. World Declaration on the Survival, Protection, and Development of Children, and Plan of Action. New York, United Nations, 1990. Grant JP. Iodine Deficiency Disorders on the Run. New York, UNICEF, 1994. UNICEF. The State of the World's Children, 1995. Oxford, England, Oxford University Press for UNICEF, 1995. Hintze G, Emrich K, Kobberling J. Treatment of endemic goiter due to iodine deficiency with iodine, levothyroxine, or both: Results of a multi centre trial. Eur J Clin Invest 1989; 19:527. Wilders-Truschning MM, Warnkrob H, Leb G, et al. The effect of treatment with levothyroxine or iodine on thyroid size and thyroid growth-stimulating immunoglobulins in endemic goiter patients. Clin Endocrinol 1993;39:281. Roher HD, Goretzki PE. Management of goiter and thyroid nodules in an area of endemic goiter. Surg Clin North Am 1987;67:233. Bockisch A, Jamitzky T, Derwanz R, et al. Optimized dose planning of radioiodine therapy of benign thyroidal disease. J Nucl Med 1993;34:1632. Nygaard B, Hegedus L, Gervil M, et al. Radioiodine treatment of multinodular nontoxic goiter. BMJ 1993;307:828. Shapiro B. Optimization of radioiodine therapy of thyrotoxicosis: What have we learned after 50 years? J Nucl Med 1993;34: 1638.

Sporadic Nontoxic Goiter Maha AI-Fehaily, MD • Orlo H. Clark, MD

The term goiter (L. guttur, throat) refers to an enlarged thyroid gland, but what constitutes "enlargement" is often not clearly defined.' Goiters can be classified according to prevalence of the disease, thyroid function, location of the thyroid (neck or mediastinum), morphology, or underlying etiology (Table 4-1). Sporadic nontoxic goiter (SNG) may be diffuse or nodular, is associated with normal thyroid function, develops in subjects living in an iodine-sufficient area, and does not result from an inflammatory or neoplastic process.' Endemic goiter is present when more than 10% of the population living in a specific geographic area have a goiter. The term sporadic goiter is used in regions with normal iodine intake and a lower prevalence of goiter. Worldwide, endemic goiter is the most common endocrine disorder, occurring in more than 850 million people, or 7% of the world population. It occurs almost exclusively in the iodine-deficient areas. Sporadic goiter affects about 5% of the adult population in the United States.' Sporadic nodular goiter is a common clinical entity. Patients often present with small, diffuse, or nodular goiters or have a solitary palpable nodule. In addition, recent studies using high-resolution ultrasonography and previous autopsy studies document that up to 50% of the general population have thyroid nodules, even when the thyroid gland is normal to palpation. In addition, about 50% of individuals with a solitary thyroid nodule to palpation have other smaller thyroid nodules by ultrasound examination." There are numerous unresolved issues regarding the etiology, natural history, evaluation, and optimal management of persons with goiter' Goiter represents an impairment of the thyroid gland's function, growth, and size. The problems that arise in patients with goiter include the following: • Growth of the gland causing compressive symptoms or cosmetic problems (Fig. 4-1) • Development of subclinical or overt thyrotoxicosis or hypothyroidism • Risk of malignancy in nodular goiter • Cretinism or congenital hypothyroidism, as occurs in as many as 10% of infants born in areas of severe iodine deficiency'

24

Causes of Goiter Several mechanisms, including the interplay of intrinsic and extrinsic factors in the thyroid, cause goiter. The goitrogenic process involves genetic, environmental, dietary, endocrine, and other factors. The most common worldwide cause of endemic nontoxic goiter, as mentioned earlier, is iodine deficiency. In patients with sporadic goiter, the cause is usually unknown. Sporadic goiter is a result of environmental or genetic factors that do not affect the general population. The various types of goiter are listed in Table 4-1.

Genetic Factors The thyroid gland contains a series of enzymes that are essential for the biosynthesis and secretion of thyroid hormones. A defect in any of these hormones can result in diminished hormone synthesis and a condition of goiter formation known as dyshormonogenesis. Because the defects are inherited disorders, dyshormonogenesis is also known as familial goiter. These enzyme defects may be partial or complete. Patients with a more severe enzymatic defect may develop goiter and cretinism early in life. When the defect is partial or less severe, goiter often develops during adolescence or later in life, and these individuals are usually euthyroid. Although familial clustering of goiter is well recognized, no simple mode of inheritance has been recognized. Familial euthyroid goiter has recently been linked to a multinodular nontoxic goiter (MNG1) locus on chromosome 14q.6,7 Concordance rates for simple goiter in female monozygotic twins have been reported higher than in female dizygotic twins (42% and 13%, respectively)." The ageadjusted cumulative risk for simple goiter from birth to age 43 years was 0.53 for female monozygotic twins and 0.18 for female dizygotic twins." These facts provide evidence of a genetic component of the etiology of goiter. Tissue refractoriness to thyroid hormones due to a thyroid-stimulating hormone receptor (TSHR) defect is a rare cause of familial goiter. A germline mutation on codon 727 of the TSHR gene on chromosome 14q31 is specifically

Sporadic Nontoxic Goiter - -

associated with toxic multinodular goiter.1O•11 Similar somatic cell mutations may activatean intrinsic growth control system leading to goiter.

Environmentally Induced Goiter IODINE DEFICIENCY

Endemic goiter is discussed in Chapter 3. An inadequate adaptive mechanism of the thyroid to protect from severe iodine deficiency results in the development of goiter. These adaptive mechanisms include increased iodide clearance, increased production of triiodothyronine (T3) relative to thyroxine (T4 ) , and increased mass of thyroid follicular cells. I Pregnancy increases the need for iodine and T4, which results from significant transfer of thyroid hormone from the mother to the fetus and also increased iodide loss in the urine. 12 Iodine-deficient thyroid tissue is more growth responsive to thyroid-stimulating hormone (TSH) than is iodine-replete thyroid tissue." Thyroid cellular growth is also influenced by the higher human chorionic gonadotropin serum concentrations that occur during pregnancy.14 ENVIRONMENTAL AND OTHER FACTORS

The development of sporadic goiter is influenced by many factors. Thiocyanate is a well-known goitrogen produced from cigarette smoke and vegetable foods such as cassava and cabbage. These goitrogens, however, seem to be of clinical importance only in areas of iodine deficiency.

The intake of an excessive amount of iodine inhibits thyroid peroxidase and results in the Wolff-Chaikoff effect. The normal gland is usually able to escape from this effect by inhibition of iodide uptake so that the intrathyroidal iodide level falls and organification resumes. However, in some patients with underlying thyroid disorders, the thyroid is unable to adapt to iodide excess and goiter and hypothyroidism ensue (iodide-induced myxedema). Patients at risk of goiter and or hypothyroidism due to failure to escape from iodine inhibition of thyroid hormonogenesis are those with Hashimoto's thyroiditis or those with reduced or damaged thyroid tissue after thyroidectomy or after radiation exposure to the neck. 15•16 Excess iodine intake in contrast media may also cause goiter with hyperthyroidism (Jodbasedow hyperthyroidism). Numerous medications also have antithyroid and goitrogenic effects. Amiodarone, which is rich in iodine (37%), has been associated with induction of hypothyroidism and hyperthyroidism. Lithium causes hypothyroidism by inhibiting (1) colloid formation stimulated by cyclic adenosine monophosphate and (2) the release of thyroid hormone from the gland. Contrast media used for imaging are rich in iodine and may cause transient hypothyroidism but not goiter. Ionizing radiation, either externally or with therapeutic doses of radioactive iodine (1 311), usually destroy thyroid tissue, causing hypothyroidism, but smaller doses (200 to 1500 rad) increase the risk of developing nodular goiter, thyroiditis, or thyroid cancer. I

Pathogenesis Goiter Growth Goiters result from focal follicular cell hyperplasia at one or multiple sites within the thyroid gland. Iodine deficiency works synergistically with other causes of goiter but does not appear to change the basic mechanisms of goitrogenesis. There is a positive correlation between the total DNA content of the goiter and goiter weight. The increased amount of interstitial tissue and colloid formation usually contributes little to the total goiter growth. An intrinsically abnormal growth pattern of some thyroid cells is usually the driving force behind goiter growth. Heterogeneous subpopulations of thyrocytes proliferate at different rates. Both extrathyroidal and intrathyroidal growth factors modulate goiter formation. Under physiologic in vivo conditions, TSH is the most important stimulator of thyroid growth and function. A decrease in iodine intake leads to decreased synthesis and

FIGURE 4-1. Frontal (A) and side (B) views of a 45-year-old man with long-standing multinodular goiter in an endemic area.

A

25

B

26 - - Thyroid Gland secretion of thyroid hormones. As a result, the serum TSH level increases, stimulating thyroid growth.'? The increase must be relatively short lived and intermittent because most patients have normal serum TSH levels. Other growth factors are obviously involved since the sizes of various nodules vary considerably in the same patient. Furthermore, goiters may grow despite administration of T 4 in doses that reduce the serum TSH level to a subnormal level or in patients with toxic nodular goiter. Thus, thyroid growth-modulating factors in addition to TSH are involved in thyroid growth. Some growth factors (e.g., insulin-like growth factor 1, epidermal growth factor, and fibroblast growth factor) have a growth-promoting effect, whereas others (e.g., transforming growth factor [TGF]-~ and activin A) inhibit growth.l" Increased expression of ras and other protooncogenes may also contribute to goiter growth.'?

Nodule Formation With increasing age, most thyroid glands and goiters become nodular. Initially, many goiters are diffuse; however, with intermittent stimulation, some diffuse goiters outgrow their blood supply and become nodular (Fig. 4_2).20,21 Some thyroid cells are more sensitive to growth factors and become larger nodules. If these nodules trap and organify iodine, the nodule may be "hot" or autonomous rather than "cold." Hot nodules are associated with TSHR and gsp mutations. In general, formation of thyroid nodules can be explained by the following mechanisms.

Heterogeneous Subpopulation of Thyrocytes with Different Proliferation Rates that Cause Focal Hyperplasia or Nodular Transformation Time. Derwahl and Studer investigated the pathogenesis of this heterogeneity and suggested that multinodular goiters are "true" benign neoplasms due to intrinsically higher growth rates of some thyrocytes.Pr" However, most, but not all, nodules in a multinodular goiter are polyclonal when compared to true neoplasms." Kopp and associates have also documented that both monoclonal and polyclonal nodules can be present within the same multinodular thyroid gland."

Somatic Mutations and Clonality of the Thyroid Nodules. Different somatic mutations of the TSHR have been identified." Mutations in oncogenes such as ras appear

to be early mutations because they are present in both benign and malignant thyroid nodules. Scarring, Necrosis, and Hemorrhage. For thyroid nodules to grow, angiogenesis and new vessel formation are required. These newly formed capillary vessels are often fragile and are sometimes unable to adequately supply the growing thyroid tissue, This may result in areas of ischemic necrosis and hemorrhage within the goiter. Inflammation and granulation tissue replace the necrotic areas, ultimately resulting in fibrosis, scarring, and calcification. The resulting network of inelastic fibrous bands' connective tissue leads to nodularity because it interferes with smooth growth of thyroid parenchyma. 1

Autonomy Thyroid nodules that. function in the presence of a suppressed blood TSH level are referred to as autonomous or hot nodules. Autonomous function and autonomous growth mayor may not be related. Thus, cold nodules and hot nodules within a nodular goiter may have exactly the same growth potential and may respond or be refractory to TSHsuppressive T 4 treatment." Some thyroid follicular cells take up and organify iodine in the absence of TSH, causing hot or autonomous nodules. As previously mentioned, these nodules usually have either TSHR mutations or, less commonly, gsp mutations. When these nodules reach a certain size and secrete increased amounts of thyroid hormone, the patient develops subclinical and then overt hyperthyroidism. This may occur either spontaneously or after exposure to an excessive amount of iodine (Jodbasedow hyperthyroidismj.F

Natural History The natural history of nontoxic goiter varies. Children in endemic areas generally have diffuse goiters, whereas sporadic goiters tend to develop at an older age and tend to be nodular. Patients with multinodular goiter are usually older and have larger goiters than do patients with diffuse or uninodular goiters. The growth rate of thyroid nodules is usually slow, but some goiters increase up to 20% yearly." Rapid growth of a nodule is usually caused by hemorrhage or cyst formation. One must also be concerned about malignant tumors such as a thyroid lymphoma or a poorly differentiated or anaplastic cancer. Patients with goiters appear to have a slightly higher risk of thyroid malignancy (discussed later). Patients with multinodular goiters and suppressed TSH levels are generally older and have a higher plasma-free T 4 level and larger goiters than those with multinodular goiters and a normal TSH. Up to 10% of patients with euthyroid nodular goiter eventually develop hyperthyroidism.P-'?

Intervention Versus Observation FIGURE 4-2. Nodular goiter can involve either one or both lobes of the thyroid gland.

Clear indications for operation (whether the patient is symptomatic or potentially symptomatic) include the following: 1. Large goiter with obstructive symptoms such as shortness of breath and dysphagia

Sporadic Nontoxic Goiter - - 27 2. Substernal goiter, especially with abnormal flow-loop study 3. Large nodule (>4 em), because patients with large solitary or dominant nodules are more likely to be symptomatic and have an increased risk of cancer" 4. Disfigurement 5. Family history of thyroid cancer or exposure to lowdose therapeutic radiation Patients with a family history of thyroid cancer are much more likely to develop thyroid cancer. Familial medullary thyroid cancer, with or without multiple endocrine neoplasia, should always be excluded. Familial non-medullary thyroid cancer, with or without Cowden's syndrome (multiple hamartomas, breast cancer, colon cancer, and nodular goiter), Gardner's syndrome,familial polyposis coli, or Carney's syndrome (schwannomas, myxomas, adrenal tumors, pigmented skin lesions), should also be considered. Exposure to low or moderate doses of therapeutic radiation also dramatically increases the risk of thyroid cancer." Previous investigations document that exposure to as little as 6 cGy radiation increases the risk of thyroid cancer sixfold.33 The risk increases as the dose of radiation increases to 2000 cGy. Higher doses of radiation, such as 5000 to 6000 cGy, result in hypothyroidism, but thyroid cancer does not appear to increase appreciably, probably because the thyroid cells are destroyed." Younger children who receive radiation are most likely to develop thyroid cancer. A genetic predisposition to developing thyroid cancer after exposure to low-dose therapeutic radiation or radiation fallout may be present.34,35 Other factors that increase the risk of thyroid cancer include rapid enlargement of the thyroid nodule, presence of a dominant firm or hard nodule, ipsilateral vocal cord paralysis, fixation to adjacent structures, ipsilateral enlarged lymph nodes, and development of new thyroids nodule in young «20-year-old) or older (>60-year-old) individuals. When two of these factors suggest a possible cancer, the likelihood of thyroid malignancy approaches 100%.36 Fineneedle aspiration (FNA) biopsy for cytology often confirms the diagnosis but should be done only when it will alter therapy. Computed tomography (CT) scanning should be used selectively in patients with very large, fixed, or substernal goiters when the limits cannot be determined clinically. CT scanning is also indicated in patients with dysphagia, dyspnea, or hemoptysis. In patients with small to moderate-sized nodular goiters without other risk factors for malignancy, an ultrasound of the thyroid gland may be helpful for subsequent comparison regarding growth, but CT or magnetic resonance imaging (MRI) scanning is not neccessary." Although the risk of malignancy in unselected patients with multinodular goiter has been considered to be about I % to 3%, there are several studies that suggest thyroid nodules within a multinodular goiter harbor malignancy at a rate similar to those with solitary thyroid nodule (5% to 10%).38-40 These figures, however, include small papillary carcinomas of questionable clinical significance. Evidence suggests that clinically important thyroid carcinoma occurs in fewer than I% of patients, given the high prevalence of multinodular goiter and the very low incidence of clinical thyroid carcinoma."

Studies indicated that about 4% of the population in the United States has multinodular goiters and that 4% of these patients harbor thyroid cancer; therefore, the estimated prevalence would be around 1.6 per 1000. However, the estimated incidence of clinical thyroid cancer is only 0.025 to 0.05 cases per 1000, suggesting that less than I of 30 histologic microcarcinomas leads to clinically relevant disease each year." In other investigations, occult thyroid cancers have been found at autopsy in up to 36% of patients.v" The clinical significance of latent cancers (autopsy studies) and incidental occult cancers «I em in diameter) found by histologic examination after removal of benign thyroid tissues has been questioned" The incidence of clinical thyroid cancer (>10 mm) obtained in mass screening is about 0.2%, and in some investigations, only about 2% or 3% of these thyroid microcancers «10 mm) ever develop into clinical thyroid cancer." Thus, occult thyroid cancers do not represent an appreciable risk to an individual when found incidentally and confined to the thyroid gland. Recent clinical studies document that about 4% to 6% of nonpalpable nodules biopsied under ultrasound guidance are malignant.Fv' To date, there are, to our knowledge, no longitudinal studies that document any clinical benefit to performing a biopsy of nonpalpable nodules less than I em in diameter; however, occult thyroid tumors are presumably of more concern in high-risk individuals with a family history of thyroid cancer or individuals with a history of exposure to low-dose therapeutic radiation.P

How Patients with Sporadic Nontoxic Goiter Should be Managed Ultrasound examination is helpful for establishing the presence of multiple, nonpalpable, and cystic nodules and provides a baseline for subsequent comparison regarding nodule growth. Certain ultrasonic features in nodular goiter may suggest malignancy. Several groupS54.56,57 have recommend performing an ultrasound-guided FNA biopsy of any nodule that is I em or larger, hypoechoic, or solid or has microcalcifications, irregular borders, central blood flow, or an absent halo. Some clinicians suggest performing a biopsy on the dominant nodule. Papini and colleagues'? have documented invasive cancers (T4) in nodules smaller than I em; thus, the size cutoff may not be accurate in predicting the malignant potential of all nodules, and suspicious nodules on ultrasound examination should be considered for biopsy. A selective approach seems to be indicated; that is, most occult nodules can be followed by ultrasound examination, but biopsy should be performed in suspicious occult nodules or nodules in high-risk patients.

Clinical Evaluation History Patients with nontoxic goiter are usually asymptomatic and seek medical advice because of a thyroid mass. Goiters are more common in women than men (,.,4:1). Sporadic goiters from dyshormonogenesis and endemic goiter due to iodine deficiency are usually first noted during childhood and

28 - - Thyroid Gland

continue to grow with age. Other causes of sporadic goiter rarely occur before puberty and do not have a peak age of occurrence. Thyroid nodules increase in incidence with age. The natural history of nontoxic goiter is characterized by slow, often progressive or intermittent growth, with many patients eventually becoming symptomatic. Although most goiters are present for years, sudden, rapid growth of a discrete nodule or thyroid lobe, as previously mentioned, should suggest possible hemorrhage into a nodule or dedifferentiation to a poorly differentiated thyroid carcinoma, anaplastic carcinoma, or possible lymphoma. Benign goiters are rarely painful or grow quickly unless recent hemorrhage into a nodule has occurred. Some goiters, especially in patients with chronic lymphocytic thyroiditis, may cause a choking sensation or pain radiating to the ear. Symptoms may be caused by compression of structures in the neck and superior mediastinum. Obstructive symptoms are more likely to occur in patients with a substernal goiter. As the substernal goiter continues to grow, the thoracic inlet may become occluded, a phenomenon known as the thyroid cork. This is because substernal goiter is confined between the sternum and the vertebral bodies and may displace or impinge on the trachea, esophagus, recurrent laryngeal nerve, and, rarely, the superior vena cava or the cervical sympathetic chain. Tracheal compression is generally asymptomatic until critical narrowing has occurred (""75% of cross-sectional area) to about 4 mm. Nocturnal or positional dyspnea and dyspnea with exertion suggest that they are caused by substernal goiter. Anxiety when raising one's arm above one's head with a reddened face and distended neck veins (positive Pemberton sign) suggests superior mediastinal obstruction. Upper respiratory tract infection or hemorrhage into a nodule or cyst may exacerbate upper airway obstruction and result in acute respiratory distress. Dysphagia occurs in about 20% of patients with substernal goiters. Ischemia and stretching of the recurrent laryngeal nerve with vocal cord dysfunction may cause hoarseness in about 4% of patients with benign substernal goiters, but cancer is more likely in these patients. Compression of the venous outflow through the thoracic inlet and sympathetic chain, causing Homer's syndrome, may rarely occur.58.59 Review of the possible causative factors of goiter and the differential diagnosis of nontoxic goiter include family history of benign or malignant thyroid disorder, a history of living in an endemic goiter area or of intake of goitrogens, a history of radiation exposure or, rarely, metastases from other organs to the thyroid gland. The last one occurs most often in patients with lung cancer, breast cancer, hypernephroma, and melanoma.

Physical Examination In general, the size of a smaller goiter is overestimated, whereas the size of larger goiters is underestimated. Thyroid enlargement is often best observed when the patient swallows. A visible goiter has usually reached a size of 30 to 40 mL (""1.5- to 2-fold increase in the size of a normal thyroid gland). One should determine whether the thyroid gland is symmetrical or a solitary nodule, a multinodular goiter, or a dominant nodule in a multinodular goiter. Does the goiter

move with swallowing, or is the goiter fixed? Are the nodules hard, firm, or soft? Is there associated lymphadenopathy? One should also determine whether there is any tracheal deviation. As previously mentioned, one can document whether there is venous obstruction by having the patient elevate his or her arms above the head. If the neck veins become prominent or the face become flushed, this is a positive Pemberton sign. 60.61 One should also evaluate the patients for signs of hypothyroidism, hyperthyroidism, or possible other medical disorders. Features that suggest malignancy include vocal cord paralysis, fixed firm nodules, or associated lymphadenopathy.F Occasionally, a patient with recurrent laryngeal nerve palsy can have a benign nodule.P

Diagnosis The differential diagnosis of a patient with nodular goiter includes benign nodular goiter, Hashimoto's thyroiditis, follicular adenoma, and carcinoma. The laboratory evaluation of a patient with a thyroid nodule or a nodular goiter should begin with a TSH measurement to determine whether the patient is euthyroid, hypothyroid, or hyperthyroid. The degree of thyroid dysfunction is often mild or subclinical, with only an isolated TSH abnormality. The diagnosis of thyrotoxicosis should be considered in all, but particularly in elderly, patients with long-standing nodular goiter and/or atrial fibrillation. In some, usually elderly, patients, the diagnosis of hyperthyroidism is not clinically apparent (apathetic hyperthyroidism). TSH is suppressed to a variable degree, and characteristically the plasma T 3 level is elevated, whereas the plasma T4level is normal (T 3 thyrotoxicosis). When the thyroid gland is only moderately enlarged and firm, Hashimoto's thyroiditis should be considered. A blood test documenting increased levels of antithyroid peroxidase antibodies or thyroglobulin antibodies helps confirm the diagnosis. Ultrasound often reveals a heterogeneous thyroid gland. FNA is helpful when there is a discrete nodule within the firm thyroid gland. Some clinicians recommend evaluating calcitonin levels in patients with nodular goiter, but most believe it is not cost-effective.v' A chest radiograph often brings attention to cervical or substernal goiter due to tracheal deviation. Occasionally, fine calcifications in a nodular goiter suggest the presence of a papillary carcinoma. Ultrasound, as previously mentioned, is particularly helpful in patients who are to be followed to assess and monitor the size of a nodule or the goiter. Some clinicians recommend treating patients with small or moderate-sized euthyroid goiter with thyroid hormone. In about 25% of these patients, the goiter decreases in size, and in others, the growth rate may decrease (see Chapter 8). CT or MRI scanning of the neck and superior mediastinum in patients with substernal or fixed goiters may reveal tracheal deviation or compression (Fig. 4_3).65.66 Thyroid scintigraphy is not indicated for the assessment of nodular goiter unless the patient has a suppressed TSH or treatment with 1311 is being considered. Euthyroid patients with large goiters usually have low iodine uptake so that a large dose of radioiodine is required.

Sporadic Nontoxic Goiter - - 29

FIGURE 4-3. CT scan of a patient with a large goiter. Note the evidence of severe tracheal compression and deviation to the right side (arrow),

Such treatment is only rarely indicated but has recently been reported to be more effective than TSH suppression." Evidence of airway obstruction can be obtained by a flowvolume loop tracing. A barium swallow is rarely indicated unless other causes of dysphagia are considered. The role of FNA has previously been discussed. We recommend FNA for selected patients with multinodular goiter who have a dominant nodule within a multinodular goiter, a large (>4 ern) nodule, nodules with ultrasonic features suggestive of malignancy, a rapidly enlarging nodule, and suspicious complex thyroid nodules (biopsy the solid component).

Treatment The available treatment options are thyroidectomy, treatment with T4, and radioiodine (Table 4_2).68,69 The treatment goals for a patient with a nodular goiter include relief of local compressive symptoms or cosmetic deformity, prevention of progressive thyroid enlargement, and removal of possible but uncommon coexistent thyroid cancer, Asymptomatic euthyroid patients with moderate-sized goiters can be safely observed. When there is any concern about malignancy, patients should have an FNA. T4 therapy is effective in reducing the size of goiters in patients with iodine deficiency or those with subclinical hypothyroidism. About half of the clinicians in the United States and Europe use TSH suppression therapy in patients with euthyroid goiters. The benefits of such therapy are disputed.P?' T4 therapy seems to be more efficacious in patients with small goiters." T4 therapy carries the risk of inducing thyrotoxicosis, especially when there is autonomy of the thyroid gland. In addition, T4 administration to the elderly may predispose to cardiac arrhythmias and cardiovascular insufficiency.P"? Long-term T4 therapy with hyperthyroidism

is also associated with reduction in bone density, especially in postmenopausal women. 78-81 This does not appear to be a problem in euthyroid patients with low-normal or minimally suppressed TSH levels. Radioiodine therapy of nontoxic goiters is used primarily in Europe. It is not standard practice in the United States unless a patient is a poor surgical risk or has chemical evidence of thyrotoxicosis. Radioiodine therapy does, however, result in goiter reduction, producing a 40% to 60% decrease in volume within 2 years. Such studies have led to an increased use of 1311 in euthyroid or hyperthyroid elderly patients with multinodular goiter, to both decrease the size and, in the latter, to treat the hyperthyroidism.P:" Prior administration of human recombinant TSH may reduce the dose of radioactive iodine required for successful therapy. 1311therapy may be particularly helpful in selected patients (see Table 4_2).84-86 Side effects of radioiodine therapy include the following: 1. Hypothyroidism (20% to 30% at 5 years)" 2. Radiation thyroiditis-the symptoms are usually mild and transient but may be devastating due to acute thyroid swelling in patients with large substernal goiters83,87 3. Induction of Graves' disease in about 5% of patients, presumably due to release of antigens stimulating an autoimmune responsev" 4. Temporary thyrotoxicosis-to avoid this possibly catastrophic complication in poor-risk patients, antithyroid drugs should be administered to patients with hyperthyroidism several weeks before the administration of 1311and/or treatment with ~-adrenergic blocking agents after 1311 administration The potential risk of radiation-associated thyroid cancer is low when 1311 therapy is used in elderly patients. Recent evidence suggests that radioiodine therapy in patients with hyperthyroidism slightly increases the risk of thyroid cancer. Unfortunately, these thyroid cancers appear to be more aggresslve.v" Younger patients with large goiters should be treated surgically because this provides definitive therapy and rapid resolution of the problem. We recommend radioiodine ablation therapy only in selected patients with nodular goiter such as those who are poor surgical risks.A prospective trial comparing the results of surgery and 1311therapy in elderly patients would be of interest. Thyroidectomy offers a rapid reduction in goiter and resolution of the problem with minimal risk when the operation is done by an experienced thyroid surgeon. Thyroidectomy also provides tissue for histologic examination and radiation exposure is not necessary. The procedure is the preferred treatment for patients with substernal goiter because goiter may swell after 1311 therapy, and there appears to be a higher risk of cancer in substernal goiters; such goiters are generally not accessible for FNA. 65,93,94 The indications of thyroidectomy in patients with goiter are listed in Table 4-2.

Extent of Surgery The extent of thyroidectomy depends on the type of goiter. For patients with unilateral goiter, lobectomy-isthmectomy is sufficient. When the goiter is bilateral, we recommend total lobectomy on the side with the largest mass and subtotal, near-total, or total lobectomy of the contralateral side.

30 - - Thyroid Gland

The reason for this recommendation is that 10% to 20% of patients develop recurrent goiter.95,96 However, when the surgeon is not completely happy about the status of the parathyroid glands and/or recurrent laryngeal nerve on the initial side, less than total thyroidectomy is recommended on the contralateral side. Total thyroidectomy has been suggested to be as safe as subtotal thyroidectomy when the operation is performed by an experienced thyroid surgeon, with a 1% to 2% incidence of injury to the recurrent laryngeal nerve and 0.5% to 5% of hypoparathyroidism. Surgical morbidity is highest in patients with very large goiters, those with invasive cancers with extensive lymphadenopathy, those with substernal goiter, and those who undergo reoperation because of recurrent goiter,97-100 Proponents of subtotal thyroidectomy believe that leaving about 2 to 4 g of thyroid tissue results in little risk of recurrence.'?' Proponents of total thyroidectomy suggest that there is a low morbidity rate of total thyroidectomy, that there

is no risk of recurrence, and that patients after total or neartotal thyroidectomy should take thyroid hormone. 102-104 We believe that total lobectomy on one side and subtotal resection on the other side, leaving a small ("'4- to 5-g) remnant of thyroid tissue posteriorly (Hartley-Dunhill operation) is the preferred operation. If recurrence were to occur after the Hartley-Dunhill operation. reoperation would be required only on one side. The administration of iodide in sporadic multinodular goiter is not recommended and may result in thyrotoxicosis (Jodbasedow phenomenon). 105

Summary Sporadic nontoxic goiter is a relatively common problem. Iodine deficiency is the most common cause of goiter worldwide. Sporadic goiter due to environmental or genetic factors is also relatively common. Nontoxic goiter can be

SporadicNontoxic Goiter - - 31 caused by iodine excess, goitrogens, genetic defects, and other unknown factors. Determination of the serum TSH level is essential in all patients with thyroid enlargement. Imaging of the thyroid gland by ultrasonography to document baseline characteristic for future comparison is helpful and FNA is recommended selectively. CT or MRI scanning is recommended only for substernal goiters or fixed lesions. Patients with a family history of thyroid cancer, those with a history of radiation exposure, and patients with large clinically suspicious nodules suggesting cancer may be treated surgically without further investigation. Patients with clinically important compressive symptoms or cosmetic concern should be managed by surgery. Radioiodine can be helpful in poor-risk patients and those with toxic nodular goiter. Asymptomatic low-risk patients should be observed. We recommend doing total lobectomy on one side and subtotal lobectomy on the other side (Hartley-Dunhill operation) to minimize complications, yet avoid recurrent goiter.

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32 - - Thyroid Gland 44. Park SH, Suh EH, Chi JG. A histopathologic study on 1,095 surgically resected thyroid specimens. Jpn J Clin OncoI1988;18:297. 45. Mitselou A, Vougiouklakis T, Peschos D, et al. Occult thyroid carcinoma: A study of 160 autopsy cases. The First Report for the Region of Epirus-Greece. Anticancer Res 2002;22:427. 46. Yamamoto Y, Maeda T, Izumi K, Otsuka H. Occult papillary carcinoma of the thyroid: A study of 408 autopsy cases. Cancer 1990;65: 1173. 47. Lang W, Borrusch H, Bauer L. Occult carcinomas of the thyroid: Evaluation of 1,020 sequential autopsies. Am J Clin PathoI1988;90:72. 48. Komorowski RA, Hanson GA. Occult thyroid pathology in the young adult: An autopsy study of 138 patients without clinical thyroid disease. Hum PathoI1988;19:689. 49. Harach HR, Franssila KO, Wasenius VM. Occult papillary carcinoma of the thyroid: A "normal" finding in Finland-a systematic autopsy study. Cancer 1985;56:531. 50. Chong PY. Thyroid carcinomas in Singapore autopsies. Pathology 1994; 26:20. 51. Yamashita H. Occult microcancer and clinical cancer. In: Clark OH, Noguchi S (eds), Hyoid Cancer: Diagnosis and Treatment. St. Louis, Quality Medical, 2000, p 105. 52. Hagag P, Strauss S, Weiss M. Role of ultrasound-guided fine-needle aspiration biopsy in evaluation of nonpalpable thyroid nodules. Thyroid 1998;8:989. 53. Khurana KK, Richards VI, Chopra PS, et al. The role of ultrasonographyguided fine-needle aspiration biopsy in the management of nonpalpable and palpable thyroid nodules. Thyroid 1998;8:511. 54. Papini E, Guglielmi R, Bianchini A, et al. Risk of malignancy in nonpalpable thyroid nodules: Predictive value of ultrasound and color-Doppler features. J Clin Endocrinol Metab 2002;87:1941. 55. Lupoli G, Vitale G, Caraglia M, et al. Familial papillary thyroid microcarcinoma: A new clinical entity. Lancet 1999;353:637. 56. Nakhjavani M, Gharib H. Diffuse nontoxic and multinodular goiter. Curr Ther Endocrinol Metab 1997;6:109. 57. Peccin S, de Castro JA, Furlanetto TW, et al. Ultrasonography: Is it useful in the diagnosis of cancer in thyroid nodules? J Endocrinol Invest 2002;25:39. 58. Rios Zambudio A, Rodriguez Gonzalez JM, Carrasco Prats M, et al. Superior vena cava syndrome caused by multinodular goiter. Rev Clin Esp 2000;200:208. 59. Anders HJ. Compression syndromes caused by substernal goitres. Postgrad Med J 1998;74:327. 60. Anders H, Keller C. Pemberton's maneuver-a clinical test for latent superior vena cava syndrome caused by a substernal mass. Eur J Med Res 1997;2:488. 61. Auwaerter PG. The Pemberton and Maroni signs. Ann Intern Med 1997;126:916. 62. Lassaletta Atienza L, Melchor Diaz MA, Gavilanes Plasencia J, et al. [Thyroid nodules: Factors suggestive of malignancy). Acta Otorrinolaringol Esp 1997;48:220. 63. Cerise EJ, Randall S, Ochsner A. Carcinoma of the thyroid and nontoxic nodular goiter. Surgery 1952;31:552. 64. Niccoli P, Wion-Barbot N, Caron P, et al. Interest of routine measurement of serum calcitonin: Study in a large series of thyroidectomized patients. The French Medullary Study Group. J Clin Endocrinol Metab 1997;82:338. 65. Netterville JL, Coleman SC, Smith JC, et al. Management of substernal goiter. Laryngoscope 1998;108:1611. 66. Jennings A. Evaluation of substernal goiters using computed tomography and MR imaging. Endocrinol Metab Clin North Am 2001;30:401. 67. Wesche MF, Tiel VB, Lips P, et al. A randomized trial comparing levothyroxine with radioactive iodine in the treatment of sporadic nontoxic goiter. J Clin Endocrinol Metab 2001 ;86:998. 68. Hurley DL, Gharib H. Evaluation and management of multinodular goiter. Otolaryngol Clin North Am 1996;29:527. 69. Arici C, Dertsiz L, Altunbas H, et al. Operative management of substernal goiter: Analysis of 52 patients. Int Surg 2001;86:220. 70. Gharib H, Mazzaferri EL. Thyroxine-suppressive therapy in patients with nodular thyroid disease. Ann Intern Med 1998;128:386. 71. Ross DS. Thyroid hormone suppressive therapy of sporadic nontoxic goiter. Thyroid 1992;2:263. 72. Lima N, Knobel M, Cavaliere H, et al. Levothyroxine suppressive therapy is partially effective in treating patients with benign, solid thyroid nodules and multinodular goiters. Thyroid 1997;7:691.

73. Glueck CJ, Streicher P. Cardiovascular and medical ramifications of treatment of subclinical hypothyroidism. Curr Atheroscler Rep 2003;5:73. 74. Burmeister LA, Flores A. Subclinical thyrotoxicosis and the heart. Thyroid 2002;12:495. 75. Mercuro G, Panzuto MG, Bina A, et al. Cardiac function, physical exercise capacity, and quality of life during long-term thyrotropinsuppressive therapy with levothyroxine: Effect of individual dose tailoring. J Clin Endocrinol Metab 2000;85:159. 76. Shapiro LE, Sievert R, Ong L, et al. Minimal cardiac effects in asymptomatic athyreotic patients chronically treated with thyrotropinsuppressive doses of t-thyroxine. J Clin Endocrinol Metab 1997;82:2592. 77. Perk M, O'Neill B1. The effect of thyroid hormone therapy on angiographic coronary artery disease progression. Can J Cardiol 1997; 13:273. 78. Sijanovic S, Kamer I. Bone loss in premenopausal women on longterm suppressive therapy with thyroid hormone. Medscape Women's Health 2001;6:3. 79. Jodar E, Martinez-Diaz-Guerra G, Azriel S, Hawkins F. Bone mineral density in male patients with t-thyroxine suppressive therapy and Graves' disease. CalcifTissue Int 2001;69:84. 80. Nuzzo V, Lupoli G, Esposito Del Puente A, et al. Bone mineral density in premenopausal women receiving levothyroxine suppressive therapy. Gynecol Endocrinol 1998;12:333. 81. Knudsen N, Faber J, Sierbaek-Nielsen A, et al. Thyroid hormone treatment aiming at reduced, but not suppressed, serum thyroid-stimulating hormone levels in nontoxic goiter: Effects on bone metabolism amongst premenopausal women. J Intern Med 1998;243: 149. 82. Bonnema SJ, Knudsen DU, Bertelsen H, et al. Does radioiodine therapy have an equal effect on substernal and cervical goiter volumes? Evaluation by magnetic resonance imaging. Thyroid 2002;12:313. 83. Huysmans D, Hermus A, Edelbroek M, et al. Radioiodine for nontoxic multinodular goiter. Thyroid 1997;7:235. 84. Huysmans DA, Buijs WC, van de Ven MT, et al. Dosimetry and risk estimates of radioiodine therapy for large, multinodular goiters. J Nucl Med 1996;37:2072. 85. Beckers C. \311 therapy of toxic and non-toxic goiters. Q J Nucl Med 1999;43:291. 86. Maurer AH, Charkes ND. Radioiodine treatment for nontoxic multinodular goiter. J Nucl Med 1999;40:1313. 87. Nygaard B, Faber J, Hegedus L. Acute changes in thyroid volume and function following IJI I therapy of multinodular goitre. Clin Endocrinol (Oxf) 1994;41:715. 88. Nygaard B, Knudsen JH, Hegedus L, et al. Thyrotropin receptor antibodies and Graves' disease, a side effect of 13\1 treatment in patients with nontoxic goiter. J Clin Endocrinol Metab 1997;82:2926. 89. Hall P, Lundell G, Holm LE. Mortality in patients treated for hyperthyroidism with iodine 131. Acta Endocrinol (Copenh) 1993; 128:230. 90. Franklyn JA, Maisonneuve P, Sheppard M, et al. Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: A populationbased cohort study. Lancet 1999;353:2111. 91. Franklyn JA, Maisonneuve P, Sheppard MC, et al. Mortality after the treatment of hyperthyroidism with radioactive iodine. N Engl J Med 1998;338:712. 92. Tezelman S, Grossman RF, Siperstein AB, Clark OH. Radioiodineassociated thyroid cancers. World J Surg 1994;18:522. 93. Nervi M, Iacconi P, Spinelli C, et al. Thyroid carcinoma in intrathoracic goiter. Langenbecks Arch Surg 1998;383:337. 94. Torre G, Borgonovo G, Amato A, et al. Surgical management of substernal goiter: Analysis of 237 patients. Am Surg 1995;61:826. 95. Rojdmark J, .Jarhult J. High long-term recurrence rate after subtotal thyroidectomy for nodular goitre. Eur J Surg 1995;161:725. 96. Cohen-Kerem R, Schachter P, Sheinfeld M, et al. Multinodular goiter: The surgical procedure of choice. Otolaryngol Head Neck Surg 2000; 122:848. 97. Thomusch 0, Machens A, Sekulla C, et al. Multivariate analysis of risk factors for postoperative complications in benign goiter surgery: Prospective multicenter study in Germany. World J Surg 2000; 24:1335. 98. Wilson DB, Staren ED, Prinz RA. Thyroid reoperations: Indications and risks. Am Surg 1998;64:674; discussion, 678. 99. Makeieff M, Rubinstein P,Youssef B, et al. Repeat surgery for thyroid nodules (excluding cancer and hyperthyroidism). Ann Chir 1998; 52:970.

Sporadic Nontoxic Goiter - 100. Shen W, Kebebew E, Duh QY, Clark OH. Substernal goiter. Arch Surg 2004; 139:656. 101. Mattioli FP, Torre GC, Borgonovo G, et al. Surgical treatment of multinodular goiter. Ann Ital Chir 1996;67:341. 102. Gough IR, Wilkinson D. Total thyroidectomy for management of thyroid disease. World J Surg 2000;24:962. 103. Delbridge L, Guinea AI, Reeve TS. Total thyroidectomy for bilateral benign multinodular goiter: Effect of changing practice. Arch Surg 1999;134:1389. 104. Marchesi M, Biffoni M, Tartaglia F, et aJ. Total versus subtotal thyroidectomy in the management of multinodular goiter. Int Surg 1998;83:202.

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105. Vagenakis AG, Wang CA, Burger A, et aJ. Iodide-induced thyrotoxicosis in Boston. N Engl J Med 1972;287:523. 106. Robbins J, Schneider AB. Thyroid cancer following exposure to radioactive iodine. Rev Endocr Metab Disord 2000; 1:197. 107. Hahn K, Schnell-Inderst P, Grosche B, Holm LE. Thyroid cancer after diagnostic administration of iodine 131 in childhood. Radiat Res 2001;156:61. 108. Hall P, Holm LE. Late consequences of radioiodine for diagnosis and therapy in Sweden. Thyroid 1997;7:205.

Thyroiditis Geeta Lal, MD • Orlo H. Clark, MD

Thyroiditis is defined as an inflammatory disorder of the thyroid gland. It may result from a myriad of etiologies and is usually classified into acute, subacute, and chronic forms (Table 5-1). Each of these is associated with a distinct clinical presentation and histology. Medical therapy remains the mainstay of management of thyroiditis, but surgical treatment is warranted in certain specific circumstances.

Eikenella corrodens, and Corynebacterium species have also been cultured. Rare other implicated organisms include Mycobacteria, Salmonella, Aspergillus, and Actinomycoses species. J In general, (X- and p-hemolytic Streptococcus and anaerobes account for about 70% of cases. Pneumocystis carinii has been identified as the causative organism in patients with AIDS. HISTOLOGIC FEATURES

Acute (Suppurative) Thyroiditis Acute thyroiditis was first described by Bauchet in 1857 and accounted for approximately 0.1 % of thyroid surgeries before the advent of antibiotic therapy. J ETIOLOGY AND PATHOGENESIS

The thyroid gland has an innate resistance to infection due to its extensive blood and lymphatic supply, high iodide content, and fibrous capsule.' Despite these protective mechanisms, acute thyroiditis may be caused by infectious agents that seed the thyroid gland (1) by the hematogenous or lymphatic route, (2) by direct spread from persistent pyriform sinus fistulas or thyroglossal duct cysts, or (3) as a result of penetrating trauma to the thyroid gland.' Takai and associates first demonstrated that acute suppurative thyroiditiscan result from persistent pyriform sinus fistulas." Since then, several investigators have demonstrated that pyriform sinus fistulas are responsible for a large proportion of cases of recurrent acute thyroiditis. These fistulas are commonly believed to be fourth branchial pouch remnants and originate at the apex of the pyriform fossa.t The tract courses in an anteroinferior direction to end blindly in the perithyroidal space or the thyroid parenchyma-? as shown in Figure 5-1. As a result, infection may lead to acute thyroiditis or soft tissue abscesses, which can secondarily extend to the thyroid. Immunosuppression may be another risk factor for the disease and acute suppurative thyroid infections and necrosis have been described in patients with acquired immunodeficiency syndrome (AIDS)8 and those undergoing aggressive chemotherapy for hematologic malignancies." Oral cavity bacteria such as Staphylococcus and Streptococcus species and anaerobes are the most common causative organisms. Other bacteria such as Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae,

34

Acute thyroiditis usually arises in a normal thyroid gland, although occurrence in a multinodular gland is not uncommon.'? Histologically, the gland demonstrates an intense inflammatory response with numerous polymorphonuclear leukocytes and lymphocytes. II Necrosis of the thyroid gland and abscess formation often ensue. CLINICAL PRESENTATION

Acute suppurative thyroiditis is more common in children and young adults and occurs equally in both sexes. The disease is often preceded by an upper respiratory tract infection or otitis media. It is characterized by severe neck pain radiating to the jaws or ear, fever, chills, odynophagia, and dysphonia. Infants may present with respiratory distress and stridor secondary to tracheal compression caused by a thyroid abscess.'? Rarely, acute suppurative thyroiditis may cause transient vocal cord palsy.'? On physical examination, erythematous skin usually overlies an extremely tender thyroid gland. The patient holds the neck in a flexed position to avoid stretching the overlying strap muscles. Fluctuance indicates an underlying abscess. These findings are more frequent on the left side and reflect the left-sided predominance of pyriform sinus fistulas.'? This is thought to be due to embryologic asymmetry of the transformation of the fourth branchial arch to form the aortic and innominate arteries or to poor development of the ultimobranchial body on the right side of the embryo.i-" Acute suppurative thyroiditis can be complicated by systemic sepsis, tracheal or esophageal rupture, jugular vein thrombosis, laryngeal chondritis and perichondritis, or sympathetic trunk paralysis.!' DIFFERENTIAL DIAGNOSIS

Several other conditions that must be considered in the differential diagnosis include subacute painful thyroiditis,

Thyroiditis - -

Hashimoto's thyroiditis, suppurative lymphadenitis, thyroid carcinoma, thyroglossal duct or branchial cleft cyst, Ludwig's angina, and dissecting retropharyngeal abscess. Laryngeal and esophageal carcinomas have also been reported to present as acute thyroiditis.P'P These disorders can often be distinguished by clinical history, physical examination, and various diagnostic tests described in the following section. Lin and colleagues studied the clinical features that may help distinguish acute thyroiditis from aggressive malignant thyroid tumors and concluded that patients with malignancy were older and more likely to have a history of dysphonia, right thyroid lobe involvement, larger lesions, anemia, and sterile thyroid aspirates." DIAGNOSTIC TESTS

Blood tests reveal leukocytosis and an elevated erythrocyte sedimentation rate (ESR). Blood cultures are useful to identify

35

the causative organisms. Thyroid function tests are usually normal, although transient elevations of triiodothyronine (T3) and thyroxine (T4 ) may occur as a result of release of preformed hormone from the inflamed gland.'? Radioactive iodine uptake (RAIU) scans are usually normal, or there is decreased uptake due to suppression of thyroid-stimulating hormone (TSH) by the release of thyroid hormones. However, if a thyroid abscess is present, an area of decreased uptake will be seen on the scan. Ultrasound is helpful to distinguish solid from cystic lesions. Fine-needle aspiration (FNA) biopsy for Gram stain, culture, and cytology confirms the diagnosis and helps guide antibiotic therapy and diagnose underlying malignancy. Computed tomography scans not only aid in the diagnosis of acute thyroiditis but also help delineate the extent of infection. 18.19 If a persistent pyriform sinus fistula is suspected, a barium swallow demonstrates the anomalous tract with 80% sensitivity. False-negative results are usually due to edema around the tract orifice during acute infection. Hence, contrast studies should be performed after antibiotic therapy during the quiescent phase.P Direct laryngoscopy is also helpful in identifying the tract. TREATMENT

Patients should be treated with parenteral antibiotics based on the results of the Gram stain and culture. Abscesses are treated by drainage, either by aspiration with a wide-bore needle or open surgical drainage. In patients with pyriform sinus fistulas, complete resection of the sinus tract, including the area of the thyroid where the tract ends, is recommended. Miyauchi and coworkers have demonstrated that complete fistulectomy is essential for cure.? Methylene blue infiltration via a Fogarty catheter is sometimes used to cannulate the tract and facilitate its identification and dissection.P

Subacute Thyroiditis Painful (de Quervain's) Thyroiditis Painful thyroiditis is a transient inflammatory thyroid disorder that was first described by de Quervain in 19042 1 and is the most common cause of a painful thyroid gland. Other eponyms for this condition include granulomatous thyroiditis. subacute granulomatous thyroiditis. or pseudogranulomatous thyroiditis. ETIOLOGY AND PATHOGENESIS

FIGURE 5-1. Gastrografin swallow showing a fistula originating in the left pyriform sinus. The arrows indicate the fistula.

Painful thyroiditis is thought to be viral in origin or result from a post-viral inflammatory response. This theory is supported by the following observations: 1. The disorder is frequently preceded by a respiratory infection, is usually self-limiting, and has a seasonal distribution (summer and fall). 2. It is often associated with specific viral infection outbreaks such as coxsackievirus, mumps, measles, adenovirus, and infectious mononucleosis. 3. Cytopathic viruses have been cultured from thyroid tissue. 4. Viral antibodies have been detected in the sera of patients with the disease.F

36 - -

Thyroid Gland

There is also evidence for a genetic predisposition, manifested by its strong association with the HLA-B35 haplotype." A model of pathogenesis suggests that antigens (either directly from viruses or from damaged thyroid tissue) are presented by macrophages in the context of HLA-B35 and stimulate cytotoxic T lymphocytes. These lymphocytes proceed to damage thyroid follicular cells. This autoimmune process, however, is self-limiting. Antibodies directed against the TSH receptor have also been described, but they seem to be related to the inflammatory process and are not believed to cause the disease. HISTOLOGIC FEATURES

The inflammatory process may involve the entire gland or a single lobe. On cut section, the involved areas are firm and yellow-white. Microscopically, the changes vary with the stage of the disease and may overlap. Microabscesses, which result from neutrophil replacement of disrupted follicles, are commonly seen during the early inflammatory stage. Later, lymphocytes, histiocytes, and plasma cells are seen to accumulate around damaged follicles. Colloid (or fragments thereof) are surrounded by multinucleated giant cells, giving this disorder the designation of granulomatous thyroiditis, as shown in Figure 5-2. 11

high fever, tOXICIty, and pronounced edema leading to obstructive symptoms. The disorder classically progresses through four stages." The initial hyperthyroid phase, due to release of thyroid hormone, lasts 3 to 6 weeks and may be accompanied by symptoms such as tremors, sweating, palpitations, and heat intolerance in 50% to 70% of patients. Patients then progress to the second or euthyroid phase. Hypothyroidism, which is the hallmark of the third phase, occurs in about 20% to 30% of patients and lasts from weeks to months. The last phase is characterized by resolution of the disease and returns to the euthyroid state in more than 90% of patients. Of note, some patients may progress directly from the hyperthyroid phase to the recovery phase, without the intervening hypothyroid phase. A few patients develop recurrent disease. DIFFERENTIAL DIAGNOSIS

Disorders that mimic the presentation of subacute thyroiditis include hemorrhage into a thyroid nodule or cyst, acute suppurative thyroiditis, painful Hashimoto's thyroiditis, infected thyroglossal duct or branchial cleft cyst, and pseudothyroiditis." The last entity is produced by rapid growth of anaplastic or poorly differentiated thyroid malignancies.

CLINICAL PRESENTATION

DIAGNOSTIC STUDIES

Painful thyroiditis occurs more commonly in women (malefemale ratio of 1:3 to I :6) between 30 and 40 years of age. It is characterized by the sudden or gradual onset of unilateral or bilateral pain in the neck, which may radiate toward the mandible or ear and is exacerbated by swallowing or neck movement. Many patients report a preceding upper respiratory tract infection with low-grade fever, neck pain, dysphagia, and flu-like symptoms with malaise and myalgias. Physical examination reveals an enlarged, exquisitely tender thyroid gland that is firm, particularly in the acute phase. The overlying skin may be erythematous if the inflammation is severe. Rarely, patients may present with

In the early stages of the disease, TSH is decreased, and thyroglobulin, T 4, and T 3 levels are elevated due to the release of preformed thyroid hormone and colloid from destroyed follicles. In contrast with Graves' disease, T 4 and T 3 are elevated in proportions reflecting their intrathyroidal content." Thyroid antibody titers (antithyroglobulin, antimicrosomal, and TSH receptor antibody) are also elevated in 10% to 20% of patients, although they bear no relationship to the state of thyroid function. The most characteristic abnormality is an elevation of the ESR greater than 100 mm/hr. In fact, a normal ESR rules out active subacute thyroiditis.F RAID is also decreased «2% at 24 hours) even in euthyroid patients due to the destruction of the thyroid parenchyma and iodine-trapping mechanism and release of thyroid hormones with TSH suppression. RAID returns to normal as the process resolves. FNA biopsy may be useful in equivocal cases or to rule out malignancy or acute thyroiditis. Thyroid ultrasound shows areas of hypoechogenicity that disappear as the disease process resolves-" as demonstrated in Figure 5-3, and thyroid ultrasound has demonstrated usefulness in predicting autoimmune thyroid disease in a multicenter study. 29 TREATMENT

FIGURE 5-2. Histologic features of subacute granulomatous thyroiditis. The thyroidparenchyma contains a chronic inflammatoryinfiltrate with a multinucleate giantcell (upper left corner) and a colloid follicle (lower right corner). (From Cotran R, KumarY, Collins T, RobbinsSL reds], Robbins Pathologic Basis of Disease, 6th ed. Philadelphia, WB Saunders, 1999, p 1135.)

Painful thyroiditis is self-limited and usually resolves within a few months without specific therapy. Therefore, treatment is primarily symptomatic. Aspirin and other nonsteroidal anti-inflammatory drugs are often the initial medications of choice for pain relief. However, prednisone (40 mg/day) may be indicated for early relief of pain and swelling in more severe cases." These drugs suppress the inflammatory response but do not alter the underlying disease process. The dose is usually tapered after a week and then discontinued within 2 to 4 weeks. If pain and swelling recur during the taper or after withdrawal, the treatment is restarted.

Thyroiditis - - 37

A

B

FIGURE 5-3. Thyroid ultrasound (transverse) showing normal thyroid echogenicity (A) and subacute thyroiditis (B). In B, the thyroid is enlarged and shows reduced echogenicity, similar to surrounding strap muscles. Arrows indicate the thyroid surface. M = muscle; T = thyroid parenchyma; C = common carotid artery; TR = trachea; VC = vertebral column. (A and B, From Pedersen OM, Aardal NP, Larssen TH, et al. The value of ultrasonography in predicting autoimmune thyroid disease. Thyroid 2000; 10:251.)

Hyperthyroidism may rarely require treatment with Pblockers. Thyroid replacement may be needed in the hypothyroid phase, if patients are symptomatic. Therapy should be withdrawn and the patient re-evaluated after 6 months. Externalbeam radiation therapy was used to treat subacute thyroiditis in the past. However, this modality as been abandoned due to a slower and less predictable response than steroids, an approximately 25% failure rate, and the risk of thyroid cancer formation." Thyroidectomy is reserved for the rare patient who has a prolonged course not responsive to medical measures.

titers are typically higher than in patients with the sporadic variant. Postpartum thyroiditis is more likely to occur in successive pregnancies. Familial clustering of cases has also been reported," and a positive family history for postpartum thyroiditis can be elicited in up to 50% of patients.t'' Silent thyroiditis can also develop after exposure of the thyroid gland to therapeutic doses of external-beam radiation" or drugs such as interferon IX used in the management of chronic hepatitis."

Painless Thyroiditis Painless thyroiditis is also known as lymphocytic thyroiditis with spontaneously resolving hyperthyroidism, subacute lymphocytic thyroiditis, painless lymphocytic thyroiditis, painless thyroiditis, or silent thyroiditis. Painless thyroiditis may occur sporadically or in the postpartum period.

The thyroid gland may be asymmetrically enlarged on gross inspection. Microscopic examination reveals a multifocal inflammatory infiltrate, consisting chiefly of smalllymphocytes. Scattered areas of disrupted and collapsed thyroid follicles are also present. Unlike Hashimoto's thyroiditis, plasma cells and germinal centers are not conspicuous, and this feature is helpful in distinguishing the two conditions."

ETIOLOGY AND PATHOGENESIS

CLINICAL PRESENTATION

Both variations of subacute painless thyroiditis are considered to be autoimmune in origin. Like Hashimoto's thyroiditis, patients with painless thyroiditis have a high prevalence of anti-thyroid peroxidase (anti-TPO or antimicrosomal) antibodies and lymphocytic infiltration of the thyroid gland. 3D Furthermore, painless thyroiditis is also associated with other autoimmune conditions such as Sjogren's syndrome," autoimmune Addison's disease.F Graves' disease." and Hashimoto's thyroiditis." There is also evidence for a genetic predisposition with an association with HLA-DR3, -DR4, and -DR5 haplotypes.Y" The evidence supporting an autoimmune origin for postpartum thyroiditis is much stronger. This variant typically occurs at about 6 weeks' postpartum in women with high TPO antibody titers in early pregnancy. This timing is thought to coincide with a decrease in the normal immune tolerance of pregnancy and consequent rebound elevation of antibody titers.'? TPO antibodies mediate thyrocyte destruction via complement activation.t" Furthermore, the antibody

Painless thyroiditis is also more common in women (malefemale ratio, 1:1.5 to 3) and occurs between 30 and 60 years of age. The clinical course parallels painful thyroiditis and is characterized by four stages-thyrotoxic (occurs 1 to 3 months' postpartum), euthyroid, hypothyroid (occurs at 3 to 6 months' postpartum), and euthyroid again (occurs by 1 year). However, only about 30% of all patients follow this classic sequence of events. Thyrotoxicosis or hypothyroidism alone is the presenting features in about 35% and 40% of patients, respectively." When hyperthyroid symptoms occur, they are transient and characterized by tachycardia, palpitations, heat intolerance, nervousness, and weight loss. The hypothyroid phase is more pronounced in terms of symptoms. Physical examination demonstrates a normalsized or slightly enlarged, slightly firm, nontender gland.

HISTOLOGIC FEATURES

DIAGNOSTIC TESTS

The results of thyroid function studies correlate with the clinical stage of disease. In the early phases, TSH is

38 - -

Thyroid Gland

suppressed and T 4 and T 3 levels are elevated, similar to painful thyroiditis. In contrast with subacute painful thyroiditis, the ESR is normal or only mildly elevated (usually <40 mm/hr) and the leukocyte counts are normal. Titers of thyroid autoantibodies, particularly TPO antibodies, are often elevated. RAID is typically low or suppressed. Approximately 45% of patients with postpartum thyroiditis also demonstrate increased hypoechogenicity of the thyroid gland on thyroid ultrasound at 4 to 8 weeks, and this finding increases to 86% at 15 to 25 weeks' postpartum." DIFFERENTIAL DIAGNOSIS

Graves' disease, factitious hyperthyroidism, granulomatous thyroiditis, and struma ovarii are some of the conditions that should be considered in the differential diagnosis of painless thyroiditis. Most of these disorders can be distinguished based on careful history, physical examination, laboratory evaluations, and RAIU scans, as outlined earlier. TREATMENT

Specific treatment is sometimes required in patients with severe symptoms. ~ blockers are useful in controlling symptoms of hyperthyroidism. Antithyroid drugs are not necessary since there is no increase in thyroid hormone synthesis. Corticosteroids have been used to shorten the hyperthyroidism phase but are generally not helpful." Thyroid hormone replacement is indicated in patients with hypothyroidism. Thyroidectomy is indicated only for the rare patients with recurrent, disabling episodes of thyroidiris." RAI ablation of the thyroid may also be used in these rare cases." CLINICAL COURSE

Despite similarities in clinical presentation, painless thyroiditis and postpartum thyroiditis differ with respect to outcomes. In a long-term study, only 2.5% of patients with subacute thyroiditis had a goiter, but 48% of patients with postpartum thyroiditis had residual thyroid abnormalities (goiter, positive TPO, or hypothyroidism) at the conclusion of follow-up." Up to 23% of patients with postpartum thyroiditis have been reported to develop permanent hypothyroidism at long-term follow-up.fv'? Women with high TPO antibody titers, hypothyroid-phase presentation, and thyroid hypoechogenicity on ultrasound are more likely to develop permanent hypothyroidism. 50 Furthermore, patients with postpartum thyroiditis are more likely to have recurrent episodes of thyroiditis, as seen in Figure 5-4. As such, patients with a history of postpartum thyroiditis should be screened periodically for the development of permanent hypothyroidism. The presence of TPO antibodies and antithyroglobulin antibodies in pregnancy have been suggested as possible markers to predict the development of postpartum thyroiditis. However, Kuijpens and associates have shown that the TPO antibody has a positive predictive value of only 33%.51 Other markers such as soluble CD4 (a product of CD4+ T lymphocytes) may be more promising. Lack of a physiologic decrease in the levels of these markers in the third trimester was predictive of recurrent postpartum thyroiditis in women with a previous history of the disease.S

A

B

c

FIGURE 5-4. Incidence of postpartum thyroiditis in three groups

of women: With a history of postpartum thyroiditis in a previous pregnancy (A); with a prior history of type 1 diabetes mellitus (B); and those who were antibody positive in a prior pregnancybut did not develop postpartum thyroiditis (C). (From Stagnaro-Green A. Recognizing, understanding, and treating postpartum thyroiditis. Endocrinol Metab Clin North Am 2000;29:417.)

Atypical Subacute Thyroiditis Variants of subacute thyroiditis, designated atypical subacute thyroiditis, have also been described. Patients may present with features of painful thyroiditis but lack the HLA-B35 haplotype" or present with painless thyroiditis without evidence of thyroid autoimmunity. 54 Further studies are needed to characterize this variant adequately.

Chronic Thyroiditis Lymphocytic (Hashimoto's) Thyroiditis Lymphocytic thyroiditis was first described in four female patients by Hashimoto in 1912 as struma lymphomatosaa transformation of thyroid tissue to lymphoid tissue.f Subsequently, Roitt and colleagues demonstrated thyroid autoantibodies in patients with this disease.56 Chronic autoimmune thyroiditis has two different clinical manifestations: an atrophic form and a goitrous form. The latter is also known as Hashimoto's thyroiditisi' and is the most common inflammatory disease of the thyroid. Prevalence rates of chronic autoimmune thyroiditis vary depending on the criteria used for diagnosis. Autopsy studies demonstrate that 40% to 45% of women and 20% of men in the United States and United Kingdom have focal thyroiditis.P-" Most autopsy and thyroid antibody studies document Hashimoto's thyroiditis in approximately 17% of women in the United States and Japan.r'' However, a recent review of population-based studies with strict criteria for the diagnosis of Hashimoto's thyroiditis reported a prevalence of 0.79% in adults with an incidence of 22 per 100,000 inhabitants."! ETIOLOGY AND PATHOGENESIS

T Cells, Autoantibodies, and Apoptosis. The autoimmune process is thought to be initiated by the activation of CD4+ T (helper) lymphocytes with specificity for thyroid antigens.v' However, the mechanism of activation of these cells is not completely understood. One hypothesis centers on molecular mimicry and postulates that viral or bacterial infection with proteins similar to thyroid proteins leads to the activation of thyroid-specific lymphocytes. In fact, serologic evidence of such infection has been documented in patients with chronic autoimmune thyroiditis,63.64 but the cumulative evidence is not convincing.P

Thyroiditis - - 39

The other more widely accepted hypothesis suggests that thyroid cells themselves present intracellular proteins to helper T cells. This theory is supported by the observation that, unlike normal thyrocytes, thyroid cells of patients with autoimmune thyroiditis express the major histocompatibility complex (MHC) class II proteins (HLA-DR, HLA-DP, and HLA-DQ),66 which are required for antigen presentation to CD4+ helper cells. Activated T cells release the cytokine interferon y,67 which further promotes the expression of these MHC molecules and thus perpetuates the autoimmune process.f Once activated, T cells can recruit cytotoxic CD8+ T cells to the thyroid. Hypothyroidism is believed to result mainly from the destruction of thyrocytes by these cells. T-helper cells also recruit self-reactive B cells to the thyroid and stimulate them to secrete autoantibodies. These antibodies are directed against three main antigens: thyroglobulin, TPO (microsomal antigen), and the thyrotropin receptor." Antibodies to the sodium-iodine symporter (NIS) have also been reported in patients with Hashimoto's thyroiditis.s? although more recent studies indicate that they are not as important as previously thought." Autoantibodies can also cause hypothyroidism via blockage of their ligands, fixation of complement, and antibody-mediated cytotoxicity (natural killer cells). However, the relative contributions of these mechanisms to thyrocyte destruction in vivo remain unresolved." Apoptosis (programmed cell death) has also been implicated in the pathogenesis of Hashimoto's thyroiditis. Thyrocytes from patients with this disease consistently show increased expression of death receptors such as FasL and decreased levels of the anti-apoptotic molecule Bcl2 when compared to cells from patients with Graves' disease." Environmental Factors. The prevalence of chronic autoimmune thyroiditis parallels that of iodine intake." Supplementation in iodine-deficient areas increases thyroid lymphocytic infiltration and prevalence of thyroid antibodies. 73,74 Supplementation in iodine-replete regions leads to reversible hypothyroidism by inhibition of the biosynthesis and release of thyroid hormone. Various drugs have also been implicated in the etiology of chronic thyroiditis. Amiodarone has a long half-life and a high iodine content and can mediate iodine-induced hyporhyroidism." Transient hypothyroidism has also been associated with lithium therapy." The effects of these medications are more pronounced in patients with thyroid antibodies than in those without antibodies. Treatment with interferon a,76 interleukin 2,77 or granulocyte-macrophage colony-stimulating factor" may also lead to reversible formation of thyroid autoantibodies, hypothyroidism, or Graves' disease. An iodine-rich diet has been shown to produce thyroiditis in chickens 79 and beagle dogs." Genetic Predisposition. Evidence for an inherited susceptibility for chronic autoimmune thyroiditis is derived from both experimental and spontaneously occurring animal models of autoimmune thyroiditis and human studies." Human family studies suggest an increased incidence of thyroid autoantibodies (up to 46%) in first-degree relatives of patients with Hashimoto's thyroiditis compared to only 15% of controls.P Segregation analyses indicate that this susceptibility is inherited in a mendelian dominant fashion with high penetrance." However, Hashimoto's thyroiditis

does not exhibit classic mendelian inheritance, and genetic predisposition appears to be complex, possibly caused by many disease-associated alleles located at different genetic loci." Further support for genetic susceptibility for Hashimoto's thyroiditis is shown by the occurrence of the autoantibodies and hypothyroidism in patients with specific chromosomal abnormalities such as Turner's'" and Down syndromes.f Available evidence suggest that at least a part of the genetic susceptibility to Hashimoto's thyroiditis may reside on the chromosomes X and 21 (which are respectively involved in these disorders). Associations with HLA-B8, -DR3, and -DR5 haplotypes of the major histocompatibility complex have also been described.f':" although the HLA locus is not believed to be a major etiologic factor.s? HISTOLOGIC FEATURES

The thyroid gland is generally mildly enlarged throughout and has a pale, grayish tan cut surface that is firm and slightly nodular. On microscopic examination, the gland is diffusely infiltrated by mononuclear cells (small lymphocytes and plasma cells) and occasionally shows well-developed germinal centers. Thyroid follicles are smaller than normal with reduced amounts of colloid. The follicles are lined by Hiirthle or Askanazy cells, which are characterized by abundant eosinophilic, granular cytoplasm as shown in Figure 5-5. In addition, the amount of interstitial connective tissue is increased and manifests itself as fibrosis. In contrast to Riedel's thyroiditis, the fibrosis does not extend beyond the gland itself. 1I In atrophic chronic thyroiditis, the fibrosis is more pronounced. Of note, existing evidence does not support the progression of the goitrous form to the atrophic form. 90,91 CLINICAL PRESENTATION

Like other autoimmune diseases, Hashimoto's thyroiditis is also more common in women (male-female ratio, 1:10 to 20) between the ages of 30 and 50 years. The most common

FIGURE 5-5. Histologic features of Hashimoto's thyroiditis. The thyroid parenchyma contains a dense lymphocytic infiltrate with germinal centers. Residual thyroid follicles lined by deeply eosinophilic Hurthle cells are also seen. (From Cotran R, Kumar V, Collins T, Robbins SL reds], Robbins Pathologic Basis of Disease, 6th ed. Philadelphia, WB Saunders, 1999, p 1135.)

40 - - Thyroid Gland presentation is that of a relatively small, firm, and granular gland discovered on routine physical examination or the awareness of a painless anterior neck mass. In unusual cases, the thyroid gland may enlarge rapidly, causing compressive symptoms and dysphonia. Pain, especially radiating to the ear, is a rare manifestation. Approximately 20% of patients present with hypothyroidism.F whereas 5% present with hyperthyroidism (hashitoxicosisj.P In classic goitrous Hashimoto's thyroiditis, physical examination reveals a diffusely enlarged, firm gland that is also lobulated. An enlarged pyramidal lobe is usually palpable. The goiter may be asymmetrical, and, rarely, nodules and enlarged lymph nodes may be palpated. Thyroid-associated ophthalmopathy occurs rarely in patients with chronic autoimmune thyroiditis. DIAGNOSTIC STUDIES

When Hashimoto's thyroiditis is suspected clinically, an elevated TSH level and thyroid autoantibodies confirm the diagnosis. About 95% of patients have increased antirnicrosomal antibody titers, whereas antithyroglobulin antibodies are positive in about 60% of patients." The microsomal antigen has been identified as TPO (the rate-limiting enzyme in thyroid biosynthesis)." Anti-TPO antibodies measured by radioimmunoassay are a more sensitive indicator of Hashimoto's thyroiditis than are antimicrosomal antibodies detected by hemagglutination studies." Antibodies to the TSH receptor are present in up to 60%,96 and antibodies to NIS can be found in 25% of patients."? RAID is variable and may mimic Graves' disease, multinodular goiter, or a hot or cold nodule/" However, the RAIU is usually normal or elevated, even in hypothyroid patients, and thus allows differentiation from subacute thyroiditis. FNA biopsy is indicated in patients who present with a solitary suspicious nodule or rapidly enlarging goiter. Most patients with thyroid lymphoma have underlying Hashimoto's thyroiditis. Patients with multiple endocrine neoplasia (MEN) type 2, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes), Addison's disease and, as mentioned earlier, Down and Turner's syndromes, have a higher than baseline incidence of chronic autoimmune thyroid disease. As such, these patients should undergo periodic TSH measurements. 57 DIFFERENTIAL DIAGNOSIS

The differential diagnosis of Hashimoto's thyroiditis includes nontoxic multinodular goiter and thyroid lymphoma. In the former, patients are usually euthyroid, the thyroid gland has more distinct nodules, and thyroid antibody levels are lower than in Hashimoto's thyroiditis. As mentioned earlier, patients with Hashimoto's thyroiditis are predisposed to thyroid lymphoma and often have a short history of a rapidly enlarging gland. About 30% of these patients present with significant compressive symptoms. CLINICAL COURSE

Some patients with subclinical hypothyroidism can progress to overt hypothyroidism. A 20-year follow-up study of patients, initially reported in the Whickham survey, with elevated TSH and positive antibodies but normal thyroxine levels (subclinical hypothyroidism), documented that 55%

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0.2

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5

10

20

50

Thyrotropin (mU per liter)

FIGURE 5-6. Probability of developing overt hypothyroidism in women within 20 years of initial measurement of serum thyrotropin (follow-up of the Whickham survey). (From Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol [Oxf] 1995;43:55.)

of female patients became hypothyroid (a progression of 4.3% per year)."? The probability of developing overt hypothyroidism in these patients is shown in Figure 5-6. Male patients and those with higher initial TSH levels had an even higher rate of progression. However, patients who had slightly elevated TSH levels but no antibodies did not progress to hypothyroidism. Rarely, patients may develop Graves' disease'!" or lymphoma. Thyroid lymphoma is a well-recognized, ominous complication of chronic autoimmune thyroiditis and has a prevalence 80 times higher than the expected frequency in this population than in a control population without thyroiditis. Most thyroid lymphomas are of the non-Hodgkin's B cell type and tend to occur in older female patients.l'" TREATMENT

Thyroid hormone replacement therapy is indicated in overtly hypothyroid patients with a goal of normal TSH levels. The management of patients with subclinical hypothyroidism (normal T 4 and elevated TSH) is controversial. Since these patients do progress to overt disease, treatment is generally recommended, especially for male patients and those with TSH higher than 10 mUlL. 57 Treatment is also indicated in euthyroid patients to shrink large goiters.P? Surgery is occasionally indicated for suspicion of malignancy or for goiters causing compressive symptoms or cosmetic deformity.

Riedel's Thyroiditis Riedel's thyroiditis is a rare variant of thyroiditis that was initially described in two patients by Riedel in 1896 and subsequently in a third patient in 1897. 103•104 It is also known as Riedel's struma or invasive fibrous thyroiditis and leads to a wood-like thyroid gland. A review of the Mayo Clinic experience disclosed 37 cases in 56,700 thyroidectomies over a 64-year period. ros

Thyroiditis - -

ETIOLOGY AND PATHOGENESIS

Riedel's thyroiditis is characterized by the replacement of thyroid parenchyma by fibrous tissue, which also invades into adjacent tissues. The etiology of this disorder is controversial and has not been resolved. This disorder has been reported to occur in patients with other autoimmune diseases such as pernicious anemia and Graves' disease. This association, coupled with the presence of lymphoid infiltration and response to steroid therapy, led some investigators to suggest a primary autoimmune etiology.l06,107 Riedel's thyroiditis is also associated with other focal sclerosing syndromes, including mediastinal, retroperitoneal, periorbital, and retro-orbital fibrosis and sclerosing cholangitis,108 suggesting that it may be a primary fibrotic disorder. HISTOLOGIC FEATURES

The histologic criteria for the diagnosis of Riedel's thyroiditis were first described by Woolner and coworkers in 1957. The thyroid is typically involved with a fibrotic process consisting of fibroblasts and collagen. The chief light microscopic features that enable this entity to be distinguished from Hashimoto's thyroiditis are (1) extension of the fibrotic ~rocess through the strap muscles and other surrounding tissue, (2) phlebitis with luminal distention by fibrous or lymphoid tissue, and (3) relatively normal remnant thyroid tissue.P? Tissue eosinophil infiltration is also a characteristic finding in fibrous thyroiditis.!'? CLINICAL FEATURES

The disease occurs predominantly in women (male-female ratio, I :3) between the ages of 30 and 60 years. It typically presents as a painless, hard anterior neck mass that progresses over weeks to years to produce symptoms of compression including dysphagia, dyspnea, choking, and hoarseness. Patients may present with symptoms of hypothyroidism as the gland is replaced by fibrous tissue. Extension of the process can also l~ad to hypoparathyroidism and, rarely, vocal cord paralysis.U'{'? Physical examination reveals a ~ard, "woo~y" thyroid gland with fixation to surrounding tIs~ues. TYPI~ally, the thyroid is diffusely involved, although unilobular disease has been described. DIFFERENTIAL DIAGNOSIS

The. differential diagnosis includes lymphoma, poorly or undifferentiated thyroid cancer, chronic thyroiditis, and granulomatous thyroiditis. DIAGNOSTIC STUDIES

An. elevate? TSH and hypocalcemia may be present in patIent~ WIth hypothyroidism and hypoparathyroidism, respectively, Antithyroid antibodies and a mild eosinophilia ~e diagnosis needs to be confirmed by open may ~e p~esent. thyroid bIOpSY, WhICh also helps exclude carcinoma. The firm and fibrous nature of the gland renders FNA inadequate. I 13 TREATMENT ~urgery is ~e mainstay of the treatment of Riedel's thyroiditis. The chief goal of operation is to decompress the trachea by wedge excision of the thyroid isthmus and to make a tissue diagnosis. More extensive resections are not advised

41

owing to the infiltrative nature of the fibrotic process that obscures usual landmarks and structures (recurrent laryngeal nerves, parathyroids, carotid arteries). Hypothyroid patients are treated with thyroid hormone replacement. External-beam radiation therapy is not usually effective. 114 Some patients remain symptomatic even after these treatment modalities. These patients have been reported to experience dramatic improvement after treatment with corticosteroids.l" In another study, these patients experienced subjective and objective relief of symptoms after several weeks of treatment with the antiestrogen medication tamoxifen (20 mg twice a dayj.!" Although estrogen receptors have been identified in normal and neoplastic thyroid tissue,'!" tumors from these patients were not positive for estrogen, and the mechanism underlying the response to tamoxifen has been postulated to be related to transforming growth factor (TGF)-~I' TGF-~I is a potent growth inhibitor of immature fibroblasts and epithelial cells!" and has been shown to be upregulated by tamoxifen.I'v!"

Summary Surgeons are rarely in the frontline of the diagnosis and management of patients with the different variants of thyroiditis. However, an understanding of these disorders is an important component of the endocrine surgeon's armamentarium in the unusual situations when surgical invention is required for localized symptoms and diagnosis. FNA biopsy for cytology and culture is helpful for diagnosis in many patients, as is careful analyses of laboratory tests.

REFERENCES I. Berger SA, Zonszein J, Villamena P, Mittman N. Infectious diseases of the thyroid gland. Rev Infect Dis 1983;5:108. 2. Miyauchi A, Matsuzuka F, Kuma K, Takai S. Piriform sinus fistula: An underlying abnormality common in patients with acute suppurative thyroiditis. World J Surg 1990; 14:400. 3. Hazard JB. Thyroiditis: A review. Am J Clin PathoI1955;25:289. 4. Takai SI, Miyauchi A, Matsuzuka F, et al. Internal fistula as a route of infection in acute suppurative thyroiditis. Lancet 1979; I :751. 5. Miyauchi A, Matsuzuka F, Kuma K, Katayama S. Piriform sinus fistula and the ultimobranchial body. Histopathology 1992;20:221. 6. Miyauchi A, Matsuzuka F, Takai S, et al. Piriform sinus fistula: A route of infection in acute suppurative thyroiditis. Arch Surg 1981;116:66. 7. Liston SL. Fourth branchial fistula. Otolaryngol Head Neck Surg 1981; 89:520. 8. Golshan MM, McHenry CR, de Vente J, et al. Acute suppurative thyroiditis and necrosis of the thyroid gland: A rare endocrine manifestation of acquired immunodeficiency syndrome. Surgery 1997; 121:593. 9. Imai C, Kakihara T, Watanabe A, et al. Acute suppurative thyroiditis as a rare complication of aggressive chemotherapy in children with acute myelogeneous leukemia. Pediatr Hematol OncoI2002;19:247. 10. Altemeier WA. Acute pyogenic thyroiditis. Arch Surg 1950;61:76. II. Cotran RS, Kumar V, Collins T, Robbins SL (eds), Robbins Pathological Basis of Disease, 6th ed, Philadelphia, WB Saunders 1999. ' 12. ~ases JA,. 'Y~n~g BM, Silver CE, Surks MI. Recurrent acute suppurative thyroiditis in an adult due to a fourth branchial pouch fistula. J Clin Endocrinol Metab 2000;85:953. 13. Boyd C:M,Esc1amado RM, Telian SA. Impaired vocal cord mobility in the settmg of acute suppurative thyroiditis. Head Neck 1997;19:235. 14. Kingsbury BE On the fate of the ultimobranchial body within the human thyroid gland. Anat Rec 1935;61:155.

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15. Wilson TD, Pickard BH, Whittam DE. Carcinoma of the larynx masquerading as acute suppurative thyroiditis. Br J Surg 1969;56:936. 16. Lin KD, Lin 10, Huang MJ, et ai. Acute suppurative thyroiditis and aggressive malignant thyroid tumors: Differences in clinical presentation. J Surg Oncol 1998;67:28. 17. Adler ME, Jordan G, Walter RM Jr. Acute suppurative thyroiditis: Diagnostic, metabolic, and therapeutic observations. West J Med 1978;128:165. 18. Bernard PJ, Som PM, Urken ML, et ai. The CT findings of acute thyroiditis and acute suppurative thyroiditis. Otolaryngol Head Neck Surg 1988;99:489. 19. Bar-Ziv J, Slasky BS, Sichel JY, et ai. Branchial pouch sinus tract from the piriform fossa causing acute suppurative thyroiditis, neck abscess, or both: CT appearance and the use of air as a contrast agent. AJR Am J Roentgenol 1996;167:1569. 20. Kubota M, Suita S, Kamimura T, Zaizen Y. Surgical strategy for the treatment of pyriform sinus fistula. J Pediatr Surg 1997;32:34. 21. de Quervain F. Die akute, nicht eiterige thyreoiditis und die beteligung der schiiddruse an akuten intoxikationen und infektionen uberhaupt. Mitt Grenzeb Med Chir 1904;Suppl 2: I. 22. Stancek D, Stancekova-Gressnerova M, Janotka M, et ai. Isolation and some serological and epidemiological data on the viruses recovered from patients with subacute thyroiditis de Quervain. Med Microbiol Immunol (BerI) 1975;161:133. 23. Nyulassy S, Hnilica P,Buc M, et aI. Subacute (de Quervain's) thyroiditis: Association with HLA-Bw35 antigen and abnormalities of the complement system, immunoglobulins, and other serum proteins. J Clin Endocrinol Metab 1977;45:270. 24. Volpe R. The management of subacute (de Quervain's) thyroiditis. Thyroid 1993;3:253. 25. Rosen IB, Strawbridge HG, Walfish PG, Bain J. Malignant pseudothyroiditis: A new clinical entity. Am J Surg 1978;136:445. 26. Amino N, Yabu Y, Miki T, et ai. Serum ratio of triiodothyronine to thyroxine, and thyroxine-binding globulin and calcitonin concentrations in Graves' disease and destruction-induced thyrotoxicosis. J Clin Endocrinol Metab 1981;53:113. 27. Singer PA. Thyroiditis: Acute, subacute, and chronic. Med Clin North Am 1991;75:61. 28. Tokuda Y, Kasagi K, lida Y, et ai. Sonography of subacute thyroiditis: Changes in the findings during the course of the disease. J Clin Ultrasound 1990;I8:2 I. 29. Pedersen OM, Aardal NP, Larssen TB, et ai. The value of ultrasonography in predicting autoimmune thyroid disease. Thyroid 2000; I0:25 I. 30. Volpe R. Is silent thyroiditis an autoimmune disease? Arch Intern Med 1988;148:1907. 3 I. Mitani Y, Shigemasa C, Taniguchi S, et ai. Clinical course of silent thyroiditis in a patient with Sjogren's syndrome: Concomitant changes of antithyroid antibodies and antinuclear antibody. Arch Intern Med 1988;148:1974. 32. Parker M, Klein I, Fishman LM, Levey GS. Silent thyrotoxic thyroiditis in association with chronic adrenocortical insufficiency. Arch Intern Med 1980;140:1108. 33. Sarlis NJ, Brucker-Davis F, Swift JP, et ai. Graves' disease following thyrotoxic painless thyroiditis: Analysis of antibody activities against the thyrotropin receptor in two cases. Thyroid 1997;7:829. 34. Sartani A, Feigl D, Zaidel L, Ravid M. Painless thyroiditis followed by autoimmune disorders of the thyroid: A case report with biopsy. J Endocrinol Invest 1980;3:169. 35. Farid NR, Hawe BS, Walfish PG. Increased frequency of HLA-DR3 and 5 in the syndromes of painless thyroiditis with transient thyrotoxicosis: Evidence for an autoimmune aetiology. Clin Endocrinol (Oxf) 1983;I9:699. 36. Jansson R, Safwenberg J, Dahlberg PA. Influence of the HLA-DR4 antigen and iodine status on the development of autoimmune postpartum thyroiditis. J Clin Endocrinol Metab 1985;60:168. 37. Amino N, Kuro R, Tanizawa 0, et ai. Changes of serum antithyroid antibodies during and after pregnancy in autoimmune thyroid diseases. Clin Exp Immunol 1978;31:30. 38. Roti E, Uberti E. Postpartum thyroiditis-a clinical update. Eur J EndocrinoI2002;14:275. 39. Singer PA, Gorsky JE. Familial postpartum transient hyperthyroidism. Arch Intern Med 1985;145:240. 40. Nikolai TF, Tumey SL, Roberts RC. Postpartum lymphocytic thyroiditis: Prevalence, clinical course, and long-term follow-up. Arch Intern Med 1987;147:221.

4 I. Hancock SL, Cox RS, McDougall IR. Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 1991;325:599. 42. Roti E, Minelli R, Giuberti T, et ai. Multiple changes in thyroid function in patients with chronic active HCV hepatitis treated with recombinant interferon a. Am J Med 1996;101:482. 43. Adams H, Jones MC, Othman S, et ai. The sonographic appearances in postpartum thyroiditis. Clin Radiol 1992;45:311. 44. Nikolai TF, Coombs GJ, McKenzie AK, et ai. Treatment of lymphocytic thyroiditis with spontaneously resolving hyperthyroidism (silent thyroiditis). Arch Intern Med 1982;142:2281. 45. Agarwal A, Mishra A, Mishra SK, et ai. Recurrent painless thyroiditis requiring total thyroidectomy. J Assoc Physicians India 2000;48:367. 46. Choe W, McDougall IR. Ablation of thyroid function with radioactive iodine after recurrent episodes of silent thyroiditis. Thyroid 1993; 3:31 I. 47. Nikolai TF, Coombs GJ, McKenzie AK. Lymphocytic thyroiditis with spontaneously resolving hyperthyroidism and subacute thyroiditis: Long-term follow-up. Arch Intern Med 1981;141:1455. 48. Tachi J, Amino N, Tamaki H, et ai. Long term follow-up and HLA association in patients with postpartum hypothyroidism. J Clin Endocrinol Metab 1988;66:480. 49. Othman S, PhiIIips 01, Parkes AB, et ai. A long-term follow-up of postpartum thyroiditis. Clin Endocrinol (Oxf) 1990;32:559. 50. Premawardhana LD, Parkes AB, Ammari F, et ai. Postpartum thyroiditis and long-term thyroid status: Prognostic influence of thyroid peroxidase antibodies and ultrasound echogenicity. J Clin Endocrinol Metab 2000;85:71. 51. Kuijpens JL, Vader HL, Drexhage HA, et ai. Thyroid peroxidase antibodies during gestation are a marker for subsequent depression postpartum. Eur J Endocrinol 2001;145:579. 52. Balazs C, Farid NR. Soluble CD4 concentrations predict relapse of postpartum thyroiditis. J Endocrinol Invest 2002;25: II. 53. de Bruin TW, RiekhoffFP, de Boer 11.An outbreak of thyrotoxicosis due to atypical subacute thyroiditis. J Clin Endocrinol Metab 1990;70:396. 54. Daniels GH. Atypical subacute thyroiditis: Preliminary observations. Thyroid 2001;11:691. 55. Hashimoto Z. Zur Kenntniss der Iymphomatosen veranderung der schiiddruse (struma lymphomatosa). Arch Klin Chir 1912;97:219. 56. Roitt 1M, Doniach D, Campbell PN, Hudson RY. Autoantibodies in Hashimoto's disease (lymphadenoid goitre). Lancet 1956;2:820. 57. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996;335:99. 58. WiIIiams ED, Doniach I. The postmortem incidence of focal thyroiditis. J Pathol Bacteriol 1962;83:255. 59. Okayasu I, Hara Y, Nakamura K, Rose NR. Racial and age-related differences in incidence and severity of focal autoimmune thyroiditis. AmJ Clin PathoI1994;101:698. 60. Yoshida H, Amino N, Yagawa K, et ai. Association of serum antithyroid antibodies with lymphocytic infiltration of the thyroid gland: Studies of seventy autopsied cases. J Clin Endocrinol Metab 1978; 46:859. 61. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol ImmunopathoI1997;84:223. 62. Weetman AP, McGregor AM. Autoimmune thyroid disease: Further developments in our understanding. Endocr Rev 1994;15:788. 63. Valtonen VV, Ruutu P, Varis K, et ai. Serological evidence for the role of bacterial infections in the pathogenesis of thyroid diseases. Acta Med Scand 1986;219:105. 64. Tomer Y, Davies TF. Infection, thyroid disease, and autoimmunity. Endocr Rev 1993;14: 107. 65. Volpe R. A perspective on human autoimmune thyroid disease: Is there an abnormality of the target ceIl which predisposes to the disorder? Autoimmunity 1992;13:3. 66. Hanafusa T, Pujol-Borrell R, Chiovato L, et ai. Aberrant expression of HLA-DR antigen on thyrocytes in Graves' disease: Relevance for autoimmunity. Lancet 1983;2: I II I. 67. Todd I, Pujol-Borrell R, Hammond LJ, et ai. Interferon y induces HLA-DR expression by thyroid epithelium. Clin Exp Immunol 1985; 61:265. 68. Dayan CM, Londei M, Corcoran AE, et ai. Autoantigen recognition by thyroid-infiltrating T cells in Graves' disease. Proc Natl Acad Sci USA 1991;88:7415. 69. Raspe E, Costagliola S, Ruf J, et ai. Identification of the thyroid Nat/l cotransporter as a potential autoantigen in thyroid autoimmune disease. Eur J Endocrinol 1995;132:399.

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70. Chin HS, Chin DK, Morgenthaler NG, et al. Rarity of anti-Na'/I" symporter (NIS) antibody with iodide uptake inhibiting activity in autoimmune thyroid diseases (AITD). J Clin Endocrinol Metab 2000;85:3937. 71. Salmaso C, Bagnasco M, Pesce G, et al. Regulation of apoptosis in endocrine autoimmunity: Insights from Hashimoto's thyroiditis and Graves' disease. Ann NY Acad Sci 2002;966:496. 72. Laurberg P. Iodine intake-what are we aiming at? J Clin Endocrinol Metab 1994;79: 17. 73. Harach HR, Escalante DA, Onativia A, et al. Thyroid carcinoma and thyroiditis in an endemic goitre region before and after iodine prophylaxis. Acta Endocrino! (Copenh) 1985; 108:55. 74. Boukis MA, Koutras DA, Souvatzoglou A, et al. Thyroid hormone and immunological studies in endemic goiter. J Clin Endocrinol Metab 1983;57:859. 75. Martino E, Bartalena L, Bogazzi F, Braverman LE. The effects of amiodarone on the thyroid. Endocr Rev 2001;22:240. 76. Gisslinger H, Gilly B, Woloszczuk W, et al. Thyroid autoimmunity and hypothyroidism during long-term treatment with recombinant interferon IX. Clin Exp ImmunoI1992;90:363. 77. Atkins MB, Mier JW, Parkinson DR, et al. Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N Engl J Med 1988;318:1557. 78. Hoekman K, von Blomberg-van der Flier BM, Wagstaff J, et al. Reversible thyroid dysfunction during treatment with GM-CSF. Lancet 1991;338:541. 79. Bagchi N, Brown TR, Urdanivia E, Sundick RS. Induction of autoimmune thyroiditis in chickens by dietary iodine. Science 1985;230:325. 80. Fritz TE, Norris WP, Kretz ND, et al. Thyroiditis in a closed colony of beagle dogs: Nondestructive methods for diagnosis. ANL-7535. ANL Rep 1968:173. 81. Barbesino G, Chiovato L. The genetics of Hashimoto's disease. Endocrinol Metab Clin North Am 2000;29:357. 82. Doniach D, Roitt 1M. Taylor KB. Autoimmunity in pernicious anemia and thyroiditis: A family study. Ann NY Acad Sci 1965;124:605. 83. Phillips D, McLachlan S, Stephenson A, et al. Autosomal dominant transmission of autoantibodies to thyroglobulin and thyroid peroxidase. J Clin Endocrinol Metab 1990;70:742. 84. Fleming S, Cowell C, Bailey J, Burrow GN. Hashimoto's disease in Turner's syndrome. Clin Invest Med 1988; I I :243. 85. Friedman DL, Kastner T, Pond WS, O'Brien DR. Thyroid dysfunction in individuals with Down syndrome. Arch Intern Med 1989;149:1990. 86. Irvine WJ, Gray RS, Morris PJ, Ting A. HLA in primary atrophic hypothyroidism and Hashimoto goitre. J Clin Lab Immunol 1978;1:193. 87. Farid NR, Sampson L, Moens H, Barnard JM. The association of goitrous autoimmune thyroiditis with HLA-DR5. Tissue Antigens 1981;17:265. 88. Stenszky V, Balazs C, Kraszits E, et al. Association of goitrous autoimmune thyroiditis with HLA-DR3 in eastern Hungary. J Immunogenet 1987; 14:143. 89. Roman SH, Greenberg D, Rubinstein P, et al. Genetics of autoimmune thyroid disease: Lack of evidence for linkage to HLA within families. J Clin Endocrinol Metab 1992;74:496. 90. Hayashi Y, Tarnai H, Fukata S, et al. A long-term clinical, immunological, and histological follow-up study of patients with goitrous chronic lymphocytic thyroiditis. J Clin Endocrinol Metab 1985;61: 1172. 91. Vickery AL, Hamblin EJ. Struma Iymphomatosa (Hashimotos's thyroiditis): Observations on repeated biopsies in sixteen patients. N Engl J Med 1961;264:226. 92. Fatourechi V, McConahey WM, Woolner LB. Hyperthyroidism associated with histologic Hashimoto's thyroiditis. Mayo Clin Proc 1971; 46:682. 93. Amino N, Hagen SR, Yamada N, Refetoff S. Measurement of circulating thyroid microsomal antibodies by the tanned red cell haemagglutination technique: Its usefulness in the diagnosis of autoimmune thyroid diseases. Clin Endocrinol (Oxf) 1976;5: 115. 94. Czarnocka B, Ruf J, Ferrand M, et al. Purification of the human thyroid peroxidase and its identification as the microsomal antigen involved in autoimmune thyroid diseases. FEBS Lett 1985; 190:147. 95. Mariotti S, Caturegli P, Piccolo P, et al. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab 1990;71 :661.

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96. Cho BY, Kim WB, Chung JH, et al. High prevalence and little change in TSH receptor-blocking antibody titres with thyroxine and antithyroid drug therapy in patients with nongoitrous autoimmune thyroiditis. Clin Endocrinol (Oxf) 1995;43:465. 97. Ajjan RA, Kemp EH, Waterman EA, et al. Detection of binding and blocking autoantibodies to the human sodium-iodide symporter in patients with autoimmune thyroid disease. J Clin Endocrinol Metab 2000;85:2020. 98. Ramtoola S, Maisey MN, Clarke SE, Fogelman I. The thyroid scan in Hashimoto's thyroiditis: The great mimic. Nucl Med Commun 1988;9:639. 99. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995;43:55. 100. Kurihara H, Sasaki J, Takamatsu M. Twenty cases with Hashimoto disease changing to Graves' disease. In: Nagataki S, Mori T, Torizuka K (eds), Eighty Years of Hashimoto Disease. Amsterdam, Elsevier Science, 1993, p 249. 101. Matsuzuka F, Miyauchi A, Katayama S, et al. Clinical aspects of primary thyroid lymphoma: Diagnosis and treatment based on our experience of 119 cases. Thyroid 1993;3:93. 102. Hegedus L, Hansen JM, Feldt-Rasmussen U, et al. Influence of thyroxine treatment on thyroid size and antithyroid peroxidase antibodies in Hashimoto's thyroiditis. Clin Endocrinol (Oxf) 1991;35:235. 103. Riedel BMCL. Die chronische, zur Bildung eisenharter Tumoren fuhrende entzundung der schilddruse. Verhandlung der Deutsche Gesellschaft fur Chirugerie 1896;25: 101. 104. Riedel BMCL. Bortellung eines Kranken mit chrinischer Strumitis. Verhandlung der Deutsche Gesellschaft fur Chirugerie 1897;26:127. 105. Hay ill. Thyroiditis: A clinical update. Mayo Clin Proc 1985;60:836. 106. Heufelder AE, Hay ill. Evidence for autoimmune mechanisms in the evolution of invasive fibrous thyroiditis (Riedel's struma). Clin Invest 1994;72:788. 107. Zimmermann-Belsing T, Feldt-Rasmussen U. Riedel's thyroiditis: An autoimmune or primary fibrotic disease? J Intern Med 1994;235:271. 108. Dehner LP, Coffin CM. Idiopathic fibrosclerotic disorders and other inflammatory pseudotumors. Semin Diagn Pathol 1998;15:161. 109. Harach HR, Williams ED. Fibrous thyroiditis-an immunopathological study. Histopathology 1983;7:739. 110. Heufelder AE, Goellner JR, Bahn RS, et al. Tissue eosinophilia and eosinophil degranulation in Riedel's invasive fibrous thyroiditis. J Clin Endocrinol Metab 1996;81 :977. Ill. McRorie ER, Chalmers J, Campbell IW. Riedel's thyroiditis complicated by hypoparathyroidism and hypothyroidism. Scott Med J 1993; 38:27. 112. Yasmeen T, Khan S, Patel SG, et al. Riedel's thyroiditis: Report of a case complicated by spontaneous hypoparathyroidism, recurrent laryngeal nerve injury, and Horner's syndrome [Clinical Case Seminar]. J Clin Endocrinol Metab 2002;87:3543. 113. Tseleni-Balafouta S, Kyroudi-Voulgari A, Paizi-Biza P, Papacharalampous NX. Lymphocytic thyroiditis in fine-needle aspirates: Differential diagnostic aspects. Diagn Cytopathol 1989;5:362. 114. Amorosa LF, Shear MK, Spiera H. Multifocal fibrosis involving the thyroid, face, and orbits. Arch Intern Med 1976;136:221. 115. Bagnasco M, Passalacqua G, Pronzato C, et al. Fibrous invasive (Riedel's) thyroiditis with critical response to steroid treatment. J Endocrinol Invest 1995;18:305. 116. Few J, Thompson NW, Angelos P, et al. Riedel's thyroiditis: Treatment with tamoxifen. Surgery 1996;120:993. 117. Clark OH, Gerend PL, Davis M, et aI. Estrogen and thyroid-stimulating hormone (TSH) receptors in neoplastic and non-neoplastic human thyroid tissue. J Surg Res 1985;38:89. 118. Arteaga CL, Tandon AK, Von Hoff DD, Osborne CK. Transforming growth factor ~: Potential autocrine growth inhibitor of estrogen receptor-negative human breast cancer cells. Cancer Res 1988;48:3898. 119. Colletta AA, Wakefield LM, Howell FV, et al. Anti-oestrogens induce the secretion of active transforming growth factor ~ from human fetal fibroblasts. Br J Cancer 1990;62:405. 120. Mirza MR. Anti-estrogen induced synthesis of transforming growth factor ~ in breast cancer patients. Cancer Treat Rev 1991; 18:145. 121. Butta A, MacLennan K, Flanders KC, et al. Induction of transforming growth factor ~I in human breast cancer in vivo following tamoxifen treatment. Cancer Res 1992;52:4261.

Hypothyroidism Kanji Kuma, MD • Shuji Fukata, MD • Masahiro Sugawara, MD

Hypothyroidism is the state of decreased thyroid hormone action at the target tissue. There are two types of hypothyroidism, on the basis of thyroid function tests: (1) clinical or overt and (2) subclinical. Patients with the former show elevated serum thyroid-stimulating hormone (TSH) and reduced serum thyroid hormone levels, which are the characteristic laboratory findings of primary hypothyroidism. The latter disorder is characterized by a mildly elevated serum TSH concentration and normal serum thyroid hormone levels. Subclinical hypothyroidism is the most common thyroid dysfunction nationwide, with a marked increase in prevalence in the elderly population.l-' Hypothyroidism, including subclinical hypothyroidism, can cause cardiovascular problems, lipid disorders, cognitive dysfunction, neurologic abnormalities, and a high rate of abortion. An extreme case of untreated hypothyroidism is myxedema coma. The timely detection of hypothyroidism and appropriate therapy with thyroid hormone are beneficial for patients and reduce perioperative morbidity as well as mortality.

Prevalence and Subclinical Forms The prevalence rates of overt hypothyroidism and subclinical hypothyroidism in the general population are 0.4% and 9%, respectively, based on the Colorado Thyroid Disease Prevalence Study.' The National Health and Nutrition Examination Survey (NHANES) III in the United States showed overt hypothyroidism of 0.3% and subclinical hypothyroidism of 4.3% in the general population in all ages.? Thus, subclinical hypothyroidism is 16 to 20 times more common than overt hypothyroidism. The prevalence of subclinical hypothyroidism increases with age and is more common in women than in men. In groups older than 70 years of age, a steep increase in prevalence of subclinical hypothyroidism is apparent; it reaches to 14% in the white population and 5% in the black population.? Subclinical hypothyroidism, therefore, should always be suspected whenever elderly patients undergo surgical procedures. Most patients with subclinical hypothyroidism have either mild symptoms of hypothyroidism or nonspecific symptoms. Before making the diagnosis of subclinical hypothyroidism, it is important to exclude other causes of elevated serum TSH concentration, such as the recovery stage from a nonthyroidal illness (serum TSH concentration can be

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mildly elevated during the recovery stage), intermittent thyroid hormone ingestion for treatment of hypothyroidism, TSH-secreting tumor, and thyroid hormone resistance.' The causes of subclinical hypothyroidism are the same as those for overt hypothyroidism listed in a later section. Patients with subclinical hypothyroidism previously were considered as having a mild form of hypothyroidism, and no clear treatment has been established. Chu and Crapo claimed that thyroid hormone treatment is seldom needed unless the serum TSH concentration exceeds 10 mU/mL,4 but these patients have more chance of myocardial infarction,' hyperlipidemia," and hyperhomocysteinemia.? The trend is to treat patients with subclinical hypothyroidism to reduce these complications; in fact, most members of the American Thyroid Association choose thyroid hormone treatment for patients with subclinical hypothyroidism."

Causes and Clinical Features Hashimoto's Thyroiditis Hashimoto's thyroiditis, known as an autoimmune or chronic lymphocytic thyroiditis, is the leading cause of hypothyroidism. The pathogenesis of hypothyroidism is complex. Three mechanisms have been proposed: (1) thyroid cell damage by the thyroid antibody-mediated complement attachment; (2) T-cell-mediated cytotoxicity; and (3) enhanced apoptosis (programmed cell death). The initial event is the formation of antibody in response to self-antigen such as thyroid peroxidase (TPO) and thyroglobulin; this event does not normally happen. If self-antigen is falsely recognized by the immune system, antibody formation takes place to the specific self-antigen, creating organ-specific autoimmunity. This leads to immune complex deposition in the basement membrane of follicular cells and complement activation, as suggested in 1977.9 Weetman and associates confirmed the presence of terminal complement complexes around thyroid follicles.'? Thyrocytes attacked by complement through antibodies were shown to release cytokines interleukin (lL)-l and IL-6," which may promote infiltration and autoactivation of lymphocytes, subsequently leading to cell destruction. However, anti-TPO titers do not always correlate with the degree of thyroid cell destruction. Thus, thyroid antibodies should not be the sole cause of cell destruction. T-cellmediated cytotoxicity then came to attention. T lymphocytes originating from the bone marrow are differentiated in the

Hypothyroidism - -

thymus and become T cells (thymus-derived lymphocytes). One population of T cells expresses the surface molecule CD8, called cytotoxic T cells, and recognizes antigen that is associated with class I major histocompatibility complex (MHC) molecules. These class I MHC molecules are present in all cells and permit the CD8 cells to recognize and destroy foreign tissues, infected cells, or tumor cells. There are two pathways to destroy thyroid cells by cytotoxic T cells. One mechanism is to release lytic granules that contain perforin and granzyme.F'" These molecules enter the target cells and activate apoptosis pathways (caspase or cytochrome c release from the mitochondria). The other mechanism is an involvement of binding of Fas ligand (CD 178, expressed on the surface of T cells and thyrocytes) to the Fas death receptor (CD95/APO) of thyrocytes. This binding (dimerization of Fas and Fas ligand) triggers activation of the intracellular apoptosis pathway using adapter protein (Fas-associated protein death domain), Whatever the initial events are, the final immune reaction is cell destruction. In 1997, Giordano and colleagues first described the presence of Fas (CD95) in thyrocytes of Hashimoto's thyroiditis and not in normal thyroid gland,!" raising the possibility of Fas-mediated apoptosis in Hashimoto's thyroiditis. Since then, cell destruction by apoptosis has been studied intensely. Details of apoptosis in Hashimoto's thyroiditis have been reviewed by Baker" and Stassi and De Maria.16 The apoptosis in Hashimoto's thyroiditis involves complex linkages among thyrocytes, cytokines, CD4 cell, and death receptors/ligand. The interactions of these factors lead to either cell death or cell survival. Cytokines-biochemical signals that help coordinate immune responses-playa particularly central role in autoimmune diseases. The most important final event is activation of cytosolic cell lysis by expression of either Fas receptor-Fas ligand and/or tumor necrosis factor (TNF)-a and the TNF-related apoptosis-inducing ligand in thyrocytes.!? How does it happen? T-helper (TH) cells expressing CD4 playa critical role in cell death and survival in autoimmune diseases. CD4 T cells recognize antigen present on the surface of antigen-presenting cells (APCs) in association with class II MHC molecules. Unlike class I MHC molecules, class II MHC molecules are expressed only on APCs such as macrophages, B cells, and dendritic cells. There are two functionally distinct subsets of TH cells based on cytokine production: Tw land T w2. Twi cells secrete interferon (INF)-y and other cytokines that are associated with inflammation and cell-mediated immune responses. Tw2 cells promote humoral immune responses and inhibit Twi cell-mediated responses by the release of IL-4, IL-5, and IL_1O.18,19 TH-l cells are predominant in Hashimoto's thyroiditis, whereas Tw2 cells are prevalent in Graves' disease, Cytokines from Twi cells, such as INF-y and to a lesser extent IL-l~, stimulate the appearance of Fas death receptor in thyrocytes.'? Thus, cytokine-mediated reactions in Hashimoto's thyroiditis favor cell death by overcoming cell survival signals of cytokines from TH-2 cells and antiapoptotic proteins, Clinical features of Hashimoto's thyroiditis include the presence of goiter and variable thyroid functional status, Most patients with Hashimoto's thyroiditis have a small goiter. On palpation, the goiter can be felt as lobulated or multinodular; the consistency varies from rubbery to firm to stony hard. The surface of the Hashimoto's

45

thyroid gland is often described as bosselated. Thyroid function can be euthyroid, hypothyroid, or hyperthyroid depending on the stage of Hashimoto's thyroiditis and its associated conditions, For instance, at the beginning of this disease, most patients are euthyroid. As the disease progresses, patients become hypothyroid. If silent thyroiditis occurs in the thyroid gland of patients with Hashimoto's thyroiditis, patients may have transient hyperthyroidism due to thyroid cell destruction. Also, true hyperthyroidism can occur if Graves' disease and Hashimoto's thyroiditis coexist. The presence of antithyroid antibodies is the hallmark of this disorder; antirnicrosomal antibodies or anti-TPO antibodies are positive in more than 95% of cases. 19 Therefore, the presence of thyroid antibodies is used exclusively as the diagnostic test of Hashimoto's thyroiditis. Antibodies against thyroglobulin, sodium-iodide symporter, and TSH receptor may be detected. Also, ultrasound findings of hypoechogenicity of the thyroid gland should assist in the diagnosis of Hashimoto's thyroidiris-" and thyroid dysfunction." The clinical conditions described in the following sections need special attention in patients with Hashimoto's thyroiditis, Pregnancy. All pregnant women should have thyroid function tests and a TPO antibody test. If pregnant women have Hashimoto's thyroiditis, postpartum thyroid dysfunction is expected in 5% to 70%.22,23 This disorder can cause a transient hypothyroidism or hyperthyroidism in the postpartum period. If hypothyroidism or subclinical hypothyroidism is discovered during pregnancy, thyroid hormone treatment must be started as soon as possible. This is because of a high spontaneous abortion rate of 60% to 70%24 and adverse effects of hypothyroidism on the neuropsychological development of children, including IQ score." Also, thyroid hormone deficiency during early fetal life (first 12 weeks of pregnancy) leads to psychomotor development abnormality in infancy/"; the fetus is dependent on maternal thyroid hormone until 12 weeks' gestation. Smoking. Smoking is a risk factor for hypothyroidism in patients with Hashimoto's thyroiditis. Fukata and coworkers showed an increased prevalence of subclinical hypothyroidism in patients with Hashimoto's thyroiditis who smoke cigarettes because of an increased serum level of thiocyanate from smoking.?" This relationship between hypothyroidism and smoking has also been described by others.28.29 In addition to hypothyroidism, smoking is associated with the development of Graves' disease, Graves' ophthalmopathy, nodular goiter, and antithyroid antibodies.P Iodine. Iodine is needed for thyroid hormone formation. However, patients with Hashimoto's thyroiditis are known to have increased sensitivity to excessive iodine causing reversible hypothyroidism.v-" although the exact mechanism is unclear. Amiodarone. One of the common sources of excessive iodine is arniodarone; this antiarrhythmic drug contains 75 mg of iodine in a 200-mg tablet. Therefore, iodine-induced hypothyroidism is a possible side effect of this medication, particularly in patients with Hashimoto's thyroiditis.'? Also, amiodarone can cause destructive hyperthyroidism followed by transient hypothyroidism.>' An elevated serum level of IL-6 is a marker of amiodarone-induced thyroditis." Lithium. This medication is used for the treatment of bipolar disorder. Lithium has multiple actions in the thyroid

46 - - Thyroid Gland gland, including inhibition of thyroid hormone secretion." thyroid hormone formation," and activation of the protein kinase C pathway.'? If the thyroid gland has marginal function (i.e., Hashimoto's thyroiditis), lithium treatment can cause hypothyroidism. In fact, lithium-induced hypothyroidism is more commonly seen in patients with Hashimoto's thyroiditis than in people without underlying thyroid disease." suggesting that the effect of lithium on the normal thyroid gland is subtle. Cytokines. INF-a and IL-2 treatment for malignant disease or hepatitis C can cause hypothyroidism in patients with Hashimoto's thyroiditis. The mechanism of induction of hypothyroidism by cytokines is still unclear, and addition of ribavirin, an antiviral therapeutic agent, to INF increases the chance of hypothyroidism.'? The development of thyroid dysfunction does not appear to be dependent on the dose of INF.40 Also, INF-a treatment can induce anti-TPO antibodies in some patients during hepatitis C treatment." The outcome of hypothyroidism in these patients seems to be partly dependent on the persistence or disappearance of anti-TPO antibodies. If anti-TPO antibodies disappear at the end of INF-a treatment, patients' thyroid status also improves."

Association with Other Autoimmune Endocrine Disorders. A small number of patients with Hashimoto's

thyroiditis may have autoantibodies to other endocrine organs, such as the pancreas, adrenal gland, and ovary, causing diabetes mellitus, adrenal insufficiency, or premature ovarian failure, respectively (polyglandular autoimmune syndrome). The association of Hashimoto's thyroiditis with adrenal insufficiency has been previously referred to as Schmidt's syndrome. Thyroid Lymphoma. Thyroid lymphoma accounts for 2% to 5% of malignant thyroid tumors and occurs exclusively in the thyroid gland of Hashimoto's thyroiditis. 42,43 When a goiter develops rapidly in an elderly patient with Hashimoto's thyroiditis, thyroid lymphoma should be suspected. This is a potentially curable malignant tumor as long as it is discovered at an early stage."

Hypothyroidism Caused by Iodine Therapy Radioactive iodine (l3II) is one of the common methods of treating patients with Graves' disease. This treatment leads to the development of hypothyroidism in most patients. The dose of l311 administered affects the onset of hypothyroidism. Of patients who receive 370 MBq (10 mCi) or more (>5.55 MBq/g of thyroid tissue), about 50% of patients become hypothyroid 1 year after treatment and about 70% of patients are hypothyroid 10 years after treatment.v-" Euthyroidism can initially be attained by treatment with a low dose of radioactive iodine (l.48 to 2.59 MBq/g of thyroid tissue delivered); however, most patients subsequently develop hypothyroidism by 10 years or later,"

Hypothyroidism Caused by External Radiation to the Neck External radiation to the neck is known to cause thyroid disorders, including hypothyroidism.f? Radiation doses of 4500 cGy or more cause hypothyroidism by 20 years in approximately 50% of patients of all ages," and more cases

occur thereafter. The effect of radiation therapy on the development of hypothyroidism is dose and duration dependent. The higher the dose and the longer the observation period, the higher the incidence of hypothyroidism. The timing of development of hypothyroidism after the initial radiation therapy can be 4 months to years, depending on the dose and duration received." Ionized radiation releases reactive oxygen species from the water molecule. 50 This appears to be the mechanism of radiation-induced hypothyroidism. In addition to hypothyroidism, radiation therapy to the neck also predisposes to hyperthyroidism, thyroid cancer, Hashimoto's thyroiditis, and benign thyroid nodules.tv" Lifelong observation is needed in patients who received external radiation therapy to the neck.

Hypothyroidism after Subtotal or Total Thyroidectomy Subtotal thyroidectomy is still an excellent form of treatment for patients with Graves' disease, particularly when antithyroid drugs and 131 1 therapy are not suitable." Surgical approach has three advantages over radioactive iodine therapy. First, the incidence of overt hypothyroidism is considerably less than after radioactive iodine therapy. Second, the incidence of hypothyroidism does not increase as much in later years. Third, patients with Graves' ophthalmopathy are less likely to develop progression than after radioactive iodine therapy. Kuma and associates characterized the type of postoperative hypothyroidism after surgery in patients with Graves' disease who underwent subtotal thyroidectomy. 52 Nearly 40% to 50% of patients experienced subclinical hypothyroidism during the first 4 years after surgery, and the incidence correlates inversely with the size of the thyroid remnant. Palit and colleagues reviewed 35 published papers regarding subtotal thyroidectomy for Graves' disease and found a 25.6% prevalence of postoperative hypothyroidism." The most important aspect of the outcome of surgery is the remnant size of thyroid tissue. The average weight of remnant tissue is 6.1 g, and the increment of each gram of thyroid tissue decreases the prevalence of hypothyroidism by 8.9% but increases the risk of recurrent hyperthyroidism." Other factors, such as the degree of lymphocyte infiltration, iodine deficiency, and medications, may affect the outcome of thyroid surgery and thyroid function.

Iodine Deficiency Iodine deficiency is a serious worldwide problem, particularly in Africa, China, southern Asia, and Europe. It is estimated that about 1 billion people are iodine deficient. About 20 million people have endemic goiter and 2 million people have endemic cretinism. 53 To form adequate amounts of thyroid hormone, 100 to 150 ug/day of iodine is needed.P If iodine intake is less than 100 ug/day, endemic goiter may develop. Further decrease in iodine intake of less than 25 Ilg/day may cause endemic cretinism.P Most patients with endemic goiter have normal thyroid function; however, hypothyroidism develops when iodine deficiency is severe. Endemic cretinism is divided into two types: neurogenic and myxedematous. 54 The former is more common than the myxedematous type and is characterized by irreversible neurologic deficits such

Hypothyroidism - -

as deafness, gait abnormality, squint, and spasticity. Curiously, neurogenic cretins are euthyroid, despite severe iodine deficiency. Myxedematous cretinism is relatively rare and is limited to parts of central Africa, Nepal, and western provinces of China. The clinical manifestation of myxedematous cretinism is attributed to hypothyroidism.

Iodide-Induced Hypothyroidism Hypothyroidism caused by excessive iodine intake has also been observed in patients having the following conditions or underlying diseases: history of postpartum thyroiditis, after a previous episode of subacute thyroiditis, and recombinant INF-a treatment.P The hypothyroidism is transient, and thyroid function returns to normal 2 to 3 weeks after iodide withdrawal; however, long-term follow-up is needed for these patients because some subsequently develop permanent primary hypothyroidism/"

Central Hypothyroidism Abnormalities of the pituitary gland, such as pituitary tumor, ischemic lesion (Sheehan's syndrome), and iatrogenic events (surgical removal or radiation therapy), can cause central hypothyroidism with decreased pituitary TSH secretion. Other rare causes of pituitary lesions include tuberculosis, syphilis, hemochromatosis, sarcoidosis, histiocytosis, and aneurysms of the internal carotid artery. Hypothalamic lesions, such as suprasellar extension of pituitary tumors or craniopharyngioma, meningioma, glioma, and metastatic tumors, can damage the hypothalamus and decrease thyrotropin-releasing hormone (TRH) secretion. This event leads to decreased TSH secretion and subsequent hypothyroidism. Chronic head trauma (e.g., in boxers) can also be the cause of hypothalamic dysfunction. Bexarotene, a retinoid X receptor-selective ligand used for treatment of T-cell lymphoma, has been shown to suppress TSH secretion and cause reversible central hypothyroidism." Hereditary central hypothyroidism is rare, and two types have been described: (1) isolated cases caused by alteration of TSH-~ and TRH receptors and (2) combined pituitary hormone deficiency caused by inactivating mutations of different pituitary transcription factors." It is important to diagnose central hypothyroidism and start treatment at an early stage.

Congenital Hypothyroidism Congenital hypothyroidism is a rare cause of hypothyroidism. There are three different etiologies: (1) athyreosis (absent thyroid); (2) dysgenesis (hypoplastic or lingual thyroid); and (3) dyshormonogenesis (congenital defect in the steps of thyroid hormone synthesis). The importance of identifying the etiology for treatment and follow-up planning has been described previously. 58

Generalized Thyroid Hormone Resistance Hypothyroidism resulting from generalized thyroid hormone resistance is a rare familial disorder. This is caused by a mutation of thyroid hormone receptor ~. Because the thyroid

47

hormone receptor does not function normally, tissues do not get messages of thyroid hormone. Thus, clinical features of hypothyroidism appear in the presence of elevated serum thyroid hormone levels.

Increased Thyroid Hormone Destruction as a Cause of Hypothyroidism Huang and coworkers first reported an infant with hepatic hemangioma who had severe hypothyroidism despite vigorous thyroid hormone treatment. The study revealed increased type 3 deiodinase activity in the liver, causing degradation of thyroid hormone by increased deiodination."

Symptoms and Signs Symptoms of hypothyroidism are listed in Table 6-1. Figure 6-1 shows the characteristic facial expression of primary hypothyroidism and secondary hypothyroidism (Sheehan's syndrome). Prominent periorbital edema is seen in patients with primary hypothyroidism, and this sign is usually absent or minimal in patients with secondary hypothyroidism. Patients with the latter disorder present with a pale face, increased wrinkles, and loss of eyebrow, particularly the lateral portions. In general, patients with overt hypothyroidism have more symptoms than those with subclinical hypothyroidism. Also, the number of symptoms and hypothyroid signs increase as they progress from subclinical hypothyroidism to overt hypothyroidism. In 1969, Billewicz and associates described a scoring system of hypothyroid symptoms and signs to assist in diagnosing hypothyroidism, because no TSH assay was available at that time/" This scoring system was re-evaluated by analyzing symptoms and signs based on modem thyroid function tests in 1997. 61 Delayed relaxation of ankle reflex is the most prominent sign of hypothyroidism with the highest specificity" ; this is

48 - - Thyroid Gland Primary hypothyroidism

A

Secondary hypothyroidism

B

FIGURE 6-1. Characteristic facial expression in primary hypothyroidism (A) and central (secondary) hypothyroidism (B).

consistent with the finding of the Billewicz group. Periorbital puffiness, slow movements, and hearing loss should be sought as hypothyroid signs because of the specificity of these signs in hypothyroidism.w-" Some patients have only mild symptoms and signs of hypothyroidism despite profound biochemical hypothyroidism, and some patients have marked symptoms despite only mild thyroid dysfunction. The discrepancy between symptoms and thyroid function tests indicates that tissue responsiveness and not serum TSH levels determines the symptoms and signs of hypothyroidism." In addition, hypothyroid patients may have many atypical clinical signs and manifestations such as sleep apnea, galactorrhea, respiratory failure, pericardial effusion, pleural effusion, dementia, depression, psychosis, adynamic ileus, and anemia. Therefore, judicious judgment is required when patients show atypical symptoms or signs of hypothyroidism. Even though these symptoms and signs suggest hypothyroidism, the final diagnosis should be made based on laboratory tests.

single test, but the accuracy of the test eventually turns out to be more cost-effective because it avoids frequent repeat testing. In summary, if thyroid status is to be screened as a routine test without clinical signs of thyroid dysfunction, serum TSH alone is acceptable. If one suspects thyroid dysfunction, both TSH and Ff4 testing should be done. Radioactive iodine uptake or thyroid scan is not needed for diagnosing hypothyroidism.

Nonthyroidal Illness as a Diagnostic Dilemma Nonthyroidal illness is an alteration of serum thyroid hormone levels due to the presence of medical illness or fasting or after surgery. The nature of this disorder and a practical approach to this disorder have been well described.F'''? Initially, these patients present with low serum triiodothyronine (T 3) levels due to decreased deiodinase 1 activity that converts T 4 to T 3 • As the disease progresses, total T 4 concentrations are reduced. When Ff4 was measured by equilibrium dialysis, FT 4 levels were usually normal/" whereas FT 4 measured by the analog method is low.68 The analog method is used in automated thyroid testing in most clinical laboratories and is significantly altered by high or low serum protein levels." Serum TSH levels vary depending on the stage of nonthyroidal illness. During the recovery stage of illness, serum TSH levels tend to be elevated. This causes difficulty in determining whether patients are hypothyroid. History of medical illness, careful physical examination, and selection of the right laboratory tests can be helpful. For instance, the presence of goiter, positive TPO antibody, and a long history of hypothyroid symptoms favor a diagnosis of hypothyroidism. Also, the level of serum TSH is known to be helpful. When serum TSH levels are higher than 20 IlIU/mL, primary hypothyroidism is likely, with a few exceptions.s?

Laboratory Testing for Detection of Hypothyroidism

Thyroid Hormone Treatment

The diagnosis of hypothyroidism is now focused on a single or most cost-effective test. A single TSH test was advocated for screening of thyroid dysfunction in 1993. 62 Serum TSH measurements use highly sensitive second- and thirdgeneration assays, based on lower limits of detection of 0.1 and O.OlIlU/mL, respectively. The TSH test accurately measures thyroid function and helps provide accurate thyroid hormone treatment. The limitation of the single TSH test is missing central hypothyroidism, since serum TSH concentrations in most patients with central hypothyroidism are normalP In addition, some patients have elevated serum TSH concentrations (immunologically active and biologically inactive TSH) despite the presence of central hypothyroidism.P Using serum free thyroxine (Ff4) alone as a diagnostic test of hypothyroidism detects hypothyroidism and monitors rapidly changing function better, but it cannot detect subclinical hypothyroidism. Also, low Ff4 alone is not sufficient to make the diagnosis of central or primary hypothyroidism. The combination of serum TSH and Ff4 is the most accurate test for detecting central as well as primary hypothyroidism/" Addition of serum Ff4 to TSH costs more than the

There are three thyroid hormone preparations: L-thyroxine (T 4) , T 3 , and combined T 4 and T 3 (desiccated thyroid [Thyrolar]). Synthetic levothyroxine (L-T4 ) is used most often and has distinct advantages: long half-life of 7 days and efficient conversion to T 3 • Thus, this medication is given once a day, and missing a dose for 1 to 2 days is not harmful. L-T4 also generates T 3 in the liver, the kidney, the brain and other tissues, providing tissue T 3 . The dose of L-T4 of 1.7 ug/kg (0.075 to 0.15 mg/day) should normalize the serum TSH level in most patients with hypothyroidism."? The daily requirement of T4 is 100 to 150 ug for adults, 50 to lOOllg for children, and 50 ug for infants. These are commonly used doses; the dose may need to be adjusted for some patients depending on body weight and severity of hypothyroidism. Patients with myocardial ischemia or cardiac arrhythmia, such as atrial fibrillation, should be treated using a small starting dose of thyroxine (0.0125 to 0.025 mg once a day)." Because of the long half-life of T 4 , once-a-week dosing is also recommended for patients who are not compliant." If L-T4 is to be given once a week, the weekly dose should be slightly higher than seven times the usual daily dose.

Hypothyroidism - -

Is additional T 3 to L-T4 beneficial? The study by Bunevicius and coworkers showed improvement in neuropsychological behavior and mood by combined T 4 and T 3 treatment in hypothyroid patients." In animal models of thyroidectomized rats, the addition of T3 to T 4 normalized plasma and tissue levels of thyroid hormone; T 4 treatment alone did not achieve such normal levels." However, the addition of T, may cause palpitations and worsening angina, particularly in elderly patients. Therefore, T 3 treatment should be used carefully if it is to be employed. Follow-up of patients who are receiving thyroid hormone replacement is critically important. It is now known that about 60% of patients receive an appropriate amount of thyroid hormone and the remaining 40% of patients take too little or too much, based on serum TSH levels in the Colorado Thyroid Disease Prevalence Study. 1 This finding is probably relevant to other geographic areas. It is now known that subclinical hyperthyroidism and subclinical hypothyroidism are risk factors for cardiovascular complications and that strictly controlling thyroid status is beneficial. To achieve normal thyroid status, serum TSH levels should be measured periodically and the thyroid hormone dose should be adjusted accordingly. The only exception is central hypothyroidism, in which a serum TSH level is not helpful; serum Ff4 and Ff3 should be used to determine the thyroid status. Ordering serum Ff3 is important because Ff4 level alone is not sufficient to determine the adequacy of thyroid hormone dose, and normalization of serum FT3 level is also needed in patients with central hypothyroidism." A biologic marker of thyroid hormone action should also be useful when serum TSH levels do not accurately determine thyroid status. Resting energy expenditure has been reported to be a sensitive marker of thyroid hormone replacement." Clinical use of this method seems to be of interest.

Conditions that Affect the Maintenance Dose of T4 Several conditions require increasing the dose of T 4 . Pregnancy is the most important because more T 4 is needed during pregnancy in patients with hypothyroidism based on serial serum TSH measurements." Similarly, patients with hypothyroidism who take estrogen require more thyroid hormone due to increased thyroid-binding protein by estrogen and subsequent decrease in available FT 4.78 Medications to decrease T4 absorption include cholestyramine, sucralfate, ferrous sulfate, aluminum hydroxide, and calcium carbonate.Ys? Increased thyroid hormone replacement should be considered if patients are on these medications. Patients should also take these medications at a different time than when they take their thyroid hormone. Measurement of serum TSH levels is an excellent method to determine the appropriate T4 dose in patients with primary hypothyroidism. In contrast, some conditions require decreased thyroid hormone dose. Androgen therapy decreases T 4-binding globulin and increases Ff4 hormone." Delayed degradation of thyroid hormone can be expected in elderly patients. Thus, patients with androgen therapy for breast cancer and elderly patients (>65 years of age) may need less thyroid hormone.

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Adverse Effects of T4 and Bone Mineral Density Sodium levothyroxine is not recognized as a foreign antigen; thus, allergic reactions to levothyroxine should not occur. However, an allergic reaction to the coloring agents of levothyroxine has been reported.F In this situation, taking a noncolored tablet prevents an allergic reaction. Thyroid hormone is known to increase osteoclastic activity.83 It is documented that patients with untreated Graves' disease will develop bone 10ss.84 This is because of persistently high levels of circulating thyroid hormone levels for prolonged periods. There is controversy regarding how patients who have had thyroidectomy for thyroid cancer should be managed. In general, TSH suppression with high-normal T3and T 4 levels is recommended. There are conflicting opinions about the risks and benefits when patients' serum TSH levels are chronically suppressed.v-" Recently, Quan and associates analyzed the effect of thyroid hormone on bone mineral density in 11 studies that also describe confounding factors relevant to bone loss." They concluded that thyroid hormone suppression treatment does not affect bone mineral density in premenopausal women and in men. However, the effect of TSH suppression in postmenopausal women remains controversial.

Surgery in Patients with Hypothyroidism Surgery in patients with undiagnosed hypothyroidism may cause a catastrophic outcome. It is essential for surgeons to know the precise approach and management of patients with hypothyroidism who may have to undergo surgery in the hypothyroid state. In this section, we describe a practical approach as well as potential problems that may occur during surgery in patients with untreated hypothyroidism.

Approach The following considerations should be taken into account: 1. Does your patient have hypothyroidism or nonthyroidal illness? 2. Does your patient require urgent or elective surgery? 3. Is your patient's cardiac condition stable? 4. Are there any significant complications of hypothyroidism that may cause problems during surgery (anemia, hyponatremia, respiratory failure, signs of adrenal insufficiency)? The first step is to make sure that patients are actually hypothyroid and not in the category of nonthyroidal illness. Patients who undergo surgery often have a picture similar to nonthyroidal illness, which is sometimes difficult to distinguish from primary hypothyroidism. The diagnosis of hypothyroidism should be established as outlined earlier in this chapter by laboratory testing. After the diagnosis is made, one needs to determine whether patients need elective or emergency surgery. If elective surgery is indicated, patients should be treated with thyroid hormone to restore the euthyroid state. This eliminates some of the hypothyroid-related surgical complications. However, difficulty arises if patients

50 - -

Thyroid Gland

have to undergo emergency surgery in the hypothyroid state. At present, there is a general consensus that emergency surgery can be done in patients with mild to moderate hypothyroidism as long as potential perioperative problems and complications are appreciated (Table 6-2). In particular, cardiopulmonary complications (hypotension, respiratory failure, heart failure), hypothermia, hyponatremia, bleeding tendency, and adrenal insufficiency should be the main concerns during and after surgery." Chronic thyroid hormone deficiency affects cardiac function by prolonging systolic and diastolic function, as seen by echocardiography.'" Even patients with subclinical hypothyroidism have an increased risk of myocardial infarction.?" hyperlipidemia," and byperhomocysteinernia,? Therefore, patients' cardiac status needs to be carefully evaluated before surgery. Because of these complications, thoughtful planning for surgery and special preoperative and postoperative management of these patients become critically important. There are three control studies in which surgery was performed on patients in the hypothyroid state. 88.91,92 Problems and complications during and after surgery were then compared with those of euthyroid patients. On the basis of these studies, we have established guidelines for the care of patients in a hypothyroid state who may have to undergo surgery (Table 6-3). Before surgery, all surgical patients in a hypothyroid state should have glucocorticoid administered because hypothyroidism can be of central origin, and even primary hypothyroid patients may experience adrenal insufficiency during surgery.92.93 It is appropriate to administer 50 to 100 mg hydrocortisone every 8 hours during the preoperative period. The normal adrenal gland produces as much as 300 mg hydrocortisone a day; thus, 100 mg of hydrocortisone given every 8 hours should be sufficient to cover all surgical stress. The dose of preoperative medications, such as sedatives, should be reduced or avoided. During intubation, one may encounter difficulty controlling the airway because of a goiter or vocal cord edema. Deep anesthesia should be avoided by adjusting the amount of anesthetic agents administered. During the operation, blood pressure and cardiac function should be monitored carefully. It is highly advisable that inotropic agents and vasopressors be ready for use should these complications arise. One should be aware that patients with severe hypothyroidism may be refractory to the administration of cathecolamines.?" After surgery, extubation may be delayed because of a combination of respiratory failure from hypothyroidism and respiratory depression caused by anesthetic agents. Therefore, monitoring of arterial blood levels is essential.

During the postoperative period, the dose of postoperative sedatives should be reduced. Complete blood count, electrolytes, and cardiopulmonary status need to be routinely checked. Infection may be more difficult to diagnose because some patients with hypothyroidism fail to become febrile. The most difficult case for physicians involves the patient with untreated or profound hypothyroidism who needs emergency surgery. The question is whether such patients should be treated with intravenous T 4 before and during surgery. To our knowledge, no comprehensive study is available in regard to the outcome of surgery with and without T4 therapy. However, surgical procedures are a precipitating cause of myxedema coma, so that patients with severe hypothyroidism should receive intravenous T 4 before surgery (i.e., 200 to 500 ug L-T4 used for myxedema coma). An electrocardiogram should be obtained prior to T 4 treatment. What should be done in patients with ischemic heart disease and profound hypothyroidism who need surgery? If elective surgery is possible, patients should be treated slowly, starting with a low dose of thyroid hormone to restore a near-euthyroid state before surgery. If emergency surgery is required in such patients, 100 to 200 ug of t,- T 4 intravenously is needed, depending on the patient's condition.

Coronary Bypass Surgery Coronary artery bypass graft surgery (CABO) is one of the conditions in which intravenous T 3 may be beneficial and has potential application. CABO can produce a picture of nonthyroidal illness with low serum T 3.95 It is speculated that this low T 3 state may have significant hemodynamic consequences

Hypothyroidism - -

similar to those seen with chronic hypothyroidism. In fact, diminished cardiac contractility altered gene expression similar to that seen in hypothyroidism developed in animals." Also, T 3 treatment increased left ventricular function in patients with congestive heart failure who also exhibited the picture of nonthyroidal illness.97•98 There have been several investigations showing the beneficial effects of T3 treatment given before and after CABG in adults and children by demonstrating increased cardiac outpUt. 99- 103 Administration of T3 had no adverse effects in most studies99•IOO,102 and even lowered the incidence of atrial fibrillation after cardiac surgery.l'" The dose of T3 administered intravenously by Klemperer and colleagues was 1.4 ug/kg of body weight over a period of 6 hours (average total dose of 110 ug) starting immediately after surgery.103 If hypothyroid patients need bypass surgery, the same strategy of intravenous T 3 treatment should be considered, but such management remains controversial. In fact, one investigation failed to find any change in outcome when Tj-treated bypass patients were compared to those receiving dopamine and to placebo groups."

Prevention Neonatal screening must be done for all infants because mental retardation and growth abnormality caused by hypothyroidism can be prevented by thyroid hormone treatment. Because serum TSH levels in normal newborns are elevated immediately after birth, blood samples should be obtained 4 to 6 days after birth. Neonatal screening is generally performed by spotting blood from the heel onto filter paper. Measurement of T, and TSH is done in the eluate from the filter paper. T4 therapy should be started immediately after the diagnosis of hypothyroidism is established. For newborn infants, the dosage is 25 to 50 ug/day: for infants 6 to 12 months old, 50 to 75 ug/day is commonly used. T4 should be crushed and mixed with milk for administration. Early treatment of infants in whom hypothyroidism was discovered 3 to 6 days after birth was associated with a normal IQ and normal growth. !04

Iodine Deficiency Iodine is an important precursor of thyroid hormone. Thus, iodine deficiency leads to impaired production of thyroid hormones that are essential for prenatal and postnatal brain development for normal cognitive and neurologic function. The importance of iodine deficiency was addressed by the Rome Conference on Nutrition and the 1990 World Summit for Children, which called for the virtual elimination of iodine deficiency by the year 2000,105 There are three methods of iodine prophylaxis: iodinated salt, iodized oil, and iodinated water. Iodinated salt is the most inexpensive and most suitable for the general population. Iodinated salt is designed to provide more than 100 ug of iodine per day, assuming that daily intake of salt is 2 to 5 g. However, iodine content in salt varies in each country. Iodized oil is a longacting iodine and can be given orally or intramuscularly. One dose of 1 mL of iodized oil contains 480 mg of iodine. If given intramuscularly, it provides enough iodine for 2 to 3 years in children and 7 years in adults. Duration of oral

51

iodized oil is 1 to 2 years. Iodination of drinking water is not widely practiced except in Italy. Iodine prophylaxis is an important project to be carried out nationwide to save many children and adults from endemic goiter and cretinism.

Prevention of Hypothyroidism after Subtotal Thyroidectomy Approximately 25% of patients develop hypothyroidism after subtotal thyroidectomy for Graves' disease." Prevention of postoperative hypothyroidism has been attempted by changing the size of remnant tissues. Increasing remnant tissue size decreases the incidence of hypothyroidism,' 1 but recurrent Graves' disease is a problem. S2.106 Shimizu and coworkers tried autotransplantation of cryopreserved thyroid tissues in four patients who developed postoperative hypothyroidism after subtotal thyroidectomy for Graves' disease.P? About 2.5 to 3.5 g of cryopreserved thyroid tissues at -80°C were autotransplanted into the muscle of the forearm, and three of the four patients were able to discontinue thyroid hormone medications.I'" This interesting technique may be applicable for the prevention of postoperative hypothyroidism in some cases.

REFERENCES I. Canaris Gl, Manowitz NR, Mayor G, et al. The Colorado Thyroid Disease Prevalence Study. Arch Intern Med 2000;160:526. 2. Hollowell lG, Staehling NW, Flanders WO, et al. Serum TSH, T4 , and thyroid antibodies in the United States population (1988-1994): National Health and Nutrition Examination Survey (NHANES III). 1 Clin Endocrinol Metab 2002;87:489. 3. Cooper DS. Subclinical hypothyroidism. N Engl 1 Med 2001 ;345:260. 4. Chu lW, Crapo LM. The treatment of subclinical hypothyroidism is seldom necessary. 1 Clin Endocrinol Metab 2001 ;86:4591. 5. Hak AE, Pols HAP, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: The Rotterdam Study. Ann Intern Med 2000; 132:270. 6. Bindels Al, Westendorp RG, Frolich M, et al. The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: A need for case-finding? Clin Endocrinol (Oxf) 1999;50:217. 7. Lien EA, Nedrebo BG, Varhug lE, et al. Plasma total homocysteine levels during short-term iatrogenic hypothyroidism. 1 Clin Endocrinol Metab 2000;85:1049. 8. McDermott MT, Haugen BR, Lezotte DC, et al. Management practices among primary care physicians and thyroid specialists in the care of hypothyroid patients. Thyroid 2001; 11:757. 9. Kalderon AE, Bogaars HA. Immune complex deposits in Graves' disease and Hashimoto's thyroiditis. Am 1 Med 1977;63:729. 10. Weetman AP, Cohen SB, Oleesky DA, et al. Terminal complement complexes and C lIC I inhibitor complexes in autoimmune thyroid disease. Clin Exp Immunol 1989;77:25. II. Weetman AP, Tandon N, Morgan BP. Antithyroid drugs and release of inflammatory mediators by complement-attacked thyroid cells. Lancet 1992;340:633. 12. Kagi D, Vignaux F, Ledermann B, et al. Fas and perforin pathways as major mechanisms of T-cell-mediated cytotoxicity. Science 1994;265:528. 13. Lowin B, Hahne M, Mattmann C, et al. T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 1994;370:650. 14. Giordano C, Stassi G, De Maria R, et al. Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis. Science 1997;275:960. 15. Baker JR lr. The nature of apoptosis in the thyroid and the role it may play in autoimmune thyroid disease. Thyroid 2001; 11:245. 16. Stassi G, De Maria R. Autoimmune thyroid disease: New models of cell death in autoimmunity. Nature Rev Immunol 2002;2: 195.

52 - - Thyroid Gland 17. Bretz JD, Rymaszewski M, Arscott PL, et aI. Death pathway expression and induction in thyroid follicular cells. J BioI Chern 1999;274:23627. 18. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996;383:787. 19. Van der Veen RC, Stohlman SA. Encephalitogenic THI cells are inhibited by TH2cells with related peptide specificity: Relative roles of interleukin (IL)-4 and IL-lO. J Neuroimmunol 1993;48:213. 20. Rago T, Chiovata L, Grasso L, et aI. Thyroid ultrasonography as a tool for detecting thyroid autoimmune diseases and predicting thyroid dysfunction in apparently healthy subjects. J Endocrinol Invest 2001;24:763. 21. Premarwardhana LD, Parkes AB, Ammari F, et aI. Postpartum thyroiditis and long-term thyroid status: Prognostic influence of thyroid peroxidase antibodies and ultrasound echogenicity. J Clin Endocrinol Metab 2000;85 :71. 22. Bagis T, Gokcel A, Saygill ES. Autoimmune thyroid disease in pregnancy and the postpartum period: Relationship to spontaneous abortion. Thyroid 2001;11:1049. 23. Amino N, Tada H, Hidaka Y. Postpartum autoimmune thyroid syndrome: A model of aggravation of autoimmune disease. Thyroid 1999;9:705. 24. Abalovich M, Gutierrez S, Alcaraz G, et aI. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002;12:63. 25. Haddow JE, Palomaki GE, Allan WC, et aI. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549. 26. Pop VJ, Kuijpens JL, van Baar AL, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999;50:149. 27. Fukata S, Kuma K, Sugawara M. Relationship between cigarette smoking and hypothyroidism in patients with Hashimoto's thyroiditis. J Endocrinol Invest 1996;19:607. 28. Nystrom E, Bengtsson C, Lapidus L, et aI. Smoking-a risk factor for hypothyroidism. J Endocrinol Invest 1993;16:129. 29. Vestergaard P, Rejnmark L, Weeke J, et aI. Smoking as a risk factor for Graves' disease, toxic nodular goiter, and autoimmune hypothyroidism. Thyroid 2002;12:69. 30. Muller B, Zulewski H, Huber P, et aI. Impaired action of thyroid hormone associated with smoking in women with hypothyroidism. N Engl J Med 1995;333:964. 31. Braverman LE, Ingbar SH, Vagenakis AG, et aI. Enhanced susceptibility to iodide myxedema in patients with Hashimoto's disease. J Clin Endocrinol Metab 1971;32:515. 32. Tajiri J, Higashi K, Morita M, et aI. Studies of hypothyroidism in patients with high iodine intake. J Clin Endocrinol Metab 1986;63:412. 33. Franklyn JA, Sheppard Me. Amiodarone and thyroid dysfunction. Trends Endocrinol Metab 1993;4:128. 34. Roti E, Minelli R, Gardini E, et aI. Thyrotoxicosis followed by hypothyroidism in patients treated with amiodarone: A possible consequence of a destructive process in the thyroid. Arch Intern Med 1993;153:886. 35. Bartalena L, Grasso L, Brogioni S, et aI. Serum interleukin-6 in amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 1994;78:423. 36. Mori M, Tajima K, ada Y, et aI. Inhibitory effect of lithium on the release of thyroid hormones from thyrotropin-stimulated mouse thyroids in a perfusion system. Endocrinology. 1989;124:1365. 37. Urabe M, Hershman JM, Pang XP, et aI. Effect of lithium on function and growth of thyroid cells in vitro. Endocrinology 1991; 129:807. 38. Myers DH, Carter RA, Bums BH, et aI. A prospective study of the effects of lithium on thyroid function and on the prevalence of antithyroid antibodies. Psychol Med 1985;15:55. 39. Carella C, Mazziotti G, Morisco F, et aI. The addition of ribavirin to interferon-a therapy in patients with hepatitis C virus-related chronic hepatitis does not modify the thyroid autoantibody pattern but increases the risk of developing hypothyroidism. Eur J EndocrinoI202;146:743. 40. Dalgard 0, Bioro K, Helium K, et aI. Thyroid dysfunction during treatment of chronic hepatitis C with interferon a: No association with either interferon dosage or efficacy of therapy. J Intern Med 2002;251 :400. 41. Carella C, Mazziotti G, Morisco F, et al. Long-term outcome of interferon-a-induced thyroid autoimmunity and prognostic influence of thyroid autoantibody pattern at the end of treatment. J Clin Endocrinol Metab 2001 ;86: 1925. 42. Aozasa K, Inoue A, Tajima A, et aI. Malignant lymphoma of thyroid gland: Analysis of 79 patients with emphasis on histologic prognostic factors. Cancer 1986;58: 100.

43. Matsuzuzka, F, Miyauchi A, Katayama S, et aI. Clinical aspects of thyroid lymphoma: Diagnosis and treatment based on our experience of 119 cases. Thyroid 1993;3:93. 44. Nofal MM, Beierwaltes WH, Patno ME. Treatment of hyperthyroidism with sodium. JAMA 1996;197:605. 45. Cunnien AJ, Hay 10, Gorman CA, et aI. Radioiodine-induced hypothyroidism in Graves' disease: Factors associated. J Nucl Med 1982;23:978. 46. Sridama V, McCormick M, Kaplan EL, et aI. Long-term follow-up study of compensated low-dose 1311 therapy for Graves' disease. N Engl J Med 1984;311 :426. 47. Tell R, Sjodin H, Lundell G, et aI. Hypothyroidism after external radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 1997;39:303. 48. Sklar C, Whitton J, Mertens A, et aI. Abnormalities of the thyroid in survivors of Hodgkin's disease: Data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 2000;85:3227. 49. Mercado G, Adelstein OJ, Saxton JP, et aI. Hypothyroidism: A frequent event after radiotherapy and after radiotherapy with chemotherapy for patients with head and neck carcinoma. Cancer 2001 ;292:2892. 50. Little JB. Cellular, molecular, and carcinogenic effects of radiation. Hematol Oncol Clin North Am 1993;7:337. 51. Palit TK, Miller CC III, Miltenburg DM. The efficacy of thyroidectomy for Graves' disease: A meta-analysis. J Surg Res 2000;90: 161. 52. Kuma K, Matsuzuka F, Kobayashi A, et aI. Natural course of Graves' disease after subtotal thyroidectomy and management of patients with postoperative thyroid dysfunction. Am J Med Sci 1991;302:8. 53. Medeiros-Neto G. Iodine deficiency disorders. Thyroid 1990;1:73. 54. Boyages SC, Halpern JP. Endemic cretinism: Toward a unifying hypothesis. Thyroid 1993;3:59. 55. Markou K, Georgopoulos N, Kyriazopoulou V, et aI. Iodine-induced hypothyroidism. Thyroid 2001;11:501. 56. Sherman SI, Gopal J, Haugen BR, et aI. Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med 1999;340: 1075. 57. Asteria C, Persani L, Beck-Peccoz P. Central hypothyroidism: Consequences in adult life. J Pediatr Endocrinol Metab 2001;14 (SuppI5):1263. 58. Hanukoglu A, Perlman K, Sharnis L, et al. Relationship of etiology to treatment in congenital hypothyroidism. J Clin Endocrinol Metab 2001 ;86: 186. 59. Huang SA, Tu HM, Harney JW, et aI. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 2000;343:185. 60. Billewicz WZ, Chapman RS, Crooks J, et aI. Statistical methods applied to the diagnosis of hypothyroidism. Q J Med 1969;38:255. 61. Zulewski H, Muller B, Exer P, et aI. Estimation of tissue hypothyroidism by a new clinical score: Evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 1997;82:771. 62. Becker DV, Bigos ST, Gaitan E, et al. Optimal use of blood tests for thyroid function. JAMA 1993;269: 2736. 63. Persani L, Ferretti E, Borgato S, et aI. Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J Clin Endocrinol Metab 2000;85:3631. 64. Wardle CA, Fraser WD, Squire CR. Pitfalls in the use of thyrotropin concentration as a first-line thyroid-function test. Lancet 2001; 357:1013. 65. De Groot LJ. Dangerous dogmas in medicine: The nonthyroidal illness syndrome. J Clin Endocrinol Metab 1999;84:151. 66. Langton JE, Brent GA. Nonthyroidal illness syndrome: Evaluation of thyroid function in sick patients. Endocrinol Metab Clin North Am 2002;31:159. 67. Chopra 11. Clinical review 86: Euthyroid sick syndrome-is it a misnomer? J Clin Endocrinol Metab. 1997;82:329. 68. Wang R, Nelson JC, Weiss RM, et aI. Accuracy of free thyroxine measurements across natural ranges of thyroxine binding to serum proteins. Thyroid 2000;10:31. 69. Nicoloff JT, Spencer CA. Clinical review 12: The use and misuse of the sensitive thyrotropin assays. J Clin Endocrinol Metab 1990;7:553. 70. Weinberg AD, Brennan MD, Gorman CA, et aI. Outcome of anesthesia and surgery in hypothyroid patients. Arch Intern Med 1983; 143:893. 71. Ellyin PM, Kumar Y, Somberg JC. Hypothyroidism complicated by angina pectoris: Therapeutic approaches. J Clin PharmacoI1992;32:843. 72. Grebe SK, Cooke RR, Ford HC, et aI. Treatment of hypothyroidism with once-weekly thyroxine. J Clin Endocrinol Metab 1997;82:870.

Hypothyroidism - 73. Bunevicius R, Kazanavicius G, Zalinkevicius R, et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999;340:424. 74. Escobar-Morreale HF, del Rey FE, Obregon MJ, de Escobar GM. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology 1996;137:2490. 75. Ferretti E, Persani L, Jaffrain-Rea ML, Giambona S, et al: Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 1999; 84:924. 76. al-Adsani H, Hoffer LJ, Silva JE. Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replacement. J Clin Endocrinol Metab 1997;82:1118. 77. Mandel SJ, Larsen PR, Seely EW, et al. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 1990;323:91. 78. Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 2001 ;344: 1743. 79. Mandel SJ, Brent GA, Larsen PRo Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 1993;119:492. 80. Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the absorption of levothyroxine. JAMA 2000;283:2822. 81. Arafah BM. Decreased levothyroxine requirement in women with hypothyroidism during androgen therapy for breast cancer. Ann Intern Med 1994;121:247. 82. Magner J, Gerber P. Urticaria due to blue dye in Synthroid tablets. Thyroid 1994;4:341. 83. Britto JM, Fenton AJ, Holloway WR, Nicholson GC. Osteoblasts mediate thyroid hormone stimulation of osteoclastic bone resorption. Endocrinology 1994;134:169. 84. Riggs BL, Melton LJ III. Involutional osteoporosis. N Engl J Med 1986;314: 1676. 85. Jodar E, Martinez-Diaz-Guerra G, Azriel S, Hawkins F. Bone mineral density in male patients with L-thyroxine suppressive therapy and Graves' disease. CalcifTissue Int 2001;69:84. 86. Nuzzo V, Lupoli G, Esposito Del Puente A, et al. Bone mineral density in premenopausal women receiving levothyroxine suppressive therapy. Gynecol Endocrinol 1998;12:333. 87. Quan ML, Pasieka JL, Rorstad O. Bone mineral density in welldifferentiated thyroid cancer patients treated with suppressive thyroxine: A systematic overview of the literature. J Surg Oncol 2002;79:62. 88. Ladenson PW, Levin AA, Ridgway EC, et al.. Complications of surgery in hypothyroid patients. Am J Med 1984;77:261. 89. Vora J, O'Malley BP, Petersen S, et al. Reversible abnormalities of myocardial relaxation in hypothyroidism. J Clin Endocrinol Metab 1985;61:269. 90. Hak AE, Pols HAP, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: The Rotterdam Study. Ann Intern Med 2000;132:270.

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91. Drucker OJ, Burrow GN. Cardiovascular surgery in the hypothyroid patient. Arch Intern Med 1985;145:1585. 92. Weinberg AD, Brennan MD, Gorman CA, et al. Outcome of anesthesia and surgery in hypothyroid patients. Arch Intern Med 1983;143:89. 93. Finlayson DC, Kaplan JA. Myxoedema and open heart surgery: Anaesthesia and intensive care unit experience. Can Anaesth Soc J 1982;29:543. 94. Myerowitz PO, Karnienski RW, Swanson OK, et al. Diagnosis and management of the hypothyroid patient with chest pain. J Thorac Cardiovasc Surg 1983;86:57. 95. Bennett-Guerrero E, Kramer DC, Schwinn DA. Effect of chronic and acute thyroid hormone reduction on perioperative outcome. Anesth Analg 1997;85:30. 96. Ojamaa K, SabetA, Kenessey A, et al. Regulation of rat cardiac Kvl.5 gene expression by thyroid hormone is rapid and chamber specific. Endocrinology 1999; 140:3170. 97. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344:501. 98. Hamilton MA, Stevenson LW, Fonarow GC, et al. Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure. Am J Cardiol 1998;81 :443. 99. Cimochowski GE, Harostock MD, Foldes PJ. Minimal operative mortality in patients undergoing coronary artery bypass with significant left ventricular dysfunction by maximization of metabolic and mechanical support. J Thorac Cardiovasc Surg 1997;113:655. 100. Klemperer JD, Klein IL, Ojamaa K, et al. Triiodothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg 1996;61:1323. 101. Bettendorf M, Schmidt KG, Grulich-Henn J, et al. Tri-iodothyronine treatment in children after cardiac surgery: A double-blind, randomized, placebo-controlled study. Lancet 2000;356:529. 102. Portman MA, Fearneyhough C, Ning XH, et al. Triiodothyronine repletion in infants during cardiopulmonary bypass for congenital heart disease. J Thorac Cardiovasc Surg 2000;120:604. 103. Klemperer JD, Klein IL, Ojamaa K, et al. Triiodothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg 1996;61:1323. 104. Moltz KC, Postellon DC. Congenital hypothyroidism and mental development. Compr Ther 1994;20:342. 105. UNICEF. The State of the World's Children. London, Oxford University Press, 1995, p 12. 106. Patwardhan NA, Moront M, Rao S, et al. Surgery still has a role in Graves' hyperthyroidism. Surgery 1993;114:1108. 107. Shimizu K, Kurnita S, Kitamura Y, et al. Trial of autotransplantation of cryopreserved thyroid tissue for postoperative hypothyroidism in patients with Graves' disease. J Am Coli Surg 2002;194:14.

Graves' and Plummer's Diseases: Medical and Surgical Management Michael Sean Boger, MD, PharmD • Nancy Dugal Perrier, MD

Historical Aspects The striking clinical malady of exophthalmic goiter, with its distinctive protruding eyes, tachycardia, nervousness, and enlarged thyroid, has been known for more than 150 years. Thyrotoxicosis was first described in 1786 by Parry, a physician in England, but was not reported until after his death in 1825. It was also noted by von Basedow and a handful of others. I To this day, on the continent of Europe, it is known as Basedow's disease. In the English-speaking world it is named for Robert James Graves because of a lucid monograph he wrote on the subject. As with many medical eponyms, however, he was not the first to describe the condition.' It was during the next century that Dr. Henry Plummer first described toxic nodular goiter, which came to be known as Plummer's disease. Both of these physicians made everlasting contributions to the field of endocrinology.

Robert James Graves (1796-1853) Robert James Graves (Fig. 7-1) was a descendant of a colonel in Cromwell's army. He was described as a brilliant student, highly cultured, handsome, and charming. In Dublin, Ireland, where he was born and trained in medicine, he received the highest educational award, the Golden Medal, for organizing medical education.' He introduced "clinical teaching," which has evolved into bedside teaching today, encouraging students to actually examine patients, present them to the professor, and write clinical histories-a novel idea at the time. 1,4 He insisted that his students attend autopsies to correlate findings there with the patient's state prior to death.' This was met with great opposition by the then current tradition that students have extensive book knowledge and little practical experience. I Dr. Graves' clinical lectures were the talk of the town, where he introduced many novel concepts including the pinhole pupil after pontine hemorrhage, timing the pulse by watch, and abandoning the practice of bleeding and starving

54

patients with pyrexia. i.as His book, Clinical Lectures on the Practice ofMedicine, is regarded as a medical masterpiece.' He was a pioneer in proper nutritional therapy for the sick and requested that his epitaph read: "He Fed the Fevers."! In 1835, he published his famous monograph, "A Newly Observed Affection of the Thyroid Gland in Females."

Three cases of violent and long continued palpitations in each of which the same peculiarity presented itself (with) enlargement ofthe thyroid gland ... the eyes assumed a singular appearance for the eye balls were apparently enlarged, so that when she slept or tried to shut her eyes, the lids were incapable of closing. When the eyes were open, the white sclerotic could be seen, to a breadth of several lines, all around the cornea. .. .The enlargement of the thyroid ... seems ... essentially different from goiter, in not attaining a size at all equal to that observed in the latter disease.6

Henry Plummer (1874-1937) The death rate in the United States from hyperthyroidism around 1908 was 25%. The extremely high mortality in goiter surgery was underscored by Samuel Gross, who stated the following:

Can the thyroid gland, when in a state of enlargement, be removed with a reasonable hope of saving the patient? Experience emphatically answers no... no sensible man will. ... Every stroke of a knife will be followed by a torrent of blood, and lucky will it be for him if his victim lives long enough to enable him to finish his horrid butchery/ By 1918, Charlie Mayo had performed his 5000th thyroidectomy. He had a personal death rate of 3%, a number touched by no one on the continent, in part due to Dr. Henry Plummer (Fig. 7-2).2 From Minnesota, Dr. Plummer was first consultant to Drs. Will and Charlie Mayo.? He developed a

Graves' and Plummer's Diseases: Medical and Surgical Management - -

55

clinical one. He was a pioneer in the development of radiographic diagnosis and therapy," His other achievements include designing the tube system for transporting patient records and the complex medical record system still in use at Mayo today." He later developed the first intercom system and irrigation system in the United States.' By 1922, Dr. Plummer was elaborating a theory about goiter disease. He led weekly "goiter lunches" to share his expertise.l When thyroxine (T4) proved to be 65% iodine, he posed the hypothesis that the extra toxic substance he postulated to be the cause of crises in exophthalmic goiter was a noniodinated molecule of T4, a compound discovered at the Mayo Clinic by Dr. Edward Kendall.s? He reasoned that a (then unknown) stimulus causes the thyroid gland to work too fast and if not enough iodine was readily available in the blood, the gland would tum out a half-finished product, a molecule of T4 with the essential iodine missing. At once, he believed that iodine should be tried on his goiter service at St. Mary's Hospital, and the results were miraculous.'

FIGURE 7-1. Dr. Robert James Graves. (From Jay V. Dr. Robert James Graves. Arch Pathol Lab Med 1999;123:284.)

special interest in the thyroid gland through his neighbor, Mr. Strain, the first goiter patient to be operated on by the Mayo brothers.' In 1913, Dr. Plummer first distinguished toxic adenomatous goiter from exophthalmic goiter. Until the availability of radioactive iodine, which made scintigraphy possible in the mid-1940s, this disease was an entirely

Against all tradition, every professor of medicine, every textbook ... following his own understanding of the function of the thyroid, [he] saved the life of a woman by injecting 5.0 mg of thyroxine intravenously/' At the Association of American Physicians in May 1923, he presented his results that administration of iodine preoperatively and postoperatively would prevent the crises that caused death after symptomatic treatment of exophthalmic goiter. He found that iodine in both nonoperative cases and as preoperative treatment significantly reduced mortality." His work turned the most treacherous operation known to surgery into one of the safest in the hands of any competent operator. It was hailed as one of medicine's greatest gifts to surgery and the Germans coined the fitting word for it-Plummerung. 2

Graves'Disease Epidemiology There are several subtle but distinct differences among patients with hyperthyroidism from Graves' and Plummer's diseases, as outlined in Table 7-1. 10-13 Graves' disease is the most prevalent autoimmune disorder in the United States and the most common cause of hyperthyroidism. The chief risk factor for Graves' disease is female gender, in part due to modulation of the autoimmune response by estrogen. Other potential precipitants of the autoimmune process

FIGURE 7-2. Dr. Henry Plummer. (From Clapesattle H. The Doctors Mayo. Rochester, MN, Mayo Foundation for Medical Education and Research, 1990.)

56 - - Thyroid Gland

FIGURE 7-3. A, Pathogenesis of Graves' hyper-

A

B

c

*

Propylthiouracil X Beta-blockers X Potassium iodide Potassium perchlorata Methimazole ~ Glucocorticoids { } Calcium channel blockers

*

thyroidism.IO·18.48,S3 Inflammatory cells infiltrate the thyroid, producing inflammatory mediators including various interleukins and tumor necrosis factor (TNF)-a. Such inflammatory mediators increase the production of stimulatory antibodies to the thyroglobulin receptor, leading to an increased production of cyclic adenosine monophosphate (cAMP) and, thus, thyroid hormones. They also bind to other receptors on thyroid follicular cells, including HLA class I, further increasing their production, and antithyroglobulin antibodies, producing a vicious cycle. B, Thyroid hormone synthesis. IO,18,48.53 The production of thyroid hormones involves (A) active transport of iodide into the follicular cell mediated by a sodium-iodide transporter in the basement membrane of the follicular cell and secretion across the apical membrane into colloid; (B) uptake of amino acids, which are then synthesized into thyroglobulin (TG) via the endoplasmic reticulum (ER), which is modified by the Golgi apparatus and secreted via exocytosis of secretory vesicles into colloid; (C) oxidation and organification of iodide into iodine via thyroperoxidase (TPO) and hydrogen peroxide; (D) iodination of TG via TPO to attach iodine to tyrosyl residues in the TG molecule to form monoiodotyrosine (MIT) and diiodotyrosine (DIT); (E) coupling of two iodotyrosine residues via TPO produces thyroid hormones thyroxine (T4) and triiodothyronine (T3) that are incorporated in the TG molecule for storage in colloid; (F) endocytosis of colloid from the lumen back into the follicular cell; (G) TG proteolysis via lysozymes into T4, MIT, and DIT; (H) deiodination of MIT and DIT into iodide; and (I) deiodination of T4 into T3, which occurs, to a lesser extent, in the thyroid gland and, predominantly, in the periphery. C, Effects of antithyroidal therapies. l3,48.S1 Propylthiouracil (PTU) and methimazole (MTM) inhibit synthesis of T 3 and T4 by serving as preferential substrates for TPO, becoming iodinated and diverting oxidized iodine away from potential iodination sites in TG. They are actively trapped by the thyroid gland against a concentration gradient. They may also inhibit the oxidation and organification of iodine and the coupling reaction. PTU, but not MTM, inhibits deiodinase in both the thyroid gland and in peripheral tissues. Both agents appear to have direct effects on the disordered immunity in Graves' disease. ~ Blockers (BB) and calcium-channel blockers (CCB) reduce the vascularity of the gland; BBs control the peripheral manifestations of hyperthyroidism. Glucocorticoids in stress doses may help stabilize the vascular bed and block conversion of T4 to T3. Potassium iodide decreases iodine transport, iodine organification, TG proteolysis, and thyroid hormone secretion. It may also inhibit the ability of thyroid-stimulating hormone and cAMP to stimulate colloid endocytosis. Potassium perchlorate inhibits the iodine-trapping mechanism.

Graves' and Plummer's Diseases: Medical and Surgical Management - - 57

include infection, particularly Yersinia enterocolitica, stress, and iodine exposure. Smoking is weakly associated but strongly associated with the development of ophthalmopathy. There is no evidence that infection affects the susceptibility to Graves' hyperthyroidism or directly induces it. No single gene is known to cause the disease or to be necessary for its development, although there is a well-established association with certain human leukocyte antigen (HLA) alleles that vary among racial groups. Prevalence is similar among whites and Asians and lower in blacks. 14

Pathogenesis Graves' hyperthyroidism is caused by thyroid-stimulating antibodies that bind to and activate the thyrotropin receptor on thyroid follicular cells, stimulating the synthesis of cyclic adenosine monophosphate (cAMP) and, in tum, thyroid hormones (Fig. 7_3A).13.15-18 Inflammatory cells infiltrate the thyroid gland and produce inflammatory mediators including various interleukins and tumor necrosis factor (TNF)-a. These inflammatory mediators stimulate the production of stimulating antibodies to the thyrotropin receptor, leading to an increased production of cAMP and, thus, thyroid hormones. These inflammatory mediators bind to and stimulate various other receptors on the follicular cells of the thyroid, including HLA class I, causing a further increase in their production and a further increase in antithyrotropin antibodies, leading to a vicious cycle. Antibodies are also produced against thyroid peroxidase and thyroglobulin. This leads to abnormalities in most organ systems, including the cardiovascular and central nervous systems. The thyroid-stimulating antibodies not only cause thyroid hypersecretion but also hypertrophy and hyperplasia of the thyroid follicles, which have a columnar and folded epithelium and little colloid. The result is the characteristic goiter (Fig. 7-4A and B). This is due to the emergence of autoreactivity of T and B cells to the thyrotropin receptor. The exact mechanisms involved are unknown. As illustrated in Figure 7-3A, there are high circulating levels of various cytokines produced by lymphocytes in the thyroid gland. There is no direct correlation between serum concentrations of thyroid-stimulating antibodies and serum thyroid hormone. There is diffuse columnar epithelial hyperplasia and colloid excess. 14 Lymphocytic infiltration is often present, occasionally resulting in the formation of germinal centers.Iv'? These intrathyroidal lymphocytes are a major source of autoantibodies, with contributions from the cervical lymph nodes and bone marrow. 14

Clinical Manifestations The manifestations of Graves' disease can be marked or subtle, with periods of exacerbation or remission. It is now recognized as a multisystem disease characterized by diffuse goiter (see Fig. 7-4B), thyrotoxicosis, infiltrative ophthalmopathy and, occasionally, by infiltrative dermopathy?" The symptoms can be functional as a result of increased circulating levels of thyroid hormones or systemic as a result of autoantibodies directed against thyroid and extrathyroid organs such as the eye or skin. In an individual patient, these

features may occur singly or in varying combinations, such that the full syndrome may never develop. The most common symptoms are nervousness, fatigue, irritability, palpitations or rapid heartbeat, heat intolerance, weight loss, tremor, and decreased menstrual periods in women. These symptoms are present in more than half of all patients with the disease. With myxedema, the skin is warm and moist and has a silky texture. Patients may have graying of the hair, vitiligo, or onycholysis. The hair becomes thinner, and alopecia may develop.v" The classic goiter is one of the most consistent features of Graves' disease. Approximately 90% of patients younger than 50 years of age have a firm, diffuse goiter compared to 75% in older patients." It is usually symmetrical, smooth, firm, and rubbery and a bruit or thrill may be present in the gland. Graves' disease can also occur in normal-sized glands, especially in the elderly." Clinically evident ophthalmopathy occurs in 50% of patients, in 75% of whom the eye signs appear within a year before or after diagnosis of hyperthyroidism. There is an inflammatory infiltrate composed predominately of activated T cells in the extraocular muscles and orbital connective tissue. This infiltrate may localize in the orbit via recognition by T cells of an orbital antigen that cross-reacts with thyroid antigen, such as the thyrotropin receptor expressed in preadipocyte fibroblasts. Cytokines stimulate the production of glycosarninoglycans, leading to edema and fibrosis.Pv" These changes displace the eyeball forward due to increased volume of tissue within the orbit and may interfere with extraocular eye muscle function.P Patients may have photophobia, eye irritation, diplopia, and change in visual acuity. Most frequently, this presents as eyelid retraction or lag and periorbital edema. Proptosis (exophthalmos) occurs in up to one third of patients (Fig. 7-5A and B). Eyelid erythema, conjunctival injection, chemosis, swelling, and eyelid edema may occur. 13.20 Dermopathy occurs in 1% to 2% of patients, almost always in the presence of severe ophthalmopathy. In fact, there are close histologic similarities between the orbital connective tissue in Graves' ophthalmopathy and the pretibial connective tissue in pretibial dermopathy (Fig. 7-5C).22 Infiltrative skin manifestations are associated with eye changes in most cases. 13.20 It is most frequent over the anterolateral aspects of the shin but can occur in other sites.'? Pretibial myxedema presents as scaly, thickened, indurated skin, often with an orange-peel texture. 19.22

Diagnosis Features for the diagnosis of Graves' disease are shown in Table 7_2.13.20.23 The clinical triad of palpitations, weight loss, and heat intolerance plus diffuse bilateral goiter usually secures the diagnosis, but one must rule out subacute thyroiditis, thyrotoxicosis factitia, and other conditions. Radioactive iodine uptake studies can demonstrate a diffuse goiter (see Fig. 7-4C). Patients with increased thyroid hormone secretion have high uptake, whereas those with low uptake indicate suppression of thyroid-stimulating hormone (TSH) levels without increased thyroid-stimulating antibodies.P A radionuclide scan is essential if subacute thyroiditis is suspected to differentiate it from Graves' disease."

58 - - Thyroid Gland

B

A

FIGURE 7-4. The characteristic diffuse goiter in Graves' disease. A, Patient with a symmetrically diffusely enlarged thyroid gland. B, Surgical specimen reveals diffuse hypertrophy and hyperplasia with a smooth, rubbery yet lobular consistency. C, Homogeneous increased technetium (99mTc) uptake on radionuclide scan. (A, Courtesy of Ken Greer, MD, Charlottesville, VA.)

c Patients with low uptake do not need treatment, because low-uptake hyperthyroidism usually implies thyroiditis, which generally resolves spontaneously. Some argue for routine testing of antibodies, whereas others note that Graves' disease can nearly always be inferred correctly on the basis of clinical findings." Therapy

The ideal therapeutic agent for Graves' disease would offer (I) prompt control of disease manifestations, (2) return to and maintenance of euthyroidism, (3) minimal morbidity and mortality, and (4) reasonable COSt,20 The current therapeutic armamentarium remains empirical with antithyroid medications, radioactive iodine ablation, and subtotal or near-total thyroidectomy. Each option has advantages, disadvantages, and complications. Factors to consider when deciding on a treatment plan for thyrotoxicosis include patient age, associated ophthalmopathy, thyroid size, presence of compressive symptoms, substernal thyroid extension, contraindications to the use of radioiodine, intolerance to antithyroid drugs, presence of a dominant nodule, response to previous therapy, and patient preference. 12

Subtotal thyroidectomy was the standard of treatment in the early part of the 20th century. The goal was to eliminate the underlying pathology while leaving a tiny thyroid remnant to achieve a euthyroid state without causing recurrent hyperthyroidism. Eastern countries such as Japan continue to use surgery as first-line therapy today. In 1946, Hertz and Roberts described radioactive iodine therapy for hyperthyroidism, which has since gradually replaced surgery as firstline therapy because of the belief that it was safer and more effective. It is inexpensive and safer for debilitated patients who may be poor surgical candidates. However, since the introduction of radioactive iodine, surgery has improved with preoperativedrug treatment and modem operative techniques. There is a worldwide variation in the use of therapy. A recent questionnaire from the American Thyroid Association demonstrated what many believe-using a selective surgical approach is an underused treatment modality in the United States when an experienced surgeon is available. Radioactive iodine is widely used in North America, whereas antithyroid medications and surgery are more commonly used in Europe, China, and Japan. Radioactive iodine is used by most clinicians for patients with recurrent or persistent hyperthyroidism," A similar survey was

Graves' and Plummer's Diseases: Medical and Surgical Management - -

A

59

B

FIGURE 7-5. Systemic manifestations of Graves' disease. Graves' ophthalmopathy with characteristic wide, staring gaze, lid lag, significant periorbital edema (A), and proptosis (B). Dermopathy (C) presenting as pretibial myxedema with nonpitting edema over the shins, scaly thickening, and skin induration, creating the characteristic orange-peel texture. (Courtesy of Ken Greer, MD, Charlottesville, VA.)

c conducted by Soloman and associates in the United States using hypothetical cases of Graves' disease." Radioiodine therapy was chosen 70% of the time, with antithyroid drug therapy as the alternative. Surgery represented only 2% of the total options selected. ANTITHYROID MEDICATIONS

Indications of a favorable response to medical therapy include a small thyroid gland, reduction in goiter size with medical therapy, biochemical euthyroidism with normalization of TSH, and decreased antibody titers." Antithyroid medications interfere with one or more steps in the biosynthesis

and secretion of thyroid hormone, as illustrated in Figure 7-3B and C.13.16-18.27.28 Initial doses are methimazole 10 to 40 mg three times daily and propylthiouracil (PTU) 100 to 300 mg three times daily and subsequently decreased to oncedaily dosing once the patient is rendered euthyroid. The rapidity of response is influenced by the severity of the underlying disease, the size of the gland reflecting hormonal stress, and the dose and frequency of the agent used. Patients generally become euthyroid within 6 to 12 weeks after starting therapy. Methimazole has the advantage of once-daily dosing and improves compliance and side effects, particularly hepatotoxicity. Side effects are less common when used in low dose compared with PTU, where side effects are not dose dependent. PTU is preferred in pregnancy and lactation due to higher protein binding. Methimazole may cause aplasia cutis, a scalp defect, in newborns. PTU is also preferred in thyroid storm when rapid normalization of serum thyroid hormone levels is critical because it inhibits peripheral conversion of T4 to triiodothyronine (T3) . However, it may cause agranulocytosis." Potassium perchlorate is used with iodine-induced hyperthyroidism related to amiodarone exposure. Pretreatment with antithyroid medications before radioactive iodine

60 - - Thyroid Gland therapy reduces radiation-induced thyroiditis that could transiently exacerbate hyperthyroidism but also reduces the effectiveness of radiation therapy. Propranolol, 5 to 40 mg four times daily, can be given to control the catecholamine response of hyperthyroidism. Two drops of saturated solution of potassium iodide (SSKl, Lugol's solution) three times a day (48 ug/drop) can be added 10 to 14 days prior to surgery to decrease the vascularity of the gland" Although it rapidly decreases serum thyroid hormone levels, most patients treated with SSKI have a rapid "escape" within 1 to 2 weeks back to hyperthyroidism. Antithyroid medications are used for 12 to 24 months and should be slowly tapered.?? Because of the high failure rate, medical therapy with curative intent is primarily indicated in adults with small, nontoxic goiter «40 g), those with mildly elevated thyroid hormone levels, and those who exhibit rapid remission with reduction of gland size. Long-term therapy may lead to remission, but approximately 40% of patients fail a 2-year course." The recurrence rate of disease is 60% after 6 months of therapy, with a latent period of 2 to 6 weeks.'? The disadvantages of these agents are that multiple daily dosing requires strong patient compliance, and they often fail to produce a lasting remission. Predictors of poor response to oral medications are large goiter size and high thyroid hormone output. The disadvantages of the major treatment modalities for Graves' disease are outlined in Table 7_3. 21,27 For methimazole and PTU, the latent period is 2 to 6 weeks due to initial stores of hormone, and after 2 years of therapy, up to 69% have a recurrence." Side effects occur in up to 7% of patients; the most serious is agranulocytosis, occurring in approximately 0.3% of cases. Hypothyroidism develops in 15% of cases. For these reasons, antithyroid therapy is most useful in patients with mild disease, in those with small goiters, and in children and adolescents.?" RADIOACTIVE IODINE

Advantages of radioactive iodine therapy are avoidance of daily medications and symptoms of hyperthyroidism. The lifetime risk of early or late hypothyroidism with radioactive iodine necessitating, lifelong replacement therapy, is 3%

per year. Euthyroidism may take 4 to 6 months to achieve, and multiple doses may be required. Hyperparathyroidism may develop from radiation exposure. It is contraindicated in pregnancy, which should be avoided for a year, and in breastfeeding mothers. Factors to consider in therapy with radioactive iodine include increased risk of benign thyroid tumors, malignant transformation in young patients, thyroid cancers that develop are more aggressive, and ophthalmopathy is more likely compared with surgery.29,30 The effect of therapy for Graves' hyperthyroidism on the course of ophthalmopathy is controversial. A recent prospective, randomized study evaluated the effects of radioactive iodine versus antithyroid medications and the effects of glucocorticoids in patients with or without Graves' ophthalmopathy." Among those treated with radioactive iodine, ophthalmopathy developed or worsened in 15% of patients 2 to 6 months after therapy. None of the patients with baseline ophthalmopathy in this group had improved eye disease. Among patients treated with a combination of radioactive iodine and prednisone, 67% of patients with ophthalmopathy at baseline had improvement and no patients had progression. In the methimazole group, 92% of patients with baseline ophthalmopathy had improved eye disease, 3% had worsening of disease, and the remainder had no change. Since treatment with antithyroid medications such as methimazole is not often followed by development or progression of ophthalmopathy, it might be argued that patients with Graves' disease who have ophthalmopathy should be treated with these agents. However, antithyroid therapy may not give satisfactory control of hyperthyroidism and, more important, hyperthyroidism can recur after withdrawal of therapy. Therefore, it is best to achieve permanent control of hyperthyroidism in patients with ophthalmopathy, which can occur only with surgery. Total thyroidectomy has been recommended for patients with severe or progressive ophthalmopathy to completely remove the abnormal thyroid antigens serving as the stimulus for damage to the extraocular muscles and optic nerve. 12 If radioactive iodine is used, the best chance for preventing ophthalmopathy is with use of steroids, although their use also comes with significant side effects. There is an

Graves' and Plummer's Diseases: Medical and Surgical Management - -

unexplained increased mortality as compared to the general population. In a study evaluating the mortality in a cohort of 7209 patients with hyperthyroidism treated with radioactive iodine, mortality from all causes and mortality due to cardiovascular and cerebrovascular diseases and fracture was increased. For cerebrovascular disease, mortality was most marked in the first year and was confined to patients aged 50 years and 01der. 32 This may reflect diastolic hypertension or atrial fibrillation, and there appeared to be a relationship between the severity of hyperthyroidism and risk of cerebrovascular disease." Therefore, the role of radioactive iodine in the treatment of Graves' disease is controversial. Radioactive iodine is a good choice for patients with recurrence after surgery, since reoperation is more technically difficult" SURGERY

Surgery for Graves' disease is underused in the United States. The advantages are that treatment is rapid and stops hyperthyroidism, avoids the possible long-term risks of radioactive iodine, and provides tissue for histologic examination. The complication rate is low in experienced hands. The disadvantages are that hyperthyroidism may persist or recur if insufficient tissue is removed and hypothyroidism usually develops after near-total thyroidectomy. The absolute and relative indications for thyroidectomy are summarized in Table 7_4. 20,24 Five percent of patients with Graves' disease develop nodules, 20% of which are malignant. Thyroidectomy is useful in patients having serious allergic reactions during medical therapy. In pregnancy, surgery is usually performed during the second trimester. Surgery is not more technically difficult in patients who have been treated medically. There is a higher chance of hypothyroidism after radioactive iodine ablation than after subtotal thyroidectomy. Radioactive iodine therapy has a 6-week to 6-month latency of onset, during which patients need to be placed on antithyroid medications, whereas surgery results in rapid remission. Total or near-total thyroidectomy appears to stabilize or improve eye manifestations, whereas radioactive iodine tends to aggravate Graves' ophthalmopathy unless given with steroids." For substernal goiters, even in the absence of symptoms, surgery is always recommended, because most patients will likely develop

61

symptoms in the future as the gland enlarges, including acute respiratory distress.s' Surgery is particularly advantageous in juvenile Graves' disease, which primarily affects female children between 11 to 15 years of age. It is the leading cause of hyperthyroidism in childhood.v' Most children present with emotional lability, hyperactivity, nervousness, and learning disabilities. In this population, medical therapy has a failure rate approaching 60% to 80% due to poor compliance, side effects, and disease aggressiveness at this age.35 When compared to surgery, radioactive iodine has a higher incidence of recurrence, hypothyroidism, and subsequent hyperparathyroidism." Additionally, the risk of cancer in patients treated with radioactive iodine is greater than in the general population and is inversely related to age. Children treated with radioactive iodine are also more likely to experience hyperparathyroidism than adults. The recommendation is to leave one remnant less than 4 g on one side as relapse is more likely.34 The anatomy of the thyroid gland and surrounding arteries and nerves must be carefully considered during surgery (Fig. 7-6). While dissecting the upper pole of the gland, carefully avoid the external branch of the superior laryngeal nerve and superior thyroid artery. An approach via the avascular space between the cricothyroid muscle and the upper pole of the gland allows a medial approach to the superior pole vessels and early ligation of the vessels directly on the thyroid capsule." The external branch of the superior

thyroid a,

Inferior thyroid a.

Recurrent laryngeal n. Ligament of Berry

FIGURE 7-6. Important anatomic considerations during thyroid surgery. The recurrent laryngeal nerve is at greatest risk for injury at three key locations: at the ligament of Berry, during ligation of branches of the inferior thyroid artery, and at the thoracic inlet. The external branch of the superior laryngeal nerve is at greatest risk when dissecting the superior pole of the gland, whereas the internal branch would theoretically be damaged at the level of the thyrohyoid membrane,

62 - - Thyroid Gland laryngeal nerve is motor to the cricothyroid muscles, and the internal branch is purely sensory, innervating the mucosal lining of the supraglottic larynx. The external branch is intimately associated with the superior thyroid artery, and the relationship of these two structures is extremely variable. In up to 20% of normal individuals and in up to 56% of patients with large goiters, it crosses the avascular space below the tip of the superior pole of the thyroid. Damage to the external branch leads to an inability to reach high pitches or project the voice or to easy vocal fatigue during prolonged speech. Although this may be subtle in everyday conversation, such a disability is significant in patients whose voice is key to their career (e.g., singers). Damage to this nerve may be reduced by beginning dissection in the avascular cricothyroid space and proceeding cephalad. Ligating and dividing the vessels near the capsule reduces the chance of injury to the external branch when it is adherent to or passing between the branches of the superior thyroid artery, which occurs in approximately 15% of cases. 37,38 Damage to the internal branch leads to anesthesia of the superior laryngeal mucosa and loss of the protective mechanism for foreign bodies in the larynx. The reported incidence of permanent damage to the external branch of the superior laryngeal nerve after surgery is approximately 1% and of the recurrent laryngeal nerve is 0 to 4%.28 There are also many variations in the relationship of the recurrent laryngeal nerve (inferior laryngeal nerve) to the inferior thyroidal artery-it may pass superficial, deep to (most common), or within the terminal branches of the artery. Thus, it is extremely important to properly identify the branches of the inferior thyroid artery in relation to the end-arteries supplying the parathyroid glands and delineate their relationship to the recurrent laryngeal nerve." Passing superiorly and medially to enter the larynx along the posterior portion of the cricothyroid muscle, it is intimately related to the capsule of the thyroid and may be invisible. The most common regions where the recurrent laryngeal nerve is at risk of injury are near the inferior thyroid artery, near the ligament of Berry, and at the inferior pole of the gland (see Fig. 7-6). All of the intrinsic laryngeal muscles are supplied by the recurrent laryngeal nerve-the posterior cricoarytenoid muscle that abducts the vocal fold, the lateral cricoarytenoid muscle that adducts the vocal fold, the thyroarytenoid that relaxes the vocal fold, the transverse and oblique arytenoid muscles that close the intercartilaginous portion of the rima glottidis, and the vocalis muscles that relax the posterior vocal ligament and tense the anterior vocal ligament. Therefore, damage to the recurrent laryngeal nerve can lead to significant pathology. Unilateral recurrent nerve damage causes the vocal cord to be adducted toward the midline causing hoarseness, temporary aphonia, and laryngospasm. Bilateral damage may lead to respiratory distress, necessitating intubation." It is not unusual for the tubercle of Zuckerkandl to extend laterally over this nerve." Hypoparathyroidism after surgery may be temporary or permanent. It is most frequent with bilateral thyroid lobectomies. Once the superior pole is mobilized, the inferior pole vessels can be carefully mobilized with preservation of the lower parathyroids, which often lie in or near the thyrothymic ligament. The parathyroids are also at risk when

dissecting cervical lymph nodes. The incidence of permanent hypoparathyroidism after thyroid surgery should be less than 2%. Hematoma is a rare complication after thyroidectomy but has devastating consequences. An expanding hematoma can severely compromise the airway and become a medical emergency." The extent of thyroidectomy performed depends on several factors. A total thyroidectomy is indicated in patients with a coexisting malignancy such as thyroid cancer or multiple endocrine neoplasia, in those with severe ophthalmopathy, or in patients unwilling to undergo reoperation or radioactive iodine therapy. Subtotal thyroidectomy is useful for most patients. Factors associated with hypothyroidism after subtotal thyroidectomy include remnant size and autoimmune activity. If a euthyroid patient is the goal, some functioning thyroid tissue must be preserved. A 4- to 7-g remnant is the most appropriate size. The classic report by Mitchie illustrated that, in the range of 2 to 8 g, increasing the remnant size by 1 g decreases the rate of postoperative hypothyroidism by about 10%.38 Increasing the remnant size above 109 does not, however, lead to further appreciable decreases in hypothyroidism but, rather, leads to more recurrences. Remnants that are 8 g or larger decrease the risk of hypothyroidism but increase the incidence of persistent or recurrent disease. Three-gram remnants are suggested for children, a population that has a higher incidence of disease recurrence.A" Witte and colleagues performed a prospective, randomized trial to further examine the effects of total versus subtotal thyroidectomy." Patients were randomized to one of three interventions: bilateral subtotal thyroidectomy with less than 4-g remnant, unilateral hemithyroidectomy and contralateral subtotal thyroidectomy with less than 4-g remnant, and total thyroidectomy. Ophthalmopathy improved in 72% of all patients. The TSH receptor antibody level showed no difference in any group. Hypoparathyroidism was most common in total thyroidectomy (28% vs. 12%, P < 0.002). If the removal of thyroid tissue could reduce the antigenic load, one would expect total thyroidectomy to be more effective than subtotal thyroidectomy in preventing eye disease. Unfortunately, total thyroidectomy may be more likely than subtotal thyroidectomy to have operative complications and postoperative hypothyroidism. Therefore, given the lack of difference in postoperative outcome and increased chance of hypoparathyroidism, total thyroidectomy is not advocated. The upper limit of 4-g total thyroid remnant size was chosen in that study because of the higher incidence of recurrent Graves' disease in patients with larger thyroid remnants. Abe and coworkers assessed the influence of subtotal thyroidectomy compared to radioactive iodine therapy on the outcome of Graves' ophthalmopathy.t? Over a 5-year period, 287 cases were studied prospectively. All patients were treated initially with antithyroid medications to maintain euthyroidism, and those having a high titer of TSH receptor antibody were considered for thyroidectomy or radioactive iodine. Among patients who did not have proptosis at baseline, the incidence of eye disease occurrence was 7.1% in the surgically treated group, 9.2% in the medically treated group, and 11.9% in the radiation-treated group. In patients treated with surgery, ophthalmopathy

Graves' and Plummer's Diseases: Medical and Surgical Management - - 63

progressed in 5.6% and was alleviated in 16.7% compared with 10.4% and 3.0%, respectively, with radioactive iodine. Eye disease improved in 75% of patients treated with surgery, in 61.5% of patients treated medically, and in only 25% of patients treated with radioactive iodine. This study further supports that surgery is a better treatment than radioactive iodine in patients with Graves' disease with eye involvement. Gupta and associates examined the effect of 1311 therapy on Graves' ophthalmopathy in 20 newly diagnosed patients with Graves' hyperthyroidism.f Patients were followed with ophthalmologic evaluations and magnetic resonance imaging at baseline, 2, and 6 months and with examination alone at 6 years. At baseline, 50% of patients showed evidence of mild Graves' ophthalmopathy. There was no significant risk for radioiodine-induced initiation or progression of mild Graves' ophthalmopathy. However, this study did not assess patients with moderate to severe Graves' ophthalmopathy in whom radioiodine may have a more detrimental effect. Recent clinical studies of thyroidectomy for Graves' disease may not reflect outcomes accurately because of small sample size, especially when estimating ideal remnant size. A meta-analysis was performed by Palit and colleagues on studies in which patients underwent total or subtotal thyroidectomy.f The purpose of the study was to determine the overall efficacy and complication rates for both procedures in Graves' disease. There were 35 studies comprising 7241 patients with a median follow-up of 5.6 years. Overall, persistent or recurrent hyperthyroidism occurred in 7.2% of patients, and successful treatment of hyperthyroidism occurred in 92%. Hypothyroidism occurred in all patients receiving a total thyroidectomy. Subtotal thyroidectomy produced a euthyroid state in more than 60% of cases, with an 8% rate of persistent or recurrent hyperthyroidism. There was no statistical difference in complication rates of the two procedures, including permanent recurrent laryngeal nerve injury or permanent hypoparathyroidism. Andaker and coworkers examined the effects of two types of subtotal thyroidectomy: (1) bilateral subtotal with 2 g of remnant tissue left on both sides and (2) the HartleyDunhill procedure with a total lobectomy and isthmectomy on one side and a 4-g remnant on the other side, as illustrated in Figure 7_7.43 They found no differences in the results but preferred the Hartley-Dunhill procedure. A bigger remnant on one side allows dissection not to be carried far enough laterally to encounter the recurrent laryngeal nerves or parathyroid glands, thereby minimizing the risk of complications. If disease were to recur, only one side of the neck would need to be re-explored. The operation is more difficult than operating on patients with nontoxic goiter or thyroid neoplasms because of the extensive vascularity of the gland in Graves' disease. However, complication rates are still low. Patients should be rendered euthyroid before thyroidectomy to prevent thyroid storm. Preoperative iodine for patients with Graves' disease is useful in reducing intraoperative bleeding, allowing better visualization and preservation of the surrounding nerves, vasculature, and parathyroid glands. 12 Thyroid storm is a medical emergency and presents as central nervous system agitation or depression, cardiovascular

A

B FIGURE 7-7. Types of subtotal thyroidectomy. A, Bilateral subtotal, with remnant tissue left on both sides. B, Hartley-Dunhill procedure, with total lobectomy and isthmectomy on one side and remnant on other side.

dysfunction, fever, and hyperthyroidism. It is precipitated by surgery, trauma, infection, and administration of an iodine load as occurs with amiodarone or after radioactive iodine treatment. Signs and symptoms resemble severe thyrotoxicosis, with profound tachycardia, fever, and confusion. Disorientation may occur from dehydration, vomiting, diarrhea, and fever, and in extreme cases overt mania or coma may occur as a late sequela." The best management of thyroid storm is prophylaxis by rendering patients euthyroid prior to surgery. It should be treated immediately with hemodynamic support and oxygen. Oral Lugol's solution (potassium iodide, SSKI), 5 drops three or four times daily, or intravenous iodinated radiographic contrast agents such as sodium ipodate block iodine uptake and the secretion of thyroid hormones (see Fig. 7-3). Antithyroid therapy should be started at least 1 hour prior to SSKI to prevent eventual worsening of hyperthyroidism. PTU blocks the peripheral conversion of L-T4 to T 3, for rapid resolution of symptoms. Fever should be controlled with nonaspirin compounds and rapid cooling with ice or cooling blankets. Aspirin should be avoided because it increases free thyroid hormone levels. ~ Blockers in high doses, such as propranolol 480 mg/day in divided

64 - - Thyroid Gland doses or a 2- to 5-mg/hr infusion, control adrenergic manifestations. Calcium channel blockers are useful in patients intolerant to ~ blockers. Glucocorticoids in stress doses help stabilize the vascular bed, block peripheral conversion of T, to T3 , and prevent adrenal exhaustion." Dialysis may be necessary in some cases, such as thyroid storm induced by amiodarone. Sedation may be necessary in cases of agitation with hyperactivity."

Plummer's Disease (Toxic Multinodular Adenomatous Goiter) Toxic multinodular goiter was first described in 1913 by Dr. Henry Plummer (see Fig. 7-2), who believed that practically all adenomatous goiters would eventually become toxic given enough time. He noted that the average interval from first detection of the goiter to subsequent development of symptoms was 15 years.45.46

Pathogenesis Nodular goiters (Fig. 7-8A) occur when hyperplasia of a small subset of follicular cells with abnormal growth potential

A

occurs at multiple sites in the thyroid gland." In contrast with Graves' disease, where the thyroid follicular cells are hyperfunctional due to an external factor, IgG, which binds to and stimulates the TSH receptor, autonomous thyroid nodules develop hyperfunction through alterations in the cell biology of the follicular cell, possibly via a somatic mutation constitutively activating cAMP.47 The development of toxic multinodular goiter is a gradual process, as Plummer noted that goiters were present an average of 17 years before becoming toxic. 45.46 Plummer's disease occurs when one or more thyroid nodules become autonomous, trap and organify more iodine, and secrete more thyroid hormone independently of control by TSH stimulation." In the remainder of the gland, the normal feedback mechanism is operative. 11 As the adenomatous areas grow, their contribution to thyroid secretion increases and TSH secretion, therefore, decreases. This decrease in TSH results in decreased activity of the extranodular tissue. One or more follicles in a diffuse goiter has greater intrinsic growth and functional capability than the others and continues to grow and function despite declining TSH secretion, causing initially a nontoxic multinodular goiter and, ultimately, a toxic multinodular goiter." There is a gradual evolution of a sporadic diffuse goiter to a toxic one. A multinodular goiter occurs due to recurrent episodes of hyperplasia and involution and is considered toxic if it

B

FIGURE 7-8. Toxic multinodular goiter (Plummer's disease). A, Patient with a multilobulated, asymmetrically enlarged thyroid gland. B, The gland is inhomogeneous and coarsely nodular with areas of fibrosis and cystic change. C, Focal regions of increased 99mTc uptake on radionuclide scan revealing multiple functioning thyroid nodules with suppressed uptake in surrounding tissue. (B from Edis AJ, Grant CS, Egdahl RH: Surgery of the thyroid. In: Manual of Endocrine Surgery, 2nd ed. New York, Springer-Verlag, 1984.)

c

Graves' and Plummer's Diseases: Medical and Surgical Management - - 65

induces thyrotoxicosis. These multinodular goiters produce the most extreme enlargement of the thyroid, up to 2 kg, and are multilobulated and asymmetrically enlarged.'? Most "hot" or "autonomous" nodules have either TSH receptor mutations (most often) or gsp (less common) mutations." There is no correlation between morphology and function of the nodules.'? In contrast to the thyroid in Graves' disease, which is soft and resembles muscle, the thyroid in Plummer's disease on cut section has irregular nodules containing brown, gelatinous colloid.'? It most commonly occurs in areas of endemic goiter."

Clinical Manifestations Plummer's disease is more common than Graves' disease in elderly patients. It accounts for 15% of cases of hyperthyroidism in nonendemic goiter regions.'? The hyperthyroidism may be caused by multiple hyperfunctioning nodules or, less frequently, a single hyperfunctioning nodule. It is differentiated from Graves' disease in that extrathyroidal manifestations and thyroid autoantibodies are not present,20,44 Approximately 80% of patients with multinodular goiter are chemically euthyroid at initial presentation.'? Patients are more likely to have a prolonged course with weight loss, depression, atrial fibrillation, and muscle wasting than with Graves' disease and thyrotoxicosis is often less obvious and easily missed.P When it presents in the young, thyrotoxicosis is seen as weight loss, anxiety, tremor, insomnia, and heat intolerance, similar to Graves' disease." Atrial fibrillation in the setting of an enlarged goiter is often the only finding in the elderly." Symptoms of dysphagia, hoarseness, dyspnea, stridor, and cough may indicate a retrosternal or intrathoracic multinodular goiter.'? It is important to monitor T 3 carefully because these patients are more likely to have T 3 toxicosis, with high serum free T 3 and normal free T4 concentrations. This may be due to limited ability of the nodules to oxidize iodide or may be due to their preponderance in areas of relatively low iodine intake. On examination, the goiter has one or more palpable nodules. Compressive symptoms such as dysphagia or dyspnea may be present. Thyrotoxicosis may be exacerbated following iodine-containing contrast media, leading to the Jodbasedow phenomenon." Toxic multinodular goiter accounts for less than 5% of cases of thyrotoxicosis in iodine-sufficient areas but nearly half of cases in relatively iodine-deficient areas. Many patients have subclinical thyrotoxicosis with few, if any, symptoms and signs of thyrotoxicosis and normal thyroid hormone levels, but others have overt thyrotoxicosis. The incidence of thyroid cancer coexisting with multinodular goiter approaches 10%, similar to that in patients with a solitary thyroid nodule. Coexistent cancer is more common with nonfunctioning nodules and in men. 10

Diagnosis Patients with toxic multinodular goiter present with increased T 3 but a normal T 4 and free T4 index (T 3 thyrotoxicosis). A thyroid scintiscan (Fig. 7-8B) classically reveals one or more areas of increased uptake and suppressed areas in between. The hot nodules are identified as areas concentrating

radioactive iodine to a greater degree than the surrounding thyroid tissue. Technetium pertechnetate is preferred over radioiodide scanning and is useful in the differentiation of toxic nodular goiter from Graves' disease or to evaluate compressive symptoms.'? However, iodine is the preferred imaging agent for a toxic goiter with a substernal component due to its higher energy photons." Autonomous function of the nodules can be demonstrated by administering suppressive doses of T 3, which does not affect the function of the nodule but decreases the uptake of the extranodular tissue. Administration of TSH increases or restores the radionuclide uptake in the quiescent tissue." In contrast with Graves' disease, administration of exogenous T 3 or T 4 does not suppress the function of autonomous nodules because their secretory activity is, by definition, independent of stimulation with pituitary TSH. In addition, the secretions of the autonomous nodules suppress pituitary TSH, causing variable reduction of the function of the extrathyroidal tissue.

Therapy Similar to treatment of Graves' disease, there are three major classes of therapy: antithyroid medications, radioactive iodine ablation, and subtotal or near-total thyroidectomy. Antithyroid medications have not been widely accepted in the treatment of Plummer's disease because they are less effective and lifetime therapy would be necessary since, unlike the usual spontaneous remission of Graves' disease, the hyperthyroidism of toxic multinodular goiter continues indeflnitely.Pr" Their use is recommended only as adjunctive when needed for the initial control of hyperthyroidism. 10 As with Graves' disease, prior to surgery, patients should be rendered euthyroid with p blockers and thionarnides." Lugol's solution, in contrast with Graves' disease, should be avoided in pretreatment of Plummer's disease because it may significantly worsen thyrotoxicosis." Radioactive iodine therapy is inferior to its role in Graves' disease because the toxic multinodular goiter often persists after therapy.r' The goal of radiation therapy in Plummer's disease is destruction of autonomous tissue and restoration of euthyroidism.t? Erickson and associates evaluated medical records of 253 patients treated for toxic multinodular goiter between 1975 and 1993. 50 Of those treated with radioactive iodine, 20% required a second treatment, compared to zero patients treated with surgery. A latency of several months occurs before treatment is effective. In the report by Erickson and associates, half of surgically treated patients had achieved success within 3 days for surgical treatment versus 3 months for radioactive iodine treatment" Similar results were found in a report by Jensen and colleagues, who evaluated the records of 446 patients treated between 1950 and 1974. 51 The dose of radioactive iodine is variable, and several doses may be needed. Uptake is often relatively low, necessitating high doses to almost twice those given to Graves' patients for successful treatment. Uptake is localized to the autonomous toxic nodules and the remaining thyroid tissue is suppressed.r' The thyroid tissue adjacent to the thyroid nodule receives about 2000 rads, which is in the carcinogenic range for the surrounding normal tissue, enough to induce

66 - - Thyroid Gland subsequent thyroid cancer. Radioactive iodine therapy in large multinodular goiters extending substernally puts patients at risk for radiation-induced thyroiditis that can, although rare, cause acute thyroid enlargement and airway compression." A follow-up study assessed solitary autonomous thyroid nodules treated with iodine.P In this study of 23 patients, 54% of nodules were still palpable, 9% had increased in size, and 36% were hypothyroid. Goldstein and Hart concluded that iodine does not eradicate the nodule. The incidence of hypothyroidism in that study was not related to gland size, thyroid function, or total dose of radiation. Radioactive iodine is an effective therapy for hyperthyroidism caused by a single hot nodule, since the suppressed normal extranodular tissue should be protected via its inability to concentrate radioactive iodine. It is also suitable for patients with mild hyperthyroidism or those considered at high risk for surgical management" A recent study suggests that patients treated with high doses of 1311, such as those needed for Plummer's disease, may have xerostomia and xerophthalmia that persist for several years after therapy.53 Seventy-nine patients were treated between 1990 and 1995 with a dose ranging from 25 to 100 mCi. The numbers of patients who reported xerostomia 1, 2, and 3 years after therapy were 33%, 20%, and 15%, respectively. The most common symptoms were dry mouth and abnormal taste; oral ulcers and sialadenitis were also reported. One explanation is that salivary glands and lacrimal tissue have sodium-iodide transporters. Induction of an autoimmune lacrimal gland dysfunction, similar to that in Sjogren's syndrome, may also occur. For these reasons, surgery is the treatment of choice in Plummer's disease, particularly if patients have obstructive symptoms or if there is concern of carcinoma in the goiter. Surgery is immediate and certain, there is a low recurrence rate, and the patient is freed from the large goiter volume and its associated cardiac manifestations. The surgical approach varies depending on the type of nodule." For solitary nodules, nodulectomy or thyroid lobectomy is the treatment of choice because cancer is rare. For toxic multinodular goiter, lobectomy on one side and subtotal lobectomy on the other side is recommended in most cases to prevent the need for bilateral reoperation in cases of recurrence.>' The approach and precautions are similar to the surgical management of Graves' disease.

Conclusions There is a key role for both the endocrinologist and endocrine surgeon in the management of hyperthyroidism due to Graves' and Plummer's diseases, and therapy involves a team approach. The three basic treatment modalities-antithyroid therapy, radioactive iodine therapy, and surgery-each have their advantages and disadvantages. Surgery is an excellent therapy for both diseases because there is no mortality, and there are few complications or recurrences. It allows a rapid and consistent method of achieving euthyroidism and avoids the long-term risks of radioactive iodine. However, experience is important. The Hartley-Dunhill procedure is the treatment of choice.

Patients should be rendered euthyroid before operation. It can be technically difficult because of gland vascularity. Radioactive iodine ablation should be considered for disease recurrence after surgery.

Acknowledgments The authors owe many thanks to the following individuals, without whom preparation of this chapter would not have been possible: Gloria Graham, MD, Associate Professor, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, for her expert guidance on the dermatologic manifestations of thyroid diseases Kenneth Greer, MD, Associate Professor, Department of Dermatology, University of Virginia Health Systems, Charlottesville, Virginia, for generously providing prize photographs of the systemic manifestations of Graves' disease Nat Watson, Jr, MD, Associate Professor, Radiological SciencesRadiology, Wake Forest University School of Medicine, for his indispensable guidance on nuclear medicine and graciously providing radiologic images Paige Clark, MD, Associate Professor, Radiological Sciences-Radiology, Wake Forest University School of Medicine, for providing technetium 99m radionuclide scans Phyllis Easter, Secretarial Assistant, Department of Surgery, Wake Forest University School of Medicine, for her endless devotion in assisting with the preparation of this chapter Andrea Hassell, Secretarial Assistant, Division of Surgery, Wake Forest University School of Medicine, for her wonderful assistance

REFERENCES I. Jay V. Dr. Robert James Graves. Arch Pathol Lab Med 1999;123:284. 2. Clapesattle H. The Doctors Mayo. Rochester, MN, Mayo Foundation for Medical Education and Research, 1990. 3. Taylor S. Graves of Graves' disease: 1796-1853. J R Coli Physicians Lond 1986;20:298. 4. Havard CWH. Medical eponyms updated: Graves' disease. Br J Clin Pract 1990;44:409. 5. Whitehead RW. Robert James Graves, physician, educator, scientist. Circulation 1969;39:719. 6. Graves RJ. Clinical lectures. Lond Med Surg J 1835;7:516. 7. McConahey WM, Pady DS. Henry Stanley Plummer. Endocrinology 1991;129:2271. 8. Anonymous. Henry Stanley Plummer, MD, 1874-1937. Int Surg 1977;62:635. 9. Keys TE. Dr. Henry Stanley Plummer, 1874-1937. Minn Med 1972;55 :957. 10. Hurley DL, Gharib H. Evaluation and management of multinodular goiter. Otolaryngol Clin North Am 1996;29:527. II. Weiner JD. Plummer's disease: Localized thyroid autonomy. J Endocrinol Invest 1987; 10:207. 12. Mittendorf EA, McHenry CR. Thyroidectomy for selected patients with thyrotoxicosis. Arch Otolaryngol Head Neck Surg 2001;127:61. 13. Weetman AP. Graves' disease. N Engl J Med 2000;343: 1236. 14. McIver BM, Morris IC. The pathogenesis of Graves' disease. Endocrinol Metab Clin North Am 1998;27:73. 15. Felz MW. Stein PP. The many "faces" of Graves' disease: I. Postgrad Med 1999;106:57. 16. Carrasco N. Thyroid hormone synthesis. In: Braverman LE, Utiger RD (eds), Werner and Inghar's The Thyroid. Philadelphia, Lippincott Williams & Wilkins, 2000, p 52. 17. Dunn IT. Biosynthesis and secretion of thyroid hormones. In: DeGroot LJ, Iameson JL (eds), Endocrinology. Philadelphia, WB Saunders, 2000, p 1290. 18. Stevens A, Lowe I. Endocrine system. In: Human Histology, 2nd ed. Baltimore, Mosby, 1997, p 251. 19. Cotran R, Kumar S, Collins T: The endocrine system. In: Robbins Pathologic Basis of Disease. Philadelphia, WB Saunders, 1999, p 1121. 20. AIsanea 0, Clark O. Treatment of Graves' disease: The advantages of surgery. Endocrinol Metab Clin North Am 2000;29:321. 21. Felz MW, Stein PP. The many "faces" of Graves' disease: II. Postgrad Med 1999;106:45.

Graves' and Plummer's Diseases: Medical and Surgical Management - - 67 22. Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med 1993;329:469. 23. Dabon-Almirante CLM, Surks MI. Clinical and laboratory diagnosis of thyrotoxicosis. Endocrinol Metab Clin North Am 1998;27:25. 24. Alsanea 0, Clark OH. Benign disorders of the thyroid gland. World J Surg. In press. 25. Olinoer D, Hesch D, Lagasse R, et al. The management of hyperthyroidism due to Graves' disease in Europe in 1986: Results of an international survey. Acta Endocrinol Suppl 1987;285:3. 26. Soloman B, Glinoer D, Lagasse R, et al. Current trends in the management of Graves' disease. J Endocrinol Metab 1990;70:1518. 27. Cooper DS. Antithyroid drugs for the treatment of hyperthyroidism caused by Graves' disease. Endocrinol Metab Clin North Am 1998;27:225. 28. Udelsman R. Thyroid gland. In: Greenfield LJ, Mulholland MW, Oldham KT, et al (OOs), Surgery: Scientific Principles and Practice. Philadelphia, Lippincott Williams & Wilkins, 2001, p 1261. 29. Tezelman S, Grossman RF, Siperstein AE, et al. Radioiodine-associated thyroid cancers. World J Surg 1994;18:522. 30. Wood LC, Ingbar SH. Hypothyroidism as a late sequelae in patients with Graves' disease treated with antithyroid agents. J Clin Invest 1979;64:1429. 31. Bartalena L, Marocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med 1998;338:73. 32. Franklyn JA, Maisonneuve P, Sheppard MC, et al. Mortality after the treatment of hyperthyroidism with radioactive iodine. N Engl J Med 1998;338:712. 33. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. N Engl J Med 1995;332:767. 34. Bergman P, Auldist AW, Cameron F. Review of the outcome of management of Graves' disease in children and adolescents. J Paediatr Child Health 2001;37:176. 35. Witte J, Goretzki PE, Roher HD. Surgery for Graves' disease in childhood and adolescence. Exp Clin Endocrinol Diabetes 1997;105 (SuppI4):58. 36. Cheetham TD, Wraight P, Hughes lA, et al. Radioiodine treatment of Graves' disease in young people. Hormone Res 1998;49:258. 37. Bliss R, Gauger PG, Delbridge LW. Surgeon's approach to the thyroid gland: Surgical anatomy and the importance of technique. World J Surg 2000;24:891. 38. Mitchie W. Whither thyrotoxicosis? Br J Surg 1975;62:673. 39. Witte J, Goretzki PE, Dotzenrath C, et al. Surgery for Graves' disease-

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44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54.

total versus subtotal thyroidectomy: Results of a prospective randomized trial. World J Surg 2000;24: 1303. Abe Y, Sato H, Noguchi M, et al. Effect of subtotal thyroidectomy on natural history of ophthalmopathy in Graves' disease. World J Surg 1998;22:714. Gupta MK, Perl J, Beham R, et al. Effect of 13l-iodine therapy on the course of Graves' ophthalmopathy: A quantitative analysis of extraocular muscle volumes using orbital magnetic resonance imaging. Thyroid 2001; 11:959. Palit TK, Miller CC, Miltenburg DM. The efficacy of thyroidectomy for Graves' disease: A meta-analysis. J Surg Res 2000;90:161. Andaker L, Johansson K, Smeds S, et al. Surgery for hyperthyroidism: Hemithyroidectomy plus contralateral resection or bilateral resection? A prospective randomized study of postoperative complications and long-term results. World J Surg 1992;16:765. Sadler GP, Clark OH, van Heerden JA, et al. Thyroid and parathyroid. In: Schwartz Sl, Shires GT, Spencer FC, et al (eds), Principles of Surgery. New York, McGraw-Hili, 1999, p 1661. Plummer HS. The clinical and pathologic relationships of hyperplastic and nonhyperplastic goiter. JAMA 1913;61:650. Plummer HS. The clinical and pathological relationship of simple and exophthalmic goiter. Am J Med Sci 1913;146:790. Siegel RD, Lee SL. Toxic nodular goiter: Toxic adenoma and toxic multinodular goiter. Endocrinol Metabol Clin North Am 1988; 27:151. Corvilain B, Dumont JE, Vassart G. Toxic adenoma and toxic multinodular goiter. In: Braverman LE, Utiger RD (eds), Werner and Inghar's The Thyroid. Philadelphia, Lippincott Williams & Wilkins, 2000, p 564. Mellen J, Wisheu S, Munzel U, et al. Radioiodine therapy for Plummer's disease based on the thyroid uptake of technetium-99m pertechnetate. Eur J Nucl Med 2000;27:1286. Erickson D, Gharib H, Li H, et al. Treatment of patients with toxic multinodular goiter. Thyroid 1998;8:277. Jensen MD, Gharib H, Naessens JM, et al. Treatment of toxic multinodular goiter (Plummer's disease): Surgery or radioiodine? World J Surg 1986;10:673. Goldstein R, Hart IR. Follow-up of solitary autonomous thyroid nodules treated with 13\1. N Engl J Med 1983;309:1473. Solans R, Bosh JA, Galofre P, et al. Salivary and lacrimal gland dysfunction after radioiodine therapy: Clinical thyroidology. J Nucl Med 2001;42:738. Edis AJ, Grant CS, Egdahl RH: Surgery of the thyroid. In: Manual of Endocrine Surgery, 2nd ed. New York, Springer-Verlag, 1984, p 210.

Use and Abuse of Thyroid-Stimulating Hormone Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms Niall O'Higgins, MCh • Andrew P. Zbar, MB • Susannah E. Harte, MD

Nodular disease of the thyroid gland is common. The medical suppressive treatment of goiter relies heavily on the ability to distinguish benign from malignant disease, largely through the use of high-resolution thyroid ultrasonography and fine-needle aspiration cytology of solitary and dominant thyroid masses. Thyroid nodules occur in approximately 0.8% of adult men and in as many as 5% of adult women in iodine-replete areas; there is a steady increase in detectable incidence after 45 years of age. 1 The prevalence of thyroid nodules is population dependent and is markedly higher in areas of endemic iodine deficiency? Exposure to low-dose ionizing radiation early in life increases the incidence of both benign and malignant nodules.v' Thyroid cancer is the most common endocrine malignancy, with an annual incidence of 10,000 new cases in the United States." Thyroid glands that are normal by palpation frequently have one or more nodules demonstrable at autopsy, and as many as 4% of patients at autopsy harbor microscopic, so-called occult, carcinomas of the thyroid.v? Ultrasonography in high-risk cases has produced a further dilemma in management with the discovery of impalpable nodules as small as 1 mm. The natural history and significance of these subclinical masses are unknown." Nodular goiter, on the other hand, is probably the most common endocrine "problem" in the world, and delineation of the value of thyroid suppression therapy in patients at low risk for carcinoma has significant implications for global health care costs.v'? The use of thyroid-stimulating hormone (TSH; thyrotropin) suppressive therapy after thyroidectomy

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for benign and malignant disease remains controversial largely because of the heterogeneity of disorders for which it has been advocated and because the natural history of malignant disease is long. Unfortunately, few randomized, controlled clinical trials exist for specific disorders such as solitary nodular disease, multinodular goiter, and differentiated carcinoma to support unequivocally the value of long-term suppressive therapy. The failure to monitor adequately the suppression of TSH in patients, to establish the compliance with suppression medication, and to evaluate nodular size objectively have also contributed to difficulties in interpreting the results in patients receiving suppressive therapy. It is clear, however, that despite an overall increase in the detectable incidence of differentiated thyroid cancer over the last 30 years, there has been a steady decrease in mortality, and this may be explained by both earlier diagnosis and more widespread use of TSH suppressive treatment. I1,12 The introduction of highly sensitive thyrotropin immunoenzymometric assays has led to a standardization of TSH suppression and permitted closer monitoring of both the efficacy of and problems with thyroxine (T4 ) treatment. However, these assays, although sufficiently sensitive to allow more accurate quantification of subnormal values, are still not routinely used in certain parts of the United States." Measurement of serum TSH permits precise levothyroxine dosage in both replacement therapy and TSH suppressive therapy when supraphysiologic doses of levothyroxine are given to maintain TSH levels below normal. Evidence of the delayed complications of overzealous and minimally

TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - -

monitored T4 replacement in both overt and subclinical hypothyroidism, most notably in inducing bone demineralization, altering serum lipid profiles, and contributing to cardiac morbidity, particularly in elderly patients, has raised concerns about the dangers of T4 therapy when used in the long term in supraphysiologic doses to suppress TSH in both benign and malignant disease." Decreased bone mineral density and an accelerated rate of bone loss have been reported in the literature in both pre- and postmenopausal women who are receiving doses of levothyroxine sufficient to produce subnormal serum TSH levels.P:" A better understanding of growth factors that affect normal thyrocyte function and that may explain TSH independence of autonomous nodules, as well as a more selective individual approach to suppressive therapy of tumors in patients deemed to have a poor prognosis, will be of value in limiting the number of patients receiving long-term suppression. Excessive levothyroxine therapy, either intentional or inadvertent, is not as innocuous as once was supposed, and studies have shown that as many as 50% of patients treated with levothyroxine therapy, who were clinically euthyroid, were overtreated based on their serum TSH concentration. 19.20

Physiology and Pharmacology Levothyroxine treatment relies on a negative feedback on pituitary thyrotropin production. In euthyroid humans, 20% of circulating 3,5,3'-triiodothyronine (T3) is produced in the thyroid gland and 80% is formed extrathyroidally by monodeiodination of Tz, largely in the liver and kidney under the action of a selenium-dependent type I deiodinase, a selenoprotein." The presence of selenocysteine renders the conversion of T4 to T3 sensitive to dietary selenium levels.P T 3 is the principal functioning thyroid hormone binding to a nuclear receptor (T3 receptor) and regulating transcription of thyroid hormone-responsive genes.P Pituitary and cerebral cortical T 3 is, however, produced predominantly by local deiodinase II action, and thus central nervous system levels of active thyroid hormone depend on both circulating T 3 and T4. Conversion of T4 to T 3 in these tissues contributes equally to or even as much as 80% to levels of nuclear bound T3. Therefore, although most peripheral tissues depend primarily on circulating T 3 levels, the central nervous system is sensitive to both circulating T3and T4.24-26 In thyrotropin suppression treatment, the aim is not principally the physiologic replacement of T 4 (and T 3) as in hypothyroidism (although this may well be necessary in patients rendered hypothyroid after total or near-total thyroidectomy), but the use of T4 is to induce a particular level of TSH suppression by supraphysiologic dosing without rendering the patient clinically hyperthyroid. In this setting, the benefit-risk equation for TSH suppression therapy must be assessed for each patient on the basis of the likely hazards of untreated thyroid disease in benign cases or the likelihood of local or systemic recurrence in carcinoma as balanced against the potential complications of prolonged T4 overdosage. Precise feedback relations between circulating thyroid hormones and pituitary TSH secretion, along with exact measurement of serum TSH concentration, are essential in

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the management of patients receiving suppressive levothyroxine therapy." Thyroid function and T 4 dosing can be monitored most accurately by new and highly sensitive immunometric assays for TSH that are sensitive for levels as low as 0.01 mUlL. The normal circulating TSH concentration is 0.5 to 3.5 mUlL, and the newer assays are at least 10 times more sensitive than the original TSH radioimmunoassays.P:" Basal TSH levels are directly proportional to the TSH response to thyrotropin-releasing hormone (TRH) stimulation, rendering this test virtually obsolete." Debate regarding the use of suppressive therapy centers on the role ofTSH as the principal growth-stimulating factor in benign and malignant disease and on the degree of TSH suppression needed. Thyroid suppression therapy has a very long history. It has been used as a treatment for goiter since the 12th century" and historically has had better clinical success in diffuse as opposed to nodular goiter." Its use was expanded by Crile to the treatment of patients with thyroid cancer using thyroid extract and desiccated animal thyroid.F Today, the principal TSH suppression agents used are levothyroxine and liothyronine. Levothyroxine is one of the most commonly prescribed medications; more than 15 million prescriptions are filled annually in the United States alone.P It is synthetically produced and is identical to T 4 secreted by the thyroid. It is the more frequently used agent and has a half-life of about 7 days. It is a more standardized preparation than Iiothyronine, being dose encoded by high-performance liquid chromatography," and its regular administration and compliance result in more stable serum levels ofT3.35 Gastrointestinal absorption is approximately 80%,36 with peak levels attained at between 2 and 4 hours, remaining above basal level for up to 6 hours.'? Liothyronine has a more powerful peripheral and central action and has a half-life of about 24 hours. It is used in emergency situations and when cessation of therapy should be limited, such as in the assessment of brittle-boned patients with thyroid cancer undergoing follow-up thyroid scanning. There is, however, considerable variation in T 4 dosing in patients during replacement and suppression" Combination preparations such as liotrix (T 4 plus T 3) and animal-derived products such as thyroid extract or thyroglobulin are rarely used today. These agents are less standardized and may lead to unwanted supraphysiologic rises in T 3, with clinically troublesome side effects for relatively low serum T 4 levels. The advantage of levothyroxine is a more controlled T 3 conversion in extrathyroidal sites, which is of value in fasting states and illness when peripheral generation of T3 is normally decreased, partly on the basis of variable absorption and bioavailability.v-" Several states, such as pregnancy, malabsorption, and caloric deprivation, and certain drugs alter levothyroxine needs, and these are of particular importance when supraphysiologic dosing is required (Table 8-1). During pregnancy, serum TSH levels increase largely as a result of an increase in T 4-binding globulins, with a consequent fall in circulating free T 4 and free T3. This is offset by a natural amelioration of such diseases as chronic autoimmune thyroiditis but, in general, T4 requirements tend to be greater. 39.40 Certain drugs may block T 4 absorption (e.g., cholestyramine." sucralfate," aluminum hydroxide," ferrous sulfate"), increase nondeiodinative T 4 clearance by pathways not leading to T 3 generation, such as

70 - - Thyroid Gland

sulfation and glucuronidation (e.g., rifampin.f carbamazepine." phenytoin [Dilantin]47), or inhibit the peripheral conversion of T, to T3 (e.g., amiodarone'v" and essential selenium deficiency'"), Conversely, levothyroxine dosage needs to be diminished in elderly persons in part because of a lower general requirement." The serum TSH levels should be monitored more often in these circumstances, with adjustment in levothyroxine dosage to maintain an appropriate therapeutic serum TSH level in those receiving suppressive therapy. Much of the concern about TSH suppressive therapy and supraphysiologic levothyroxine dosing has arisen from reports about the long-term complications of replacement therapy for primary and subclinical hypothyroidism.52 Does it matter whether thyrotropin levels are reduced below 0.1 mUlL in an otherwise healthy person with no clinical features of hyperthyroidism? There is increasing evidence that excessive levothyroxine administration, resulting in suppressed serum TSH levels, is associated with physiologic alterations in peripheral tissue. In several studies, as many as 50% of patients requiring levothyroxine replacement alone who were clinically judged to be euthyroid were actually deemed overtreated on the basis of TSH concentration.P Some evidence implicates overtreatment with harmful effects, particularly in elderly patients, most notably a sustained increase in nocturnal heart rate, a reduction in systolic ejection time, an increase in urinary sodium excretion, an increase in hepatic and muscular enzyme activity as well as serum ferritin level, and potentially hazardous alterations in blood lipid profile. In short, these are the metabolic effects of subclinical hyperthyroidism.54-56 It is becoming increasingly clear, however, that bone resorption is a significant problem in prolonged levothyroxine

usage, as indicated by an increase in serum and urinary calcium, a decrease in parathyroid hormone level, a rise in urinary excretion of pyridinium cross-links (specific markers for bone resorption), and a rise in serum osteocalcin (a peripheral marker for bone formation). These effects are not confined to postmenopausal women and are exaggerated when suppressive as opposed to replacement therapy is used,57-60 Premenopausal women treated with excess levothyroxine show a predominantly cortical bone loss, measured in wrist and hip, as opposed to trabecular bone loss, measured in the spine. 15-17 Postmenopausal women, on the other hand, show reductions in both cortical and trabecular bone mineral density.!"!? The risk is appreciably higher in patients who are already at risk for osteoporosis (heavy smokers and patients with inadequate calcium intake, steroid dependence, alcoholism, or prior hyperthyroidism), although this subclinical form of hyperthyroidism has not been associated with a clinical rise in symptomatic fractures." The development of osteopenia during TSH suppressive therapy is of increased concern because up to 70% of patients with nodular thyroid disease or thyroid cancer are female and have been receiving supraphysiologic suppressive treatment for decades. Conversely, undertreated patients (hormone replacement cases after thyroidectomy or iodine 131 therapy) suffer from subclinical hypothyroidism. Debate exists about the relative risks of this condition if left untreated, although on a background of impaired left ventricular function, the consequences are likely to be deleterious.f Overzealous TSH suppressive therapy may have major effects on lipid metabolism and cardiac function.

Thyroxine and Lipid Metabolism There is an overall increase in hyperlipidemia in overt hypothyroidism, and there have been claims of higher mortality from ischemic heart disease in undertreated patients. 63.64 In subclinical hypothyroidism the biologic efficacy of thyroid hormone replacement has been confirmed with observed changes in serum lipoprotein concentration, improvement in cognitive performance and indices of cardiac function, and reduction of subjective symptoms. The majority of patients show no fundamental changes in lipid profile during levothyroxine treatment for TSH suppression.f but occasional reports of deleterious changes in relative high-density lipoprotein (HDL)-low-density lipoprotein (LDL) cholesterol concentration have been documented.w'" Franklyn and colleagues''? have argued that supraphysiologic levothyroxine may be distinctly beneficial because of its effects on LDL cholesterol in reducing the number of cardiac events in those so treated, but it may not be possible to extrapolate the effects on lipid profile from replacement to suppressive therapy; this study was confined to women and showed a beneficial effect only in patients older than 35 years. The total cholesteroVHDL and LDL/HDL ratios, which are correlated with increased cardiovascular disease risk, have been shown to decrease with TSH suppressive therapy.70-72 That beneficial effects on lipids may be

TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - -

achievable only by inducing subclinical hyperthyroidism implies that the advantages of such deliberate treatment must be offset in each case against the expected delayed cardiac morbidity and the known consequences for bone metabolism.P

Thyroxine and Ischemic Heart Disease Clearly, T4 replacement is necessary to prevent the development of overt hypothyroidism in postsurgical patients. There is also an annual conversion rate of 3% from subclinical to clinical hypothyroidism after 131 1 therapy and slightly less than 1% per year after thyroidectomy. Post-thyroidectomy hypothyroidism is more likely in elderly patients and in those who have circulating thyroid auroantibodies.V" Myocardial infarction and angina are both recognized complications of levothyroxine therapy in hypothyroid patients, even in dosages as small as 25 ug/day. Forty percent of patients with a history of angina are unable to tolerate fully suppressive doses of T4 . 76 Patients with known cardiac disease who are older than 65 years should, therefore, be treated with caution. Substantial increases in both heart rate and left ventricular contractility tend to increase myocardial oxygen consumption, although slight reductions in ventricular afterload may offset this effect." It is likely that only a small percentage of patients will experience new-onset angina with TSH suppressive therapy; about 33% of patients will have significant improvement in preexisting angina, 50% will remain stable, and about 16% will worsen. Cardiac function was observed in a randomized l-year trial of levothyroxine therapy (mean dose 71 ug/day) in patients with subclinical hypothyroidism. There was no demonstrable difference in systolic time intervals between treatment and placebo groups. Abnormal values however, were restored to normal in the five patients with the most abnormal baseline values."? Other studies have shown improved cardiac contractility of up to a 10% mean increase in left ventricular ejection fraction with maximal exertion by the patient.?? Levothyroxine in such patients should be initiated at 50 ug, with 25-/lg increments at 3-month intervals until TSH is suppressed to one tenth of normal. In clinical practice, the vigor with which TSH suppression is undertaken is related more to the underlying condition for which it is prescribed than to the likelihood of worsening preexisting cardiovascular disease. Whether evidence exists for justification of suppressive therapy still remains unclear. In suppressive therapy, there remains a need (despite logistic difficulties in its conduct) for a longitudinal study to assess the effects of levothyroxine on bone metabolism in defined groups of patients. The theoretical advantages of a possible reduction in morbidity from cardiac disease must be balanced against the effects on a susceptible population of levothyroxine-induced osteopenia. However, there appears to be no difference in overall morbidity between the patients with normal TSH levels and those with mildly suppressed TSH levels." Clearly, although lessons can be learned from patients

71

treated with replacement T4 for hypothyroidism, the metabolic and systemic effects may not be readily extrapolated to patients in whom it is used for deliberate TSH suppression. In patients treated with T4 suppression, clinical judgment alone is insufficient to monitor cases."

Thyroid-Stimulating Hormone Suppression and the Solitary Thyroid Nodule Studies in this area are confusing in that they include a heterogeneous collection of goiters (such as nodules with functional autonomy or cystic degeneration), are frequently uncontrolled and poorly randomized, fail to establish compliance or consistent TSH suppression, and do not objectively evaluate nodule size and treatment response. Inclusion in a suppressive treatment arm relies on the absolute ability to distinguish a benign from a malignant nodule largely on the basis of accurate fine-needle aspiration cytology.82-86 TSH suppressive therapy is of unproven benefit in the solitary nodule. The reported incidence of reduction in thyroid nodule size varies from 9% to 68%,87.88 although disappearance of the nodule is rare. Several controlled, randomized, double-blind trials have failed to show significant reduction in nodular size on the basis of volumetric calculation by high-resolution ultrasonography, although most studies have shown a marked reduction in contralateral thyroid lobar volume during T4 therapy provided it is carried on for periods exceeding 6 months. 78,87-91.93-99 In three prospective randomized studies involving a total of 167 patients with mean treatment periods ranging from 6 months to 18 months, levothyroxine was shown to be no more effective than placebo in reducing nodule size. 93.97, l oo However, in other studies, nodule size decreased more than 50% in 56% of levothyroxine-treated patients with serum TSH suppression.f Both these studies lacked placebo control groups for comparison but still recorded a decrease in nodule size during levothyroxine therapy greater than the natural 15% to 30% observed spontaneous regression rate (Table 8-2). Further, some of these studies have confirmed that there is a natural tendency for up to one third of solitary nodules to regress spontaneously during follow-up beyond 1 year. In some, this is explained by hormonally insensitive events such as cystic degeneration, resorption of colloid, or necrosis of follicular epithelia, and in others, it is explained by regression of surrounding normal, hormonally responsive thyroid. Treatment of the solitary nodule medically in this way should be undertaken with caution; it must be remembered that fine-needle aspiration cytology has a false-negative rate of 5% and that up to 15% of solitary nodules continue to grow with adequate TSH suppressive treatment.101.I02 Studies suggest that the response of a nodule to T4 is independent of age, duration of nodule, pretreatment nodular size, TRH-TSH amplitudes, initial technetium uptake, and pretreatment thyroglobulin level. The large or complex nodule should not be medically treated because it is less likely on average to respond and because cytologic sampling error is always possible.

72 - - Thyroid Gland

Recommendations for the Use of Thyroxine in the Solitary Thyroid Nodule Given that the expected nodule response rate slightly exceeds the reported natural regression rate, suppression therapy may be considered to be of slight benefit. If it is to be used (perhaps in the context of an institutional trial), it must be for the proven solitary nodule that has unequivocally negativecytology,is homogeneously solid on ultrasonography, and has normal or reduced uptake on technetium 99m pertechnetate scanning (Fig. 8-1). These nodules ideally should be associated with a normal thyroid profile and negative thyroglobulin and thyroid peroxidase autoantibody status. Patients with a large nodule, particularly if it possesses echogenic heterogeneity or has been present for longer than 2 years, or in whom there is a history of head and neck irradiation, should not be treated in this manner. One may aim for a TSH suppression level of 0.05 to 0.10 mUlL in premenopausal patients without cardiac risk factors and for a level of 0.1 to 0.3 mUlL in postmenopausal women, particularly those with a known history of osteoporosis, and in men older than 65 years with a recognized cardiac history. Treatment is continued for 6 months to 1 year with clinical and ultrasonographically calculated nodular volume based on anteroposterior length and width, assuming the nodule to be a spherical ellipsoid. This is complemented by assessment of the contralateral thyroid lobar volume to gauge response to suppression.l'" Ultrasonography is essential in the follow-up of these patients because of its greater accuracy in nodule assessment and because it eliminates patients' and clinicians' bias.l'" If the nodule regresses, treatment may be stopped after 6 to 12 months of therapy and reinstituted if it remains stable or gradually enlarges after 6 months of therapy cessation. If the nodule actually enlarges with compliant therapy, repeated fine-needle aspiration cytology or thyroidectomy is mandatory to exclude

Clinical solitary nodule

~High-resolution

Ultrasonography

!

confirjmed solitary-

i: TSH Thyroglobulin autoantibodies

/FNA Negative TSH suppression

»> Premenopausal

----. Postmenopausal

<60 years of age

Prior cardiac disease

TSH = 0.05-0.1 mUll

TSH

<,

/

= 0.1-0.3 mUll

Follow-up sensitive

TSH assay Contralateral thyroid volume and nodule volume assessed by ultrasonography Serum thyroglobulin measurement

/

Nodule enlarges

~

FNA repeat

FIGURE 8-1. An algorithm for the use of thyroxine (T4 ) in a solitary thyroid nodule. FNA =fine-needle aspiration; T 3 =triiodothyronine; TSH = thyroid-stimulating hormone.

TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - -

the possibility of malignant degeneration. This phenomenon, however, although well recognized, is relatively infrequent. In treating such patients with thyroid hormone, more questions are raised than are answered. Most notably, what are the desired endpoints in the treatment of patients with a benign thyroid nodule? Is mere regression acceptable, or is complete nodular disappearance required? What is the mechanism behind spontaneous nodule regression? Is the treatment cost-effective? Is there a nodule limiting size? Finally, how does TSH suppressive therapy work if it works at all?

Thyroid-Stimulating Hormone Suppressive Therapy and Nodular Goiter Apart from the solitary nodule and thyroid carcinoma, TSH suppression therapy may be used for a range of thyroid diseases, most notably nontoxic multinodular goiter, diffuse goiter (including chronic autoimmune thyroiditis), functionally autonomous nodules, neonatal goiter, and postpartum goiter. It also has specific use in the patient who has a known history of irradiation to the thyroid area and in the prevention of recurrent nodular disease after partial thyroidectomy.

Nontoxic Multinodular Goiter: Theories of Pathogenesis and Thyrocyte Regulation The pathogenesis and hence the treatment of multinodular goiter are debatable. If a goiter were simply induced by uninhibited TSH stimulation, one might expect it to be a diffuse goiter. Early studies by Taylor suggested a "natural" progression from diffuse toward multinodular.l'" Indeed, TSH levels are in general not elevated in sporadic goiters. Studer and Ramelli 105 suggested that newly generated follicles involve thyrocyte clones that may retain the ability to concentrate iodine (hot nodules) or that have lost that ability (cold nodules). This phenomenon, coupled with an impairment of blood supply during growth, may lead to areas of fibrotic regression and dystrophic calcification indicative of a degenerate multinodular goiter. 105 Changes in follicular function are probably due to environmental factors, such as the local iodine supply.l'" failing blood supply to an active goiter.I'" and the relative aging of cellular components, which has been shown in the aging mouse thyroid as a transformation of normally functioning follicles into irreversibly cold follicles. 108 Genetically separable thyrocyte clones probably also generate nodular heterogeneity. This in itself does not explain all the features of a multinodular goiter, in particular the natural tendency toward autonomous nodule formation or the variability of metabolic function such as TSH-inducible adenosine monophosphate activity within the goiter. I 09 •JIO Moreover, multinodular goiters have unique growth patterns with variable iodine turnover and demonstrate growth that is discordant with radioscintigraphic function, which separates their behavior from that of other types

73

of goiter. The cells from human multinodular goiters in tissue culture have variable TSH dependence, with cells with equivalent growth potential clustering near one another. Presumably, the clones with inherent growth potential respond to strong extrathyroidal stimuli (such as TSH or epidermal growth factor) and differ from the clones with low mitotic activity that respond to weak stimuli (such as endemic iodine fluctuation or the activity of local goitrogens) over very prolonged periods. Further evidence, although controversial, has implicated a putative set of thyroid growth-stimulating immunoglobulins (TSIs) in multinodular goiter development, which are thought to act independently of the TSH but through the TSH receptor. 101,I I J- 113 We believe most evidence suggests that TSIs work through the TSH receptor.The newly generated follicles are then integrated into the growing goiter by cellular adherence to the dominant follicle, by papillary protrusion into the follicular lumen, and by the formation of daughter follicles. All of these processes incorporate cellular groups with widely differing iodinating capacities and TSH responsiveness 114 but with individual follicular similarity in terms of ultrastructure, metabolic activity, and receptor expression.l'
Thyroid-Stimulating Hormone Suppressive Treatment of the Multinodular Goiter Sporadic, nontoxic multinodular goiters are pathologically diverse with cystic, colloid, hemorrhagic, fibrotic, and calcific components. Their natural history is characterized by unpredictable periods of stability in size and function and occasionally by rather sudden enlargement. There is considerable debate about the efficacy of levothyroxine suppressive treatment of the nonendemic, nontoxic multinodular goiter, and the results are even less satisfying in many cases than those for solitary nodular disease because of the greater amount of pathologic thyroid tissue that is likely to be hormonally insensitive, the variability of TSH dependence given the likelihood of multiple other thyroid growth factors, and the difficulty in objectively evaluating the response of dominant nodules. This should be coupled with the fact that up to 10% of dominant masses within multinodular goiters may actually spontaneously regress during follow-up.'!" A randomized study of 115 patients showed a total reduction in thyroid volume of more than 13% (by ultrasonographic measurement) in 58% of patients receiving TSH suppressive doses of levothyroxine for an average of 9 months. The thyroid volume was also shown to increase on cessation of levothyroxine therapy. I 19

74 - - Thyroid Gland

Evidence for the routine use of suppressive levothyroxine in multinodular goiter is varied. Two controlled clinical trials to assess this question demonstrated benefit in reduction in overall goiter size in about 50% of cases (Table 8_3).119.120 Accurate and consistent assessment of dominant nodules within an abnormal gland, along with a concern that malignancy may coexist in a small percentage of cases, makes the routine use of TSH suppressive therapy for this condition inappropriate except in patients for whom surgery is contraindicated.98,121 No clear response association exists with patient's age, duration of goiter, family history of thyroid disease, pretreatment thyroid volume, or preliminary radioactive iodine uptake.99.122-125 The mechanism in the patients who respond is unknown, but T4 has been shown to influence thyrocyte growth synergistically in the presence of other growthstimulating factors.!" Many questions remain concerning this type of treatment. What constitutes response? Is complete regres-sion necessary, and is uniform regression ever possible? Considering that a significant proportion of patients are never submitted for surgery, what is the true underlying incidence of carcinoma?

point in continuing treatment if an effect is not observed within this time. It should also be noted that after surgery for nodular nontoxic goiter, only 15% of patients experience recurrence; hence, potentially lifelong treatment is unnecessary in 85%. One randomized trial comparing levothyroxine therapy versus no therapy after thyroid lobectomy showed no difference in thyroid size after a follow-up of 1 year when the thyroid remnant size was recorded ultrasonographically.F' Several large retrospective studies, including a total of 656 patients and mean follow-up of 5 to 8 years, showed that postoperative levothyroxine therapy did not decrease the frequency of goiter recurrence, which on average was 10% at 8 years. 128 In many patients older than 50 years, dominant nodules never change in size after discovery. Because of the logistic difficulty in assessing response to suppressive treatment in multinodular goiter, we do not recommend its use, although other clinicians do.

Recommendations for the Use of Thyroxine in the Nontoxic Multinodular Goiter

Diffuse nontoxic goiter can be sporadic or endemic. Iodine treatment is clearly the treatment of choice over T4 therapy in endemic cases, as shown by Hintze and colleagues!" in a 1989 multicenter trial. The most common cause of adult diffuse nontoxic goiter in nonendemic areas is chronic autoimmune thyroiditis. Both microsomal cytoplasmic and thyroid peroxidase autoantibodies are evident in 10.3% of adult women and 2.7% of adult men in clinical surveys of sporadic goiter. Conversely, about one third of patients with detectable antibodies have clinical goiters. 1 Chronic autoimmune thyroiditis is also the most common cause of sporadic childhood and adolescent goiter, of which there is a spectrum of illness ranging from focal thyroiditis to Hashimoto's thyroiditis. Such patients typically have high titers of antimicrosomal antibodies and are often hypothyroid, either clinically or subclinically. Levothyroxine is given to both euthyroid and hypothyroid patients with chronic goitrous thyroiditis of this type and has been shown to be associated with a mean reduction in palpable thyroid volume.!" This type of treatment must be balanced against a small chance of spontaneous regression of active Hashimoto's

In practical terms, if TSH suppressive treatment is to be tried, it would be logical to give enough levothyroxine to reduce the TSH consistently to 0.5 mUlL. If the goiter decreases in overall size or remains static (both clinically and by ultrasonography), treatment may be continued indefinitely in a low dose (perhaps in patients younger than 60 years), with periodic monitoring of TSH and thyroglobulin levels to assess the patient for the likelihood of functional anatomy. If the goiter clinically enlarges, further evaluation for underlying carcinoma is necessary. If the serum TSH concentration is low in the clinically euthyroid case to begin with, levothyroxine is contraindicated because of the likelihood of subclinical incipient functional autonomy. The natural history of these glands is toward hyperthyroidism over a 15- to 25-year period of goiter follow-up. Goiters that respond usually do so within a period of 6 months of commencement of therapy, so there is little

Thyroxine Suppressive Therapy and Diffuse Goiter

TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - - 75

disease in a subgroup of patients with detectable thyrotropinblocking antibodies, which inhibit the peripheral action of TSH.13J.l32 The natural history of autoimmune thyroiditis, however, is in general toward inexorable hypothyroidism at a rate of roughly 5% per year, especially in patients with very elevated antibody titers.73.133·134 Few trials of levothyroxine suppressive therapy in diffuse goiter have been conducted (Table 8_4).135-137 These suggest a reasonable response rate for adequately suppressive therapy over a 3- to 6-month period, although the level of TSH suppression required is not known. Clearly, if the gland is unresponsive after 6 months of compliant therapy, levothyroxine should usually be withdrawn. One study observed that a return to normal of the serum TSH resulted in a mean decrease of 32% in thyroid volume, with almost 50% attaining normal thyroid size after 2 years of therapy.138

Thyroid-Stimulating Hormone Suppression and the Post-Thyroidectomy Patient Levothyroxine may prevent clinical hypothyroidism after bilateral or subtotal thyroidectomy and occasionally after unilateral Iobectomy.P? In three randomized, controlled trials comparing levothyroxine with placebo, there was no demonstrable difference in nodular recurrence after a range of thyroid operations in the TSH-suppressed patients.14o-142 Miccoli and colleagues'< demonstrated an advantage for suppressive as opposed to substitutive T4 dosing on echographic follow-up at 3 years, but this was in an area of endemic goiter in northern Italy, where the rate of nodular recurrence postoperatively is normally relatively high. The particularly high early recurrence of echographically demonstrable postoperative recurrence after thyroidectomy in the latter article (78% on substitutive T4 therapy) may not be indicative of the general Western experience. Large, uncontrolled, retrospective series, however, with prolonged follow-up over periods ranging from 5 to 8 years, have failed to demonstrate an advantage for patients treated with levothyroxine after surgery.122,143,144 The role of T4 therapy in patients with normal serum TSH concentration who have had thyroid lobectomy only is debatable. Its use has mainly been advocated in cases in which preoperative autoantibody titers are high and postoperative hypothyroidism is anticipated rather than for prevention of recurrence,

although antibody titers do not clearly discriminate in untreated cases for the development of either overt or subclinical hypothyroidism. 145 After subtotal thyroidectomy, it is clearly recognized that with extended follow-up moderate hypothyroidism develops in about 20% of cases. This depends largely on the size of the thyroid remnant.!" the degree of lymphocytic infiltration of the gland,"? the preoperative level, if present, of complement-fixing thyroid antibody.l" and the original condition for which thyroidectomy was performed. 149 There is evidenceI43.150-154 from Westermark and colleagues that T4 dosage needs to be higher in the patients treated with subtotal thyroidectomy than in those treated by unilateral lobectomy to reduce TRH stimulation of TSH secretion, implying that pituitary TRH responsiveness needs a longer period of recovery after supraphysiologic T4dosing than basal TSH production.l" Because of the variability of goiter growth, both de novo and postoperatively, and the fact that a certain percentage of patients exhibit flat TRH-TSH responsiveness preoperatively, other mechanisms apart from the TSH receptor must be invoked, most notably the presence of TSIs. Because of the expression by thyroid tissue of human leukocyte antigen DR, it has been postulated that a secondary autoimmune process may be induced as part of the goitrous phenomenon.l" On balance, there is little evidence for the routine use of suppressive as opposed to replacement therapy after lobectomy or subtotal thyroidectomy. This must be weighed against the known hazards of secondary surgery to the thyroid in terms of recurrent laryngeal nerve injury and serious sustained hypoparathyroidism should reoperation be needed for recurrent goiter,157,158

Thyroid-Stimulating Hormone Suppression and Miscellaneous Benign Goiters Levothyroxine has been advocated for a variety of benign goitrous conditions, most notably in the follow-up of patients who have experienced irradiation to the head and neck in some cases of functionally autonomous nodules and in postpartum and neonatal goiter. Irradiation during childhood or adolescence for a range of benign conditions (tinea capitis, tonsillar and thymic enlargement, acne vulgaris, or head and neck vascular malformations) has been associated with a substantial increase

76 - - Thyroid Gland in both benign and malignant nodules of the thyroid as well as an increase in parathyroid adenomas.159-162 Controversy exists in regard to the optimal management of patients both with and without palpable thyroid nodules who have been exposed to low-dose irradiation to the thyroid area. Evidence suggests that thyroid suppressive therapy is as likely to be successful in this group of patients as in those with sporadic multinodular goiter, but the main difficulty seems to be in the delineation of underlying malignancy.95.163.164 Shimaoka and coworkers'P were the first to conduct a double-blind study of suppressive treatment using T3, desiccated thyroid, or both, in irradiated patients with measurable thyroid nodules. In 1500 patients exposed with a 34% incidence of nodules and an average interval between radiation exposure and nodule detection of 27 years, TSH suppression of nodules was possible in 18% of patients over 6 months of therapy. This approach was uncontrolled, however, and made no attempt to assess the efficacy of suppression in a heterogeneous group of patients. Clearly, there is a risk of underlying malignancy in this group on the order of 5% of those without clinical nodules and 40% of those with clinical nodules. Thus, and in the presence of a clinical nodule, because of this possibility as well as the potential for cytologic sampling error, total thyroidectomy is generally advocated. A question remains, however, regarding the role of suppressive therapy in patients without either clinical or subclinical nodules. The rationale for treating the latter group of patients is that an intact pituitary thyroid axis is needed for the production of thyroid tumors that are likely to be TSH sensitive, as has been demonstrated in rats by the protective effect of hypophysectomy on the irradiated thyroid.165.166 In a study by Fogelfeld and associates.P' 511 patients exposed were monitored for up to 40 years after irradiation following initial surgery for benign thyroid nodules, with an overall nodular recurrence rate of 19.5%. Thyroid hormone supplementation reduced the incidence of recurrent nodules from 35.8% in the untreated group to 8.4% in the treated group. TSH suppressive therapy, however, had no effect on the rate of underlying malignancy, which was 19.2%.151 The implication is that recurrent nodules of this type, which develop during TSH suppressive therapy, are much more likely to be malignant. Such a study should, however, be viewed with caution because of its lack of randomization, its failure to substantiate effective TSH suppression in many cases, and the nonstandardization of T4 dosage. Given that there is an increased incidence of hypothyroidism and thyroid nodules in children exposed to head and neck irradiation for such conditions as Hodgkin's disease, neuroblastoma, Wilms' tumor, and leukemia, as well as in adults irradiated for breast cancer and lymphoma, the role of TSH suppressive therapy in an expanding population of patients needs to be defined.167.168 The question remains whether patients who have been exposed should have suppressive treatment in the absence of nodules as well as the correct management of ultrasonographically demonstrable impalpable nodules. It should also be recognized that the rate of falsenegative fine-needle aspiration cytology is significantly higher in the irradiated gland. 169 What is also unknown is the role of TSH suppressive treatment during the time of neck irradiation.

Autonomously functioning nodules represent about 5% of all solitary or dominant nodules in the thyroid gland. Toxicity is more a feature of nodule size, with nodules smaller than 2.5 em in diameter rarely causing clinical hyperactivity. Young patients with functionally autonomous nodules with low TSH levels are more likely to experience clinical toxicity and have a slightly higher incidence of malignancy. 170 Functional status of such nodules with low TSH concentration is best assessed by both technetium 99m and iodine 123 scanning because the discordant nodule (hot on 99mTc, cold on 1231) is more likely to represent a carcinoma. Although the growth and function of many of these nodules appear to be TSH independent, the true incidence of hyperthyroidism over prolonged follow-up is only about 10%.171 These nodules may also be characterized by a relative increase in the T 3ff4 ratio (T 3 toxicosis). Furthermore, there is a moderate rate of spontaneous regression of these autonomous nodules with time, and their development may represent one part of the spectrum of multinodular goiter. 104 Because autonomous thyroid nodules are uncommon and because patients with these nodules are treated with either radioiodine or surgery, their true natural history remains unknown. The demonstration of a responsive TSH receptor mechanism in these cases, as evidenced by an intact TSH adenylate cyclase system in tissue culture.F? and the fact that exogenous T4 has been shown to reduce the radioiodine uptake and size in certain nodulesI73.174 imply that there is at best only partial autonomy from TSH influence. These more "dependent" cases are on average smaller with preserved and unsuppressed surrounding parenchyma and over time tend to involute or undergo degenerative change. However, the role of TSH suppression in such cases is quite unclear because there is a risk of rendering patients subclinically hyperthyroid if treatment is based merely on the presence of a low preliminary TSH concentration or if the nodule inadvertently undergoes spontaneous degeneration during suppressive treatment.!" It is likely that these so-called autonomous nodules represent a heterogeneous mix of thyroid tissues, with some follicles predisposed toward hyperfunction, autonomy, and TSH independence and others toward autonomous growth or function, or both, exhibiting some initial T 4 responsiveness but later undergoing degeneration and hypofunction. Because these features are essentially unpredictable, TSH suppressive therapy is usually not recommended. T 4 may also be of value in the treatment of transient goitrous hypothyroidism in infants exposed to the transplacental passage of thyrotropin receptor antibodies in maternal chronic autoimmune thyroiditis. Changes in T 4-binding globulins and relative subclinical reductions in circulating free T4 and T3 during pregnancy are not compensated for by increased thyroid hormone secretion by the gland because of lack of functioning thyroid tissue. Such patients, with Hashimoto's disease during pregnancy, tend to suffer from repeated episodes of transient postpartum thyroid dysfunction, which may require suppressive treatment in its own right and ultimately replacement therapy because of the small risk of clinical hypothyroidism in multiparous cases.l?"

TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - - 77

Thyroid-Stimulating Hormone Suppression and Thyroid Cancer Controversy exists in thyroid cancer management about the extent of surgery, the use of 131 1 ablation therapy, the place of thyroglobulin assay in follow-up, and the role and level of TSH suppressant treatment. Further, there is debate about the degree of TSH dependence of differentiated thyroid carcinomas and the importance of other thyroid growth factors.

Thyroid Growth Factors and Thyroid Carcinoma Thyroid tumors vary markedly in prognosis, and the natural history of differentiated tumors is long. The control of thyroid cell growth is complex and is influenced by many hormones and growth factors operating through distinctly different cell signal transduction systems. Classically, TSH is considered the major thyroid growth hormone, and, although there is no dispute about its role in stimulating thyroid gland function, its effects on thyroid growth and particularly abnormal growth are in question. TSH stimulates "differentiated" thyroid functions, most notably iodine uptake and organification as well as thyroglobulin synthesis, by activating a membrane-bound adenylate cyclase system and increasing intracellular cyclic adenosine monophosphate; this results in cytoplasmic protein phosphorylation and increased nuclear transcription. I?? In general, follicular thyroid neoplasms have enhanced adenylate cyclase activity in response to TSH stimulation and tend to have an inverse correlation with the state of aggressiveness of the tumor.!" It is also evident that TSH functions through the phosphatidyl inositol phosphokinase C-intracellular calcium system because it is known that high dietary calcium, particularly in areas of endemic iodine deficiency, promotes goiter formation. I?9,180 Elevated levels of TSH promote thyroid tumors in rats, and these tumors can be prevented by treating with thyroid hormone (TSH suppressionj.l'" TSH is generally considered a relatively weak factor for human thyroid cell growth in tissue culture. 182 The cells tend to be very heterogeneous in their response, 183 and transplanted human thyroid tumors ultimately demonstrate TSH independence in vitro. 165 The fact remains that thyroid tumor tissue has demonstrable TSH receptor sites, although the importance of these sites clinically is another matter.P' The list of known thyroid growth factors is quite long (Table 8-5) and includes 'I'Sls, epidermal growth factor, epidermal growth factor receptor (EGFr), insulin-like growth factors, and prostaglandin E2. Inhibitors of thyroid growth in vitro include transforming growth factor ~, somatostatin, and vitamin A 185-187 EGF functions as a powerful thyroid growth stimulant, possibly more active than TSH and perhaps acting synergistically with TSH, promoting cell growth but inhibiting cellular differentiated functions.188.189 Further, EGFr expression has been shown to be associated with reduced disease-free survival in differentiated tumors. 190.J91 Thyroid cell proliferation is further affected by growthpromoting oncogenes and inhibited by tumor suppressor genes.

Their protein products presumably replace known specific growth regulators, growth factor receptors, and signal transducers. TSIs and fibroblast growth factor function as circulating growth factors. The protooncogene c-erb B2 (HER-2/neu) is a plasma membrane receptor and the ras oncogene a signal transducer for thyroid growth. 192 c-erb B2 is a surface growth receptor that has been shown to be frequently overexpressed in a proportion of breast and ovarian cancers and to correlate with poor prognosis. 193 Oncogenes, whether natural (protooncogenes) or viral, encode protein products, which act in either the nucleus or cytoplasm. Both ras and c-myc oncogenes are overexpressed in about 60% of differentiated thyroid neoplasms; prognosis is worse in the cases in which c-myc is heavily encoded. 194,195 Frauman, Lemoine, Wyllie, and Clarkl96-2oo and their colleagues have discussed the subject in great depth. Both the tumor suppressor gene p53, which has been heavily implicated in the tumorigenesis of colorectal carcinoma, and platelet-derived growth factor have been found to be overexpressed in anaplastic tumors. 201,202 It is evident then that TSH suppression in thyroid cancer is likely to have only a partial role in tumor control, perhaps similar to that of tamoxifen therapy in women with breast cancer.

Thyroid-Stimulating Hormone Suppressive Therapy in Thyroid Cancer TSH suppressive therapy was first advocated for thyroid carcinoma by Dunhill in 1937 203 and was used extensively in the treatment of disseminated differentiated thyroid cancer by Crile. 204 The rationale for its use has subsequently been the demonstration of TSH receptors in malignant tissue from differentiated thyroid cancers of follicular cell origin and the noted increase in adenylate cyclase activity in response to TSH stimulation in vitro. 205,2o6 Thyroid tumors, however, that already have increased basal TSH adenylate cyclase activity are unlikely to be particularly responsive to TSH suppression.P?

78 - - Thyroid Gland It is clear that 80% of patients with papillary thyroid cancer and many cases of follicular thyroid cancer do well almost regardless of how they are treated.208.209 TSH suppression has been shown to date to have no proven benefit in patients with medullary thyroid carcinoma. The use of TSH suppressive therapy has to show survival advantage over prolonged follow-up for the patients deemed to have poor prognoses and, in view of the potential side effects of long-term suppressive treatment, it seems sensible to individualize its use on the basis of expected likelihood of local or systemic recurrence. Factors associated with a particularly poor prognosis in differentiated thyroid cancer include poor 1311 uptake (such as Htirthle cell variantsj.i'? decreased adenylate cyclase response to TSH,178 DNA aneuploidy,"! the expression of EGFr,191 and the extent of initial surgical treatment. 212 This has been complemented by the AGES classification devised by Hay and colleagues to classify patients as high risk and low risk on the basis of age, histologic grade, extent of primary tumor, and primary size.213 Notably, patients older than 40 years at diagnosis with tumors larger than 4 em with marked DNA aneuploidy have been shown to have markedly worse disease-free and overall survival.i" In this sense, it is advocated that TSH suppressive therapy should be adjusted to individual prognostic factors to avoid unnecessary radical surgery, radiation exposure, and the costs associated with monitoring patients at minimal risk for recurrent disease. The use of TSH suppression is very much aligned with the view that differentiated thyroid carcinoma should be treated by total thyroidectomy. The advantage of total thyroidectomy in such cases is to permit both diagnostic and, where appropriate, ablative radioactive 131 1 to be administered without the problem of a competing thyroid lobe as well as to diminish the likelihood of troublesome recurrence in the central neck, which is difficult to treat and whose surgical therapy is fraught with considerable morbidity.215·216 Other advantages of total thyroidectomy in this setting include the removal of the contralateral lobe, which has as much as an 80% chance of containing a microscopic focus of carcinoma,"? as well as the elimination of the very small risk of a differentiated tumor dedifferentiating into an anaplastic cancer.t" Total thyroidectomy permits better potential ablation of metastatic disease and allows serum thyroglobulin levels to be more reflective of recurrence. The evidence for T 4 treatment actually improving survival in differentiated carcinoma is at best uncontrolled. Mazzaferri 219,220 and Massin-" and their coworkers showed the best long-term survival in the patients treated by total thyroidectomy, ablative radioiodine, and deliberate TSH suppression. A beneficial effect has been reported in both papillary and follicular cancer,222 in papillary cancer alone,22o and in neither.F' The most convincing evidence comes from Mazzaferri, who was able to show a cumulative recurrence rate for papillary carcinoma of 17% for patients receiving T 4 compared with 34% when no T 4 was used over a lO-year follow-up period.P' This retrospective series was neither controlled nor randomized. However, another large study failed to show any improvement in survival with thyroid hormone therapy.-" T 4 is probably tumor static and not tumoricidal. The dose requirements and level of required TSH suppression are

simply not known.F" No study has documented conclusively the optimal degree ofTSH suppression, and patients' compliance is an issue that remains largely unexplored. Because of the heterogeneity of thyroid cancers, their variable prognostic indicators, the required length of follow-up needed to demonstrate survival advantage, and a general failure to record uniformly both the presence and extent of TSH suppression, it seems unlikely that such a controlled, randomized, prospective trial assessing the value of levothyroxine, particularly in carcinoma subgroups, will ever be conducted.F' Suppression of TSH to less than 0.1 mUlL is recommended. The average daily dose of T 4 to achieve this level of suppression is usually 2.2 to 2.5 ug/kg. Because low-risk cases represent about 75% of all patients-" and the incidence of local recurrence is greatest within the first 5 years after thyroidectomy.-" it is recommended that high-level TSH suppression be used for this initial period, allowing the TSH concentration to rise to between 0.1 and 0.3 mUlL if no recurrences are demonstrable at 5 years.

Recommendations for the Use of Levothyroxine in Thyroid Cancer The consensus recommendation currently is that TSH suppressive therapy should be given postoperatively to all patients with differentiated thyroid cancer. The exact definition of appropriate TSH suppression to suppress tumor growth adequately remains unclear. Studies with very large numbers and follow-up would be required to detect significant differences. The true efficacy of ablative 131 1 has never been established in a controlled clinical setting. 228,229 In the postoperative setting in the cases believed to be high risk (the older male patient with a tumor larger than 4 em with either capsular or angioinvasion if follicular or extensive lymphadenopathy if papillary), T 4 replacement therapy is avoided for 4 to 6 weeks. This allows maximal TSH stimulation to occur and permits a valuable assessment of postoperative thyroglobulin levels (because thyroglobulin levels increase as serum TSH levels increase in patients with remnant normal thyroid tissue or metastatic thyroid cancer after thyroidectomyj.P" In some patients with rapidly growing metastases, it may be critical to minimize TSH stimulation of the tumor after thyroidectomy or 1311scanning or ablation, and this is best achieved by the use of T3, which, because of its shorter half-life, needs to be discontinued for only about 2 weeks to stimulate TSH for diagnostic or therapeutic purposes.P' It can be seen that radioiodine scanning and ablation are not trivial undertakings. The need to stop replacement therapy and to render the patient at least subclinically hypothyroid, along with the precautions necessary in the use of radiopharmaceuticals, must be coordinated by a nuclear medicine physician with a specific interest and experience in thyroid tumor treatment. The timing of the first scan, the indications for remnant removal or ablation, and the interval between scanning are all matters of controversy. Serum thyroglobulin determination is also comparable to or more sensitive than 131 1 scanning in the follow-up of

TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - -

patients with differentiated carcinoma. Thyroglobulin is a large glycoprotein synthesized by thyroid follicular cells and stored in colloid, providing the tyrosyl groups for iodination and coupling to form both T 3 and T 4. TSH stimulates thyroglobulin release, and thus serum thyroglobulin is elevated in any disease associated with an increased mass or activity of the gland. As a result, it is elevated in endemic and sporadic goiter, thyroiditis, and benign and malignant thyroid neoplasms.P? Its use in the assessment of patients after total thyroidectomy is roughly equivalent to that of radioiodine scanning. 233 -238 In 8% to 22% of cases of differentiated thyroid carcinoma, thyroglobulin measurement is difficult, however, because of circulating antithyroglobulin antibodies leading to spuriously high levels.P? although the newer use of monoclonal antibodies to thyroglobulin and immunometric assays will lessen this problem.s'" A serum concentration suppressed according to a second-generation assay with a TSH of less than 0.1 mUlL may be readily detectable by a third-generation assay with a limit of 0.01 mUlL. The term "undetectable" then becomes obsolete when assessing TSH suppression and is relative to the assay used. Equally, in a small group of patients with nonfunctioning but differentiated metastases (particularly elderly patients with invasive Hiirthle cell tumors), both thyroglobulin measurement and sestamibi or thallium scanning or technetium pyrophosphate bone scanning, or a combination, are superior to diagnostic 1311 scans. 24 1,242 TSH suppression has been shown to reduce recorded levels of thyroglobulin in patients with proven functional metastases, and thus thyroglobulin levels are best assessed with the patient not receiving replacement thyroid hormone. 243 ,244 An elevated thyroglobulin concentration with a normal 1311 diagnostic scan without thyroid hormone should alert the clinician to the possibility of nonfunctioning osseous or pulmonary metastases and result in careful clinical assessment with standard radiologic methods for detecting metastatic disease, such as computed tomography scanning, skeletal surveys, and magnetic resonance imaging. When treated with therapeutic doses of 1311, some of these patients have their thyroglobulin levels decrease to below 3 ng/mL, and metastatic tumor is seen on a follow-up scan (approximately 5 days after treatment). The value of thyroglobulin measurement after simple lobectomy in thyroid cancer is clearly debatable, but if it is elevated after such surgery in patients receiving levothyroxine suppression (i.e., above the normal range for an intact thyroid lobe), a search for metastatic disease should be initiated. 232,245 An algorithm for the use of TSH suppression therapy, based on data from Schlumberger and colleagues.s" is shown in Figure 8-2.

Conclusion Treatment by supraphysiologic dosing of levothyroxine is done to create adequate suppression of TSH without inducing clinical evidence of hyperthyroidism. The rationale is that TSH is one of the principal stimulants of thyroid growth. Its use is recommended in patients after a total thyroidectomy for differentiated carcinoma of the thyroid, particularly

79

After total thyroidectomy (wait 4-6 weeks off T4 or 2 weeks off T3)

!

131 1 total

body scan T4, TSH, TG, pregnancy test, if female Anti·TG antibody status

~

TG < 2.5

!

Annual clinical examination Every 5 years 131)

TG > 5

!

Annual clinical examination

scan

131 1 scan

TG TG

Chest x-ray film

Chest x-ray film

A

Low TG off T4

High TG off T4 Ablative

131 1

""T"

Ablative 131 1

CT scan of neck and chest Bone scan Thallium-201 scan

FIGURE 8-2. An algorithm for the use of thyroid-stimulating hormone (TSH) suppression in the follow-up of thyroid carcinoma. CT =computed tomography; 1311 =iodine 131; TG =thyroglobulin; T3 = triiodothyronine; T4 = thyroxine. (Data from Schlumberger M, Travagli JP, Fragu P, et al. Follow-up of patients with differentiated thyroid carcinoma: Experience at Institute Gustave-Roussy, Villejuif. Eur J Cancer Clin Oncol 1988;24:345.)

in the first 5 years after surgery when there are prognostic factors that imply a worse overall prognosis for the tumor. Suppressive therapy is not recommended in patients with multinodular goiter after thyroid resection for benign disease because of the difficulty in assessing dominant masses within an abnormal gland. Replacement therapy to avoid hypothyroidism may be useful. Suppression treatment must be stopped before diagnostic scanning and thyroglobulin assessment in malignant disease. Treatment with T4 to suppress TSH must be monitored closely because of the risks of subclinical hyperthyroidism and T4-induced osteopenia and cardiac dysfunction, particularly in elderly persons.

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TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - 161. Duffy Bl, Fitzgerald PT. Thyroid carcinoma in childhood and adolescence: A report of28 cases. Cancer 1950;3:1018. 162. Favus Ml, Schneider AB, Stachura ME, et al. Thyroid cancer occurring as a late consequence of head and neck irradiation: Evaluation of 1056 patients. N Engl 1 Med 1976;294:1019. 163. Shimaoka K, Getaz EP, Razack M, et al. Screening program for radiation associated thyroid carcinoma. NY State 1 Med 1979;79:1525. 164. Razack MS, Shimaoka K, Sako K. Suppressive treatment of thyroid nodules in patients with previous radiotherapy to the head and neck. Am 1 Surg 1988;156:290. 165. Nadler Nl, Mandavia M, Goldberg M. The effects of hypophysectomy on the experimental production of rat thyroid neoplasms. Cancer Res 1970;30:1909. 166. Maloof F. The effects of hypophysectomy and of T4 on radiation induced changes in rat thyroid. Endocrinology 1955;56:209. 167. Kaplan MM, Garnick MB, Gelber R, et al. Risk factors for thyroid abnormalities after neck irradiation for childhood cancer. Am 1 Med 1983;74:272. 168. Schimpff SC, Diggs CH, Wiswell IG, et al. Radiation related thyroid dysfunction: Implications for treatment of Hodgkin's disease. Ann Intern Med 1980;92:91. 169. Rosen m, Palmer lA, Bain 1, et al. Efficacy of needle biopsy in post irradiation thyroid disease. Surgery 1983;94:1002. 170. Thomas CG lr, Croom RD. Current management of the patient with an autonomously functioning nodular goiter. Surg Clin North Am 1987;67:315. 171. Hamburger Jl, Evolution of toxicity in solitary non-toxic autonomously functioning thyroid nodules. 1 Clin Endocrinol Metab 1980;50:1089. 172. Larsen PR, Yamashita K, Dekka A, et aI. Biochemical observations in functioning human thyroid adenomas. 1 Clin Endocrinol Metab 1973; 36:1000. 173. Silverstein GE, Burke G, Cogan R. The natural history of the autonomous hyperfunctioning thyroid nodule. Ann Intern Med 1967; 67:539. 174. Thomas CG lr, Tamil M, Braverman MI, et aI. TSH suppression in the management of autonomously functioning thyroid lesions. World 1 Surg 1986;10:797. 175. Hamburger 11. Spontaneous degeneration of autonomously functioning thyroid nodules-Potential therapeutic pitfall. Thyroidol Clin Exp 1989;1:27. 176. Fung HYM, Kologlu M, Collison K, et al. Postpartum thyroid dysfunction in Mid Glamorgan. Br Med 1 (Clin Res Ed) 1988;296:241. 177. Clark OH. Thyrotropin binding and adenylate cyclase activation in normal and neoplastic human thyroid tissue: Lack of effect of thyroglobulin. 1 Clin Endocrinol Metab 1982;54:1157. 178. Siperstein AE, Zeng QH, Gum ET, et al. Adenylate cyclase activity as a predictor of thyroid tumour aggressiveness.World 1 Surg 1988; 12:528. 179. Taylor S. Physiologic considerations in the genesis and management of nodular goiter. Am 1 Med 1956;20:698. 180. Kobayashi K, Shaver lK, Liang W, et al. Increased phospholipase C activity in neoplastic thyroid membrane. Thyroid 1993;3:25. 181. Nichols CW lr, Lindsay S, Sheline GE. Induction of neoplasms in rat thyroid glands by X irradiation of a single lobe. Arch Pathol 1965; 80:177. 182. Westermark B, Karlsson FA, Walinder O. Thyrotropin is not a growth factor for human thyroid cells in culture. Proc Natl Acad Sci USA 1979;76:2022. 183. Scnipper LE. Clinical implications of tumour cell heterogeneity. N Engl 1 Med 1986;314:1423. 184. Schroder S, Miller-Gartner HW, Schroiff R, et al. Morphological demonstration and quantification of TSH binding sites in neoplastic and non-neoplastic thyroid tissue. Virchows Arch A Pathol Anat HistopathoI1986;409:555. 185. Loebenstein BG, Buchan G, Serdegli R, et al. Transforming growth factor-B (TGF-~) regulates thyroid growth. 1 Clin Invest 1989;83:764. 186. Dumont lE, Takeuchi A, Lamy F, et al. Thyroid control: An example of a complex regulation network. Adv Cyclic Nucleotide Res 1981; 14:479. 187. Duh QY, Clark OH. Growth factors for thyroid neoplasms. Prog Surg 1988;19:205. 188. Errick lE, Eggo MC, Burrow GN. Epidermal growth factor (EGF) inhibits thyrotropin mediated synthesis of tissue specific proteins in cultured bovine thyroid cells. Mol Cell Endocrinol 1985;43:51.

83

189. Westermark K, Karlsson FA, Westermark B. Epidermal growth factor modulates thyroid growth and function in culture. Endocrinology 1983;112:1680. 190. Duh QY, Gum ET, Gerend PI, et al. Epidermal growth factor receptor in normal and neoplastic thyroid tissue. Surgery 1985;98:1000. 191. Asklen LA, Myking AO, Salvesen H, et al. Prognostic impact of epidermal growth factor receptor in papillary thyroid carcinoma. Br 1 Cancer 1993;68:808. 192. Aasland R, Lillenhaug lR, Male RJ, et aI. Exposure of oncogenes in thyroid tumours: Coexpression of c-erb/neu and c-erb, Br 1 Cancer 1988;57:358. 193. Siamon Dl, Godolphin W, Jones LA, et al. Studies of the HER-2/neu protooncogene in human breast and ovarian carcinoma. Science 1989;244:707. 194. Terrier P, Sheng ZM, Schlumberger M, et al. Structure and expression of c-myc and c-fos protooncogenes in thyroid carcinoma. Br 1 Cancer 1988;57:43. 195. Lemoine NR, Mayall ES, Wyllie FS, et al. Activated ras oncogenes in human thyroid carcinoma. Cancer Res 1988;48:4459. 196. Frauman AG, Moses AC. Oncogenes and growth factors in thyroid carcinogenesis. Endocrinol Metab Clin North Am 1990;19:479. 197. Lemoine NR, Wyllie FS, Thurston V, et al. Ras oncogene activation: An early event in human thyroid tumour genesis. Ann Endocrinol 1988;49: 191. 198. Wyllie FS, Lemoine NR, Williams ED, et al. Structure and expression of nuclear oncogenes in multistage thyroid tumour genesis. Br 1 Cancer 1989;60:561. 199. Clark OH, Duh QY. Thyroid growth factors and oncogenes. In: Bens C, Edison T (eds), Oncogenes and Tumour Suppressor Genes in Human Malignancies. Boston, Kluwer Academic, 1993, p 87. 200. Clark OH, Duh QY. Factors influencing the growth of normal and neoplastic tissue. Surg Clin North Am 1987;67:281. 201. Heiden NE, Gustavsson G, Claesson-Welsh L, et al. Aberrant expression of receptors for platelet derived growth factor in an anaplastic thyroid carcinoma cell line. Proc Math Sci USA 1988;85:9302. 202. Ito T, Seyama T, Mizuno T, et al. Unique association of P53 mutation with undifferentiated but not with differentiated carcinomas of the thyroid gland. Cancer Res 1992;52:1369. 203. Dunhill TP. The surgery of the thyroid gland (the Lettsomian lectures). Trans Med Soc Lond 1937;60:234. 204. Crile G lr. The endocrine dependency of certain thyroid cancers and the danger that hypothyroidism may stimulate their growth. Cancer 1957;10:1119. 205. Larsen PR, DeRubertis F, Yamashita K, et al. In vitro demonstration of iodide-trapping defect but normal thyrotropin (TSH) responsiveness in benign and malignant "cold" thyroid nodules. Trans Assoc Am Physicians 1972;85:309. 206. Abe Y, Ichikawa Y, Muraka T, et al. Thyrotropin (TSH) receptors and adenylate cyclase activity in human thyroid tumours: Absence of high affinity receptor and loss of TSH responsiveness in undifferentiated thyroid cancer. 1 Clin Endocrinol Metab 1981;52:23. 207. Clark OH, Gum ET, Siperstein AE, et al. Guanyl nucleotide regulatory proteins in neoplastic and normal human thyroid tissue. World J Surg 1988;12:538. 208. Clark OH, Levin K, Zeng QH, et al. Thyroid cancer: The case for total thyroidectomy. Eur 1 Cancer Oncol 1988;24:305. 209. Clark OH. Total thyroidectomy: The treatment of choice for patients with differentiated thyroid carcinoma. Ann Surg 1982;196:361. 210. Ryan 11, Hay ID, Grant CS, et al. Cytometric DNA measurements in benign and malignant Hiirthle cell tumours of the thyroid. World1 Surg 1988;12:482. 211. Smith SA, Hay 10, Goellner lR, et al. Mortality from papillary thyroid carcinoma: A case controlled study of 56 lethal cases. Cancer 1988;62: 1381. 212. Clark OH, Duh QY.Thyroid cancer. Med Clin NorthAm 1991; 75:211. 213. Hay 10, Grant CS, Taylor WF, et al. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: A retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 1987;102:1088. 214. Grant CS, Hay 10, Gough IR, et al. Local recurrence in papillary thyroid carcinoma: Is extent of surgical resection important? Surgery 1988;104:954. 215. Beahrs OH, VandertollDl. Complications of secondary thyroidectomy. Surg Gynecol Obstet 1963;117:535.

84 - - Thyroid Gland 216. Calabro S, Auguste LJ, Attie IN. Morbidity of completion thyroidectomy for initially misdiagnosed thyroid carcinoma. Head Neck Surg 1988;10:235. 217. Russel WO, Ibanez ML, Clark RL, et aJ. Thyroid carcinoma: Classification, intraglandular dissemination and clinicopathological study based upon whole organ sections of 80 glands. Cancer 1963; 11:1425. 218. Colin KH, Backdahl M, Forslund G, et aJ. Biologic considerations and operative strategy in papillary carcinoma: Arguments against the routine performance of total thyroidectomy. Surgery 1984;96:957. 219. Mazzafeni EL, YoungRL, Oertel JE, et aJ.Papillary thyroid carcinoma: The impact of therapy in 576 patients. Medicine (Baltimore) 1977; 56:171. 220. Mazzafeni EL, Young RL. Papillary thyroid carcinoma: A 10 year follow up report of the impact of therapy in 576 patients. Am J Med 1981;70:511. 221. Massin JP, Savoie JC, Gamier H, et aJ. Pulmonary metastases in differentiated thyroid carcinoma. Cancer 1984;53:982. 222. Staunton MD, Greening WP. Treatment of thyroid cancer in 293 patients. Br J Surg 1976;63:253. 223. Cady B, Cohn K, Rossi RL, et aJ. The effect of thyroid hormone administration upon survival in patients with differentiated thyroid carcinoma. Surgery 1983;94:979. 224. Mazzaferri EL. Papillary thyroid carcinoma: Factors influencing prognosis and current therapy. Semin OncoI1987;14:315. 225. Cady B, Cohn K, Rossi RL, et aJ. The effect of thyroid hormone administration upon survival in patients with differentiated thyroid carcinoma. Surgery.1983;94:978. 226. Burmeister LA, Goumaz MO, Mariash CN, et aJ. Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid carcinoma. J Clin Endocrinol Metab 1992;75:344. 227. McConachy WM, Hay rD, Woolner LB, et aJ. Papillary thyroid carcinoma at the Mayo Clinic 1946 through 1970: Critical manifestations, pathologic findings, treatment and outcome. Mayo Clin Proc 1986; 61:978. 228. Bierwaltes WHo The treatment of thyroid carcinoma with radioactive iodine. Semin Nucl Med 1978;8:79. 229. Krishnamurthy GT, Blalud WHo Diagnostic and therapeutic implications of long term radioisotopic scanning in the management of thyroid carcinoma. J Nucl Med 1972;13:924. 230. Aufferman W, Clark OH, Thurner S, et aJ. Recurrent thyroid carcinoma: Characteristics on MR images. Radiology 1988;168:75. 231. Busnardo B, Bui F, Girelli ME. Different rates of thyrotropin suppression after total body scan in patients with thyroid carcinoma: Effects of regular doses of thyroxine and triiodothyronine. J Endocrinol Invest 1983;6:35. 232. DeVathaire F, Blanchon S, Schlumberger M, et al. Thyroglobulin helps to predict recurrence after loboisthmusectomy in patients with differentiated thyroid carcinoma. Lancet 1988;I :52.

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Approach to Thyroid Nodules Paul R. Maddox, MCh, FRCS • Malcolm H. Wheeler, MD

Thyroid nodules are the most common thyroid disorder, and their incidence increases with advancing age. 1 The prevalence of palpable thyroid nodules in adult Americans has been estimated to be 4% to 7%2; about 9 million adults harbor a thyroid nodule.' and new nodules appear at a rate of 0.08% per year," However, the true prevalence of thyroid nodules has been shown to be far greater," Autopsy studies reveal that 50% of adults had nodules, most of which were impalpable.t'' In agreement with these data, Horlocker and colleagues have shown, using high-resolution ultrasonography, that 50% of patients have thyroid nodules by the age of 50 years." Most thyroid nodules are benign, and thyroid cancer is comparatively rare, with an incidence of approximately 4 per 100,000 individuals per year." constituting only 1% of all malignancies' and 0.5% of all cancer-related deaths." Postmortem data, however, have demonstrated that occult thyroid cancer, which is mostly papillary, has a prevalence ranging from 6% to 28%.10,11 Although the natural history of thyroid carcinoma usually involves a slow, indolent course, with a death rate of only 6 per 1 million, it is equally true that small, seemingly innocuous tumors with a diameter smaller than 1 ern have been known to develop into progressive metastatic disease and cause death. 12 It is the anxiety induced by the fear of malignancy within the solitary thyroid nodule against a background of common benign nodular disease that generates the diagnostic dilemma for the clinician. Consequently, the management of thyroid nodules has been controversial.P:!" with the ironic stance of some physicians advocating aggressive surgery" and many surgeons continuing to advise a more conservative approach." Clearly, the truth must lie in the gray area between these two extremes, and the approach to thyroid nodule management must be a selective one, embracing the appropriate use of continually improving diagnostic techniques, thereby identifying those patients with malignancy who require surgery and avoiding thyroidectomy in most patients with benign lesions.

Clinical Evaluation Careful clinical assessment with particular attention to clinical risk factors (Table 9-1) gives important indicators

for the diagnosis and requirements for surgery, Most thyroid nodules are asymptomatic, presenting as a chance finding by the patient or during a medical examination. Pain is uncommon, but a malignant lesion may occasionally cause discomfort in the neck. With respect to single and multiple nodules, current evidence suggests that when a dominant nodule appears in a multinodular gland, the risks of malignancy are probably the same as those in a true solitary nodule. I? The development of a new single nodule (Fig. 9-1) or the rapid growth of an existing dominant nodule (Fig. 9-2) may suggest malignancy, but a malignant nodule can also be extremely slow growing, present for many years before a diagnosis is made. However, the sudden presentation of a painful swelling in the thyroid is almost pathognomonic of hemorrhage into a colloid nodule. This is important to recognize because spontaneous resolution will occur within a few weeks, obviating any need for medical intervention. Children younger than 14 years of age who present with a solitary nodule have a 50% chance of malignancy.P:'? but some evidence suggests that this increased risk may be a consequence of exposure to ionizing radiation" Previous thyroid irradiation confers a risk of malignartcy in a palpable nodule of 20% to 50%21-23; therefore, a history of neck irradiation clearly influences surgical management, lending support toward a more aggressive approach. Geographic factors may play a role in papillary cancer, which has been found to have an increased incidence in iodine-rich regions.s' The incidence of follicular cancer is increased in iodine-deficient endemic goitrous areas." Although thyroid nodules are more frequently found in women, a solitary nodule in a male conveys a greater risk of malignancy. A family history of endocrine disease should suggest the diagnosis of medullary thyroid carcinoma. This rare tumor constitutes 7% of all thyroid malignancies but may be familial in more than 20% of cases as multiple endocrine neoplasia (MEN) type 2A or 2B syndrome or rarely as a non-MEN familial syndrome. Coexistent endocrine disease, particularly pheochromocytoma, must clearly be sought and adequately treated before any thyroid surgical intervention. Papillary carcinoma is also occasionally familial" and has been described with familial adenosis polyposis (Gardner's syndromej" and ataxia-telangiectasia" The patient with a thyroid nodule is usually euthyroid, but features of thyroid dysfunction may help establish

85

86 - - Thyroid Gland

the diagnosis. For example, hyperthyroidism in a patient presenting with a solitary nodule suggests a toxic autonomous nodule, whereas associated hypothyroidism may indicate nodular Hashimoto's disease or possibly lymphomatous change within a Hashimoto's goiter. Palpation determines whether the thyroid lesion is a true solitary nodule or a dominant nodule within a multinodulargoiter,but in approximately 50% of cases a clinically solitary nodule is found to be part of a multinodular gland." This distinction has been given inappropriate attention in the past, and current evidence suggests similar malignancy rates in the two types of glands.v-" This fact is particularly relevant in the multinodular goiter with a dominant nodule increasing rapidly in size, which clearly should be treated as a true solitary nodule. A hard, fixed nodule is likely to be malignant, but some papillary carcinomas present as cystic lesions, and follicular carcinoma can be hemorrhagic and soft. Conversely, a benign colloid nodule can be hard with dystrophic calcification; therefore, consistency is not a reliable feature. However, associated lymphadenopathy is strongly suggestive of malignancy, and the so-called lateral aberrant thyroid with cystic change within a cervical lymph node involved with papillary carcinoma can occasionally be mistaken for a branchial cyst. Presentation with a recurrent laryngeal nerve palsy in the absence of respiratory disease or previous thyroid surgery is a strong indicator of malignancy with direct nerve invasion. Occasionally, nerve palsy can occur as a result of local pressure symptoms of benign colloid nodular disease.

FIGURE 9-2. Dominant nodule within a multinodular goiter.

These coexistent pressure symptoms on the esophagus or trachea will independently be indications for surgery despite any consideration of potential malignant disease.

Diagnostic Procedures Thyroid dysfunction is assessed by measurement of free thyroxine (T4 ) , thyroid-stimulating hormone (TSH), and free triiodothyronine (T3) , but, as previously stated, most patients with a thyroid nodule are euthyroid. A malignant nodule may occasionally be found in association with thyroiditis or Graves' disease, but it is rare for a malignant nodule to actually be the cause of hyperthyroidism. Thyroid antibody titers and thyroglobulin measurement add little to the clinical assessment. Retrostemal extension may be further assessed with radiographs of the chest and neck, but magnetic resonance imaging (MRI) and computed tomography (CT) are currently the best modalities to assess intrathoracic extension. When there is a positive family history suggestive of MEN 2 syndrome, serum calcitonin should be measured as an aid to diagnosis but has most usefulness in serial monitoring of the patient after surgery for medullary thyroid cancer.

Thyroid Scintigraphy

FIGURE 9-1. Solitary thyroid nodule.

Isotope scanning of the thyroid has been used to classify nodules into those that are nonfunctioning ("cold"), normally functioning ("warm"), and hyperfunctioning ("hot") as a result of their ability to take up the commonly used isotopes iodine 123 and technetium Tc 99m pertechnetate. The finding of a hot nodule is usually consistent with benignity, and, because of the limitations of the procedure, the few cases of malignancy associated with hot nodules 32,33 are probably a consequence of a cold focus of cancer being adjacent to the hot lesion, leading to incorrect interpretation. More than 80% of nodules are cold (Fig. 9-3), but fewer than 20% of these are malignant. 34,35 About 10% are warm, and 10% of these are malignant. Only 5% of scans have hot nodules, with fewer than 5% being malignant." Furthermore, it is well recognized that there may be a discrepancy in imaging between 1231 and 99mTc scintigraphy." In summary, isotope

Approach to Thyroid Nodules - - 87

FIGURE 9-4. Small tumor seen within a cyst cavity with high-

resolution ultrasound scan.

FIGURE 9-3. Thyroid isotope scan of a cold nodule.

scanning is extremely poor in differentiating between benign and malignant lesions, and its practical role is actually now limited to the identification of autonomously functioning thyroid tissue.

Ultrasonographic Scanning Ultrasonography is an operator-dependent modality but is capable of identifying impalpable nodules as small as 0.3 mm in diameter." Ultrasonography discriminates cystic from solid lesions but, disappointingly, does not aid in the overall diagnosis of malignancy. Originally, it was thought that the hypoechoic lesion, as with breast carcinoma, was more likely to be malignant," but overlap of sonographic findings has led to a low specificity.'? Recently, the association of sonographically detected thyroid calcifications with malignant dominant nodules has been found to increase diagnostic accuracy." It is difficult to assess mixed lesions on ultrasonography because, although they may usually represent colloid disease with associated hemorrhage in degeneration, they may also be indicative of a tumor within a cyst wall (Fig. 9-4). We consider that conventional ultrasonography has limited routine practical value in the assessment of thyroid nodules.

Needle Biopsy and Aspiration Cytology Needle core biopsy is a reliable diagnostic technique for differentiating benign from malignant nodules with conventional histology" and particularly in the assessment of dominant nodules with coexistent long-standing Hashimoto's disease, where cytologic interpretation of possible lymphoma may be difficult. It suffers, however, from inherent disadvantages in that it is a painful procedure and has poor patient compliance. Complications range from hematoma and hemorrhage

to tracheal puncture and recurrent laryngeal nerve damage. The theoretical fear of seeding of malignancy along the needle tract appears to have been greatly exaggerated, and Miller4 2 did not see this complication in more than 3000 biopsies, with a false-negative rate of only I%. However, lesions smaller than 3 em may not be amenable to this technique. Fine-needle aspiration cytology (FNAC) is an alternative and more acceptable method that is now commonly used (Fig. 9-5). Pioneering work in Scandinaviav" subsequently led to almost universal acceptance of FNAC as the procedure of choice in diagnostic assessment of thyroid nodules. Cytologic assessment may use a wet fixed specimen (Papanicolaou stain) or an air-dried preparation (MayGriinwald-Giemsa). In our own center, we have modified the FNAC technique to use the cell block method, in which the thyroid architecture is preserved to facilitate a diagnosis. Immunocytochemical studies and special stains can also be performed. At least six passes of the needle are used in each case. FNAC has good patient compliance with few complications, and it is easy to repeat the sampling if required. FNAC can confidently identify colloid nodule; thyroiditis, papillary medullary, and anaplastic cancer; lymphoma; and even secondary cancer (Fig. 9-6). The major limitation of FNAC is in the evaluation of the follicular nodule: histology is required for distinguishing between the benign follicular adenoma and follicular carcinoma, the diagnosis of which rests on the presence of capsular and vascular invasion. Core biopsy for these follicular lesions diagnosed on FNAC may add further useful information, but any follicular neoplasm diagnosed by cytology should be regarded as potentially malignant and should be selected for formal surgical excision. The finding that DNA aneuploidy often occurs in follicular adenomas as well as in carcinomas'<" lends further support for the view that follicular neoplasia should be regarded and treated as a single entity.

88 - - Thyroid Gland

FIGURE 9-5. Fine-needle aspiration cytology performed with the

use of a syringe holder with a 23-gauge needle, with the patient supine and the lesion fixed between two fingers. In this situation, glovesand appropriate infection control barriers would be used. Obviously, there must be a low false-negative rate and false-positive rate for a surgeon to rely on FNAC in overall assessment and selection for surgery. Two large studies using FNAC before surgery have demonstrated a false-positive

rate of 0% with an acceptable low false-negative rate of 2.2% (falling later to 0%)45 and 0.7%, respectively." It is concluded that FNAC is a safe, reliable, accurate means of differentiating benign from malignant thyroid nodules. Henry and associates'? demonstrated that using an immunocytochemical technique for detection of thyroperoxidase (TPO) (with the monoclonal antibody termed MOAB 47) may be a useful adjunct to FNAC in the preoperative diagnosis of malignancy, with reported sensitivity, specificity, and overall accuracy of 100%, 86.7%, and 89%, respectively. An FNAC that is reported as suspicious presents a difficult dilemma, but it is better to err on the side of caution, leading to increased false-positive results but an increased sensitivity for the method. Grant and colleagues'" reported 23% of suspicious lesions to be malignant, with similar findings documented by other workers. 45,50 Inadequate samples should not be regarded as negative but as an indication for repeat aspiration, perhaps with an ultrasound-guided technique." The implementation of FNAC in the diagnostic assessment has led to an increasing incidence of malignancy in several series of patients undergoing surgery, from 10% to 31 % up to 50%,4,52,53 and to improved selection, with the total number of cases coming to thyroid surgery drastically reduced, with favorable cost implications.w-" FNAC has been deemed so valuable that some authors have recommended that no patient with a goiter be denied the diagnostic technique. 56 In 1994, Delbridge and coworkers'? showed that proton magnetic resonance spectroscopy (PMRS) analysis of FNAC specimens may further enhance diagnostic evaluation and help avoid unnecessary surgery for benign follicular neoplasms.

A

B

c

o

E

F

FIGURE 9-6. The cytologic features of thyroid nodules. A, Colloid nodule; B, Hashimoto's thyroiditis; C, papillary carcinoma; D, follicular neoplasm; E, anaplastic carcinoma; F, secondary deposit melanoma.

Approach to Thyroid Nodules - -

Current research on galectin-3 shows great potential to improve the differential diagnosis on cytology. The galectins are a family of ~-galactoside binding lectins and galectin-3 has been shown to be overexpressed in malignant thyroid tissue58-6 1 compared to a normal background, and also in comparison to follicular adenoma or hyperplastic thyroid tissue (Fig. 9-7). Work is now currently under way in Newcastle, United Kingdom/? to assess galectin-3 expression in preoperative FNAC and determine its potential role as a marker of well-differentiated thyroid cancer. We await further confirmatory reports of these new advances, and perhaps the use of all four modalities (FNAC, TPO, PMRS, and galectin-3) may maximize overall accuracy, sensitivity, and specificity. In conclusion, FNAC is a highly accurate and cost-effective diagnostic technique of low morbidity, providing a valuable

89

adjunct to the clinical assessment in the overall selection of patients with thyroid nodules for surgery.

Thyroid Cysts FNAC serves as a diagnostic and therapeutic tool for the management of simple thyroid cysts. Simple cyst aspiration eliminates many small lesions, but surgical excision may still be required in about 6% when there is a residual nodule.P Certainly, negative cytology does not exclude a neoplasm, and if there is a residual palpable lesion after aspiration, surgery is recommended. After cyst aspiration, tissue adjacent to the cyst wall should be sampled by reaspiration. It seems reasonable to reaspirate recurrent cysts for up to three times if necessary, but if this persists, surgery is indicated. Cysts larger than 4 em in diameter should be resected in view of the increased risk of malignancy.-v" A sudden painful presentation of an acute hemorrhagic colloid nodule produces a blood-stained aspirate, and the lesion will resolve spontaneously; otherwise, blood in the aspirate should be regarded with suspicion of malignancy and surgery is advised.

Spontaneous Resolution

A

The natural history of benign thyroid nodules has received scant attention in the past and is important to predict outcome and determine appropriate management. A long-term follow-up (6.1 years) study by Grant and associates" of FNAC in 641 patients focused on the demonstration of a low false-negative rate of 0.7% but did not document exact changes in the untreated benign thyroid nodules, suffering from the inherent weakness of review by telephone, correspondence, or referring physician letter. However, the fate of putatively benign solitary thyroid nodules by clinical reexamination after 10 to 30 years has been studied by Kuma and colleagues.v who demonstrated that most nodules reduce in size and nearly 36% disappear. There was, however, a malignancy rate of 26.3% in enlarging nodules. A more recent study by the same group'< has used physical re-examination (by the same two clinicians) and clinical and ultrasound-guided FNAC to assess the nature of nodules of 9 to 11 years' duration. This study again demonstrated that 99% of benign nodules remained benign; most decrease in size or disappear during this follow-up period. An increase in nodule size remains a worrying clinical feature (occurring in 21% to 23%), with a malignancy rate of 4.5%; clearly, there should be a high index of clinical suspicion for such enlarging lesions.

B

Medical Treatment

FIGURE 9-7. A, Galectin-3 expression in thyroid follicular carcinoma tissue. Invasion of the capsule by strongly positive follicular carcinoma cells (brown cytoplasmic stain for galectin-3) is demonstrated (x40). B, Galectin-3 expression in papillary carcinoma cells (brown cytoplasmic stain to the right of the photograph) in comparison to the negative-staining normal thyroid cells on the left (x40). (A and B, Courtesy of Drs. Pallavi Mehrotra and Tom Lennard.)

Although thyroid hormone administration may be beneficial "suppressive therapy" for diffuse colloid goiter, once nodule formation has developed, patients are unlikely to benefit. 67.68 TSH suppression with exogenous T4 may also reduce the size of some malignant nodules.s? This clearly underscores the problem of potential misdiagnosis for the unwary when

90 - - Thyroid Gland to diagnosis, clinical assessment remains the fundamental basis for selection for surgery and may lead the surgeon to operate irrespective of cytologic findings. In an endemic goitrous area, patients are selected for surgery because of coincidental pressure symptoms (e.g., dyspnea, dysphagia, or choking sensation) associated with a progressive expansion in nodular disease. Assessment with flow-loop respiratory function tests and CT or MRI of the neck can be helpful in such cases. In a consecutive series of 100 patients undergoing surgery for histologically proven benign solitary nodules at the University Hospital of Wales, Cardiff, 50% had significant pressure symptoms warranting surgery.

using this therapy as a nonoperative management of thyroid nodular disease. Toxic nodular goiter (Plummer's disease) may identify a toxic nodule (or at least ascertain the side of activity) with radioiodine scanning and surgery is usually recommended if the nodule is greater than 3 em diameter or symptomatic. Radioiodine treatment for toxic multinodular goiter usually requires higher or repeated doses than for Graves' disease, but toxic solitary nodule (toxic adenoma) is usually well controlled by a single treatment, although radioiodine may not diminish nodule size. One follow-up study has demonstrated that 50% remain unchanged and 10% actually increased in size." Where the patient has symptomatic pressure symptoms and the goiter is relatively large, radioiodine does not relieve local symptoms and surgery is indicated, almost certainly if the nodule is larger than 3 em in diameter. However, radioiodine may be indicated for elderly patients or those with a significant risk of general anesthesia.

Thyroid Surgery for Nodular Disease Thyroid and other endocrine surgery requires a multidisciplinary team approach with, in particular, an anesthesiologist and surgeon both skilled in this particular field. At open operation, the ipsilateral side is initially examined together with the nodule, its characteristics are assessed, and any lymphadenopathy is noted. The contralateral lobe is palpated through the strap muscles to determine whether any nodularity is present that may not have been clinically evident.

Indications for Surgery The overall assessment of clinical risk factors coupled with the findings of FNAC constitute the fundamental basis of selection for surgery. Although cytology is an invaluable aid

1------

1 Solitary ThyroidNodule

I

Hyperthyroid

! FNAC

! 123-1 scan

! >3cm diameter surgery

Suspicious

I

! <3cm diameter

131-1

• >4 cm diameter • Blood • Recurrence RepeatFNACin 6 months-Benign

I DiSCh:rge I

~--I I

Recurrence SUrg:ry

1

FIGURE 9-8. Scheme of management for solitary thyroid nodule. FNAC = fine-needle aspiration cytology. (Adapted from Famdon JR. Endocrine Surgery: A Companion to Specialist Surgical Practice, 2nd ed. Philadelphia, WB Saunders, 2001.)

Approach to Thyroid Nodules - -

If the nodule is truly unilateral, a total thyroid lobectomy (removing isthmus and pyramidal lobe en bloc) is indicated, preserving both parathyroid glands, the external branch of superior laryngeal nerve, and the recurrent laryngeal nerve. This approach is advocated because it enables a full histologic examination of the lesion without any risk of tumor spillage into the operative field. It is a safe procedure with low morbidity when performed in experienced hands. Unilateral subtotal lobectomy should not be used because it makes a possible reoperation on this side quite difficult and is associated with a higher risk of complications. Frozen section histology may confirm preoperative diagnosis and can aid decision making for definitive surgery. If benign disease is identified, no further resection is required unless there is significant contralateral multinodular disease, when a subtotal unilateral lobectomy or, as some authors may prefer, a complete, total thyroidectomy is recommended." If the report is one of papillary or medullary tumor, then one should proceed to carry out a formal total thyroidectomy and appropriate lymph node clearance. There is little evidence to support the use of a formal en bloc dissection technique for these nodes. The difficulty occurs with the follicular lesion where frozen section may be unreliable and paraffin section histology is required to be certain of frank capsule invasion. If this fails to be seen on frozen section analysis or there is discordance between FNAC and frozen section interpretation, it is a simple matter to await the final histology and reoperate a few days later to perform a definitive, complete, total thyroidectomy, removing the contralateral thyroid lobe in safe virgin territory. A minimally invasive follicular carcinoma is adequately treated by unilateral lobectomy alone. By adopting this conservative approach, the risk of underoperation has been found to be small, amounting to fewer than 6% of cases with thyroid nodules," and thereby avoids the hazards of unnecessary extensive surgery. A summary of the management of the patient with a solitary thyroid nodule is shown in Figure 9-8.

Summary Nodular disease of the thyroid is common, whereas malignancy is rare. The differentiation of a malignant nodule from a benign nodule hinges on fundamental clinical assessment coupled with FNAC. This approach provides a safe, reliable, and cost-effective method of selecting patients for surgery who truly need it and avoids an unnecessary operation in the remainder who do not already have mechanical and pressure symptoms resulting from an enlarging goiter.

Acknowledgments The authors express their gratitude to Pallavi Mehrotra, BAES Research Fellow, and Tom Lennard, Professor Breast and Endocrine Surgery, Head of The School of Surgical and Reproductive Sciences, and Consultant Surgeon, The Medical School University of Newcastle-upon-Tyne, for their help in supplying Figure 9-7.

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32. Abdel-Razzak M, Christie JH. Thyroid carcinoma in an autonomously . functioning nodule. J Nucl Med 1979;20;1001. 33. Hoving J, Piers A, Vermey A, et al. Carcinoma in hyperfunctioning thyroid nodule in recurrent hyperthyroidism. Eur J Nucl Med 1981;6:131. 34. Blum M, Rothschild M. Improved nonoperative diagnosis of the solitary, cold thyroid nodule: Surgical selection based on risk factors and three months of suppression. JAMA 1980;243:242. 35. Ashcraft MW, van Herle AJ. Management of thyroid nodules: II. Scanning techniques, thyroid-suppressive therapy, and fine-needle aspiration. Head Neck Surg 1981;3:297. 36. Turner JW, Spencer RP. Thyroid carcinoma presenting as a pertechnetate "hot" nodule, but without 1311 uptake: Case report. J Nucl Med 1976;17:22. 37. Radecki PD, Arger PH, Arenson RL, et al. Thyroid imaging: Comparison of high-resolution real-time ultrasound and computed tomography. Radiology 1984;153:145. 38. Solbiati L, Volterrani L, Rizzato C, et al. Thyroid gland with lowuptake lesions: Evaluation by ultrasound. Radiology 1985;155:187. 39. Simeone JF, Daniels GH, Mueller PR, et al. High-resolution real-time sonography of the thyroid. Radiology 1982; 145:431. 40. Kakkos SK, Scopa CD, Chalmoukis AK, et al. Relative risk of cancer in sonographically detected thyroid nodules with calcifications. J Clin Ultrasound 2000;28:347. 41. Miller JM, Hamburger JJ, Kini S. Diagnosis of thyroid nodules: Use of fine-needle aspiration and needle biopsy. JAMA 1979;241:481. 42. Miller JH. Needle biopsy of the thyroid: Methods and recommendations. Thyroid Today 1982;5:1. 43. Soderstrom N. Aspiration biopsy puncture of goitres for aspiration biopsy. Acta Med Scand 1952;144:237. 44. Einhorn J, Franzen S. Fine-needle biopsy in the diagnosis of thyroid disease. Acta Radiol 1962;58:321. 45. Lowhagen T, Granberg PO, Lundell G, et al. Aspiration biopsy cytology (ABC) in nodules of the thyroid gland suspected to be malignant. Surg Clin North Am 1979;59:3. 46. Joensuu H, Klemi P, Eerola E. DNA aneuploidy in follicular adenomas of the thyroid gland. Am J Pathol 1986;124:373. 47. Cusick EL, Krukowski ZH, Ewen SWB, et al. DNA aneuploidy in follicular thyroid neoplasia. Br J Surg 1989;76: 1095. 48. Grant CS, Hay 10, Gough IR, et al. Long-term follow-up of patient with benign thyroid FNA cytologic diagnosis. Surgery 1989;106:980. 49. Henry JF, Denizot A, Porcelli A, et al. Thyroperoxidase immunodetection for the diagnosis of malignancy on fine-needle aspiration of thyroid nodules. World J Surg 1994;18:529. 50. de Roy van Zuidewijn DBW, Songun I, Hamming J, et al. Preoperative diagnostic tests for operable thyroid disease. World J Surg 1994;18:506. 51. Morgan JL, Serpels JW, Chang MP. Fine-needle aspiration cytology of thyroid nodules: How useful is it? ANZ J Surg 2003;73:480. 52. AI-Sayer HM, Krukowski ZH, Williams VMM, et al. Fine-needle aspiration cytology in isolated thyroid swellings: A prospective two-year evaluation. BMJ 1985;290:1490.

53. Galloway JW, Sardi A, De Conti RW, et al. Changing trends in thyroid surgery: 38 years' experience. Am Surg 1991;57:18 . 54. Hamberger B, Gharib H, Melton LJ, et al. Fine-needle aspiration biopsy of thyroid nodules: Impact of thyroid practice and cost of care. Am J Med 1982;73:381. 55. Cusick EL, MacIntosh CA, Krukowski ZH, et al. Management of isolated thyroid swellings: A prospective six-year study of fine-needle aspiration cytology in diagnosis. BMJ 1990;301:318. 56. Franklyn JA, Daykin J, Young J, et al. Fine-needle aspiration cytology in diffuse or multinodular goitre compared with solitary thyroid nodules. BMJ 1993;307:240. 57. Delbridge L, Lean CL, Russell P, et al. Proton magnetic resonance and human thyroid neoplasia: II. Potential avoidance of surgery for benign follicular neoplasms. World J Surg 1994;18:512. 58. Gaffney RL, Carney JA, Sebo TJ, et al. Galectin-3 expression in hyalinizing trabecular tumours of the thyroid gland. Am J Surg Pathol 2003;27:494. 59. Beesley MF, McLaren KM. Cytokeratin 19 and galectin-3 immunohistochemistry in the differential diagnosis of solitary thyroid nodules. Histopathology 2002;41 :236. 60. Aratake Y, Umeki K, Kiyoyama K, et al. Diagnostic utility of galectin-3 and CD26IDPPIV as preoperative diagnostic markers for thyroid nodules. Diagn Cytopathol 2002;26:366. 61. Bartolazzi A, Gasbarn A, Papotti M, et al. Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions. Lancet 200 1;357: 1644. 62. Lennard T. Personal communication, 2003. 63. Crile G. Treatment of thyroid cysts by aspiration. Surgery 1966;59:210. 64. Ashcraft MW, van Herle AJ. Management of thyroid nodules: I. History and physical examination, blood tests, x-ray tests, and ultrasonography. Head Neck Surg 1981;3:216. 65. Kuma K, Matsuzuka F, Kobayashi A, et al. Outcome of long-standing solitary thyroid nodules. World J Surg 1992;16:583. 66. Kuma K, Matsuzuka F, Yokozawa T, et al. Fate of untreated benign thyroid nodules: Results of long-term follow-up. World J Surg 1994;18:495. 67. Gharib H, James EM, Charboneau JW, et al. Suppressive therapy with levothyroxine for solitary nodules: A double-blind controlled clinical trial. N Engl J Med 1987;317:70. 68. Molitch ME, Beck JR, Dreisman M, et al. The cold thyroid nodule: An analysis of diagnostic and therapeutic options. Endocr Rev 1984;5:185. 69. Mazzaferri EL, Young RC. Papillary thyroid carcinoma: A IO-year follow-up report of the impact of therapy in 576 patients. Am J Med 1981;70:511. 70. Goldstein R, Hart IR. Follow-up of solitary autonomous thyroid nodules treated with iodine. N Engl J Med 1983;309:1473. 71. Reeve TS, Delbridge L, Cohen A. Total thyroidectomy: The preferred option for multinodular goitre. Ann Surg 1987;206:782. 72. Layfield LJ, Mohrmann RL, Kopland KH, et al. Use of aspiration cytology and frozen section examination for management of benign and malignant thyroid nodules. Cancer 1991;68: 130.

Childhood Thyroid Carcinoma Jay K. Harness, MD • David E. Sahar, MD

Historical Aspects Carcinoma of the thyroid was first described in a child in 1902. 1 It was not until 1951 that medullary carcinoma was described by Hom. 2 Nonmedullary, differentiated thyroid carcinoma (DTC) in children and adolescents is an uncommon disease with a high incidence of cervical metastasis and a favorable prognosis. DTC is the most frequent malignant endocrine tumor of childhood. The association of thyroid carcinoma with the use of external low-dose irradiation to the head and neck during childhood has been well documented.' The rapid increase in reports on children with DTC began in 1935 and peaked in 1955. Winship and Rosvoll observed a mean latency period of 8 years between irradiation exposure and detection of thyroid carcinoma.' Although radiation treatment of various benign conditions has been abandoned, cases of childhood DTC continue to be identified. Worldwide, the most dramatic increase in thyroid carcinoma in children has occurred in Belarus and Ukraine after the 1986 Chernobyl nuclear power plant accident in northern Ukraine. The initial clinical presentation of childhood DTC, as reported in one of the largest U.S. series, has changed considerably in those diagnosed since 1971.4 Before 1971, most patients seen with childhood DTC had a history of head and neck irradiation, presented with advanced cervical lymphadenopathy, had more locally infiltrative tumors, and had nearly a 20% incidence of pulmonary metastasis. Since 1971, childhood DTC has often been less locally advanced, and fewer patients have been presenting with distant metastasis. For years, controversy has continued over the extent of thyroid surgery for DTC in adults. The lack of a unified approach in adults quite naturally leads to an intensified debate as to the appropriate surgical therapy in children and adolescents. Total thyroidectomy may be viewed as overtreatment that is associated with increased morbidity. On the other hand, total thyroidectomy with low morbidity can be seen as the most acceptable form of therapy because

it may provide a lower incidence of local regional disease, enhance the efficacy of therapeutic radioactive iodine ( 1311), and improve mortality. These and other issues require further review to determine whether a unified treatment regimen for childhood DTC can be proposed.

Incidence and Etiology Carcinoma of the thyroid gland affects approximately 11,000 people in the United States each year, with a femaleto-male ratio of nearly 3: 1. It accounts for 90% of all endocrine malignancies and kills approximately 1300 people annually.' In the United States, childhood thyroid carcinoma constitutes approximately 3% of all childhood cancers. Its incidence rate is three to five cases per million per year.6•7 Childhood DTC is so uncommon that even the largest referral centers in the United States may see only two or three cases per year. It may take 35 to 50 years to develop a series of only 100 patients. Childhood thyroid cancer constitutes 3% to 4.8% of all thyroid cancers in the general population but a much larger proportion of radiation-related thyroid carcinomas.S? In 1950, Duffy and Fitzgerald reported a 32% incidence of low-dose head and neck irradiation in children with thyroid carcinoma, and a series reported by Winship and Rosvoll in 1970 demonstrated an 80% incidence.v'? Such exposure contributed substantially to the peak in the number of patients seen from 1950 to 1965, whereas its abandonment was largely responsible for the decrease in patients by 1970. Figure 10-1 shows this referral pattern at a university medical center. The increased number of new patients seen since 1970 appears to be related to established referral patterns and not necessarily to an increase in the incidence of childhood DTC. Several series of thyroid carcinoma in children and adolescents published since 1970 reported an incidence of radiation exposure ranging from 3% to 57% (mean, 21%).4.11-14

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10-1. Patients with childhood differentiated thyroid carcinoma treated at the University of Michigan Medical Center, 1935-2000.

FIGURE

A child's thyroid is more susceptible than an adult's to the tumorigenic effect of radiation. This has been seen in the results of studies carried out on Marshall Islanders and on residents of Hiroshima and Nagasaki and from the longterm outcome study by the University of Illinois College of Medicine, the Michael Reese Hospital (Chicago) study.P"? It has been noted from these last reports that the typical latency period from exposure to irradiation and the appearance of thyroid cancer ranges from 8 to 11 years. However, latency periods as short as 3 years have been found in both the Michael Reese Hospital series and in reports after the Chernobyl accident.l":" The Chernobyl nuclear power plant accident on April 26, 1986, led to widespread contamination. About 70% of the most contaminated territory of the former Soviet Union was located in the republic of Belarus. The entire spectrum of radioactive products of nuclear fuel decay also contaminated major populations of Ukraine. Iodine radionuclides entered the body through inhalation or by mouth, which in tum resulted in large radiation doses to the thyroid glands. The total dose of thyroid exposure was caused primarily by 1311 and 1331. Additional external gamma radiation exposure and internal exposure were attributed to cesium and other radionuclides. Children younger than 7 years of age living in the resettlement zone around the power plant received the maximal thyroid exposure. The average dose in these children ranged from 2.1 to 4.7 Gy, depending on the district in which they lived. 19 The effects of radioactive iodine took place against a background of endemic goiter, which is characteristic of many Belarus regions. A large-scale screening program was started in 1990. A total of 10,000 children were examined8000 from contaminated territories and 2000 from control areas. The incidence of thyroid carcinoma was 6.2 per 1000 in

contaminated areas and none in control areas.'? This largescale survey found that children of the republic of Belarus had a significant increase in thyroid nodule disease, including adenoma, nodular goiter, and especially carcinoma. 19 Thyroid carcinoma has been reported to be increased in endemic goiter areas, in Graves' disease, in autonomous nodules, in Hashimoto's thyroiditis, after therapeutic use of 131 1, and after radiation therapy for Hodgkin's lymphoma.P'" Medullary thyroid carcinoma, inherited in an autosomal dominant fashion in 30% of cases, occurs in the syndromes of familiar medullary carcinoma and multiple endocrine neoplasia (MEN) types 2A and 28. These entities are described in detail in Chapter 76. Although not as clearly described, heredity also plays a role in familial papillary carcinoma syndrome and other genetic disorders. Three-andone-half to 6% of patients with papillary carcinoma have an affectedrelative." Papillary carcinoma may occur in association with autosomal dominantly inherited Gardner's syndrome and familial polyposis.F-" In comparison with medullary carcinoma, cytogenetic and molecular genetic studies of papillary and follicular carcinomas have been relatively less common. Advances in cytogenetic and molecular biology have led to a better understanding of the biology of thyroid carcinoma at the genome level. Analysis of cytogenetic studies show chromosome lOq abnormalities to be more common in papillary tumors, whereas chromosome 3 abnormalities are associated with follicular cancer. A tumor suppressor gene in the short arm of chromosome 3 may be important in the development and progression of follicular carcinoma." In 1987, the role of a thyroid-specific oncogene retlPTC was described in papillary thyroid carcinoma (PTC). Mutational rearrangement of novel upstream regulators leads to increased expression of the

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ret/PTC chimeric gene and unregulated ret tyrosine kinase activity." This mutation is found in spontaneous as well as radiation-induced (Chernobyl accident) PTC.3l It is more common in children than in adults. A report by Nikiforov and associates found rearrangements of the ret oncogene in 71% of sporadic PTC in children from the United States and 87% in children from the radiation-contaminated areas of Belarus.F Differential expression of ret/PTC type (ret/PTC1, retIPTC2, retIPTC3) has been reported in spontaneous and radiation-induced groups." Increase in telomerase expression has also been shown in thyroid tumors, which has been thought to confer immortal status to thyroid cancer cells." Mutation in the ras oncogene has also been described in PTC, although less frequently in children compared to adults." This mutation has been described as a prognostic factor in papillary carcinoma.P Finally, growth factors have been shown to be important in promoting growth and recurrence in PTe. Vascular endothelial growth factor (VEGF), VEGF receptor (FIt-I) and hepatocyte growth factor/scatter factor, and hepatocyte growth factor/scatter factor receptor (cMET) play an important role in the clinical outcome of thyroid carcinoma. VEGF expression appears to be increased in large tumors and in those destined to recur. Furthermore, these growth factors are increased in children with PTC compared with adults." Hepatocyte growth factor/scatter factor and cMET overexpressions are found in tumors with high recurrence." Ongoing molecular and genetic research is providing greater insight into the pathogenesis and outcomes of childhood PTe. Such insights will hopefully lead to more uniformed therapeutic interventions.

Pathology Papillary carcinoma is the most common malignant tumor of the thyroid in both adults and those 18 years of age and younger. However, differences do exist between adult and childhood PTe. Thyroid cancers in children have a higher incidence of lymph node metastasis, extension outside the thyroid capsule, and distant metastasis, especially lung, than do those in adults.4.8.l0-l4,38.39 Despite the more aggressive clinical and biologic behavior of childhood thyroid cancers, the mortality rate in children is much less than in adults." Papillary carcinoma appears as a firm, nonencapsulated or partially encapsulated lesion. It may be small and intrathyroidal or extrathyroidal. Calcifications and cysts may be present. Microscopically, papillary carcinomas contain predominant or focal papillary areas as well as follicles. Psammoma bodies are found in 40% to 50% of papillary carcinomas. The nuclei have classically been described as pale, clear, ground-glass, empty, or "Orphan Annie eyed." Papillary carcinoma typically shows areas of sclerosis either centrally or at the peripheral invasive margins." Papillary carcinoma invades lymphatic spaces, giving rise to multifocal lesions through intraglandular spread. Lymphatic invasion also accounts for the high incidence of regional nodal metastases.f The follicular variant of papillary carcinoma is an important subtype in children. These tumors may appear grossly and microscopically encapsulated. A follicular pattern of

FIGURE 10-2. Tissue section showing tightly packed, small follicles containing colloid. Note the nuclear chromatin clearing and irregular, thickened, and occasionally cleft nuclear membranes, classically seen in papillary thyroid carcinoma (hematoxylin-eosin).

growth is seen that includes ground-glass nuclei, psammoma bodies, desmoplastic reaction, and papilla in nodal metastases." Figure 10-2 shows pathologic features representative of the follicular variant of papillary carcinoma. Some authors believe there is a great propensity for vascular invasion in metastases beyond regional lymph nodes with this subtype. 42.44 In contemporary series, the follicular variant constitutes 21% to 25% of pediatric thyroid carcinomas.w" The diffuse sclerosis variant of papillary carcinoma often presents as goitrous enlargement with replacement of both lobes by firm and calcified tumor." This subtype tends to be a tumor affecting children, teenagers, and young adults. It appears to be an aggressive form of papillary carcinoma; one series reported a 100% incidence of regional nodal metastasis at the time of diagnosis and a subsequent 25% incidence oflung metastasis.f'These tumors have numerous psammoma bodies, causing the gland to feel stony hard on palpation. Plain radiographs of the neck can show diffuse calcification of the thyroid. The solid variant form of papillary carcinoma is considered to be a poorly differentiated papillary cancer.'? Microscopically, the tumor grows with nests without papilla or follicle formation. This is an unusual variant about which there is no uniformity of morphologic definition. Its prognostic implications are unknown.50 Pure follicular carcinoma of the thyroid occurs somewhat less frequently in patients 18 years of age and younger. In several large series of childhood thyroid carcinoma in which detailed histologic analyses were included, pure follicular carcinoma constituted 2.7% to 7% of total cases. 4.12.51 It is certainly possible that some tumors classified as follicular carcinoma were, in fact, the follicular variant of papillary carcinoma. If this were true, then the incidence of childhood follicular carcinoma is even lower than in reported series. Hiirthle cell tumors and thyroid sarcomas are unusual tumors seen in childhood and may develop more frequently in persons exposed to radiation.P-"

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Clinical Presentation The clinical presentation of childhood thyroid carcinoma has changed in several ways over the past several decades. The 1992 report on the University of Michigan experience demonstrated important changes in history and clinical presentation." The study compared patients treated from 1936 to 1970 with those treated from 1971 to 1990. The Michigan surgeons found that 50% of the former group reported a history of head and neck irradiation compared with only 3% in the latter group. Similarly, the incidence of palpable cervical adenopathy at initial presentation decreased from 63% to 36%; the rate of local infiltration of the primary cancer fell from 31% to 6%; and the rate of initial pulmonary metastases decreased from 19% to 6%. Alternatively, the incidence of finding a palpable mass or thyroid nodule on presentation increased from 37% to 73%.4 This meaningful change in presentation may reflect an increased awareness by pediatricians of the importance of routine examination of the thyroid. It appears that, at least in the Michigan experience, patients were being diagnosed at an earlier stage of their disease. A palpable thyroid nodule in a child or adolescent, especially a male, is thyroid cancer until proved otherwise. Thyroid carcinoma has been found in 22% to 50% of childhood thyroid nodules brought to surgical exploration. 54-56 All reports suggest that carcinoma is roughly twice as likely to be found in children with thyroid nodules as in adults. Persistent lymphadenopathy must be of concern because it is a common presenting finding in childhood thyroid carcinoma." Most thyroid cancers in children are asymptomatic. A careful history should be taken to determine whether dysphasia, hoarseness, or a change in the voice is present. These are often findings suggestive of a more locally advanced stage. Pulmonary metastases are usually asymptomatic. Initial pulmonary metastases are not uncommon in childhood thyroid carcinoma and should be screened for by initial chest radiograph, computed tomography (CT) scan of the chest, serum thyroglobulin determination, and postoperative 1311 whole-body scanning. Table 10-1 summarizes the initial extent of disease reported in several large series. Cervical lymph node metastases in these reports were confirmed by pathologic examination. Pulmonary and distant metastases were diagnosed by radiograph or 1311 scanning or both.

Diagnostic fine-needle aspiration (FNA) biopsy is a useful procedure, especially when it is positive for carcinoma. FNA can be performed on either the primary thyroid nodule and/or a palpable enlarged cervical lymph node. Ultrasound guidance of diagnostic FNA biopsies provides increased assurance of the proper location of the needle tip in a target lesion. When adequate samples are taken, ultrasound-guided FNAs have fewer false-negative results/" Diagnostic excision lymph node biopsy is occasionally useful if there is no palpable thyroid nodule or if an FNA of the node is negative. If all diagnostic efforts fail, then a child with a palpable thyroid nodule should undergo total lobectomy of the involved side. Nucleation of a nodule is unacceptable, and the diagnostic resection should be nothing less than a total thyroid lobectomy.

Treatment Surgical The debate over the most effective or appropriate extent of surgical resection in adults for DTC has continued for years; little wonder, then, that there is no uniformity of opinion about the treatment of childhood thyroid cancer. The ideal therapy would (1) eliminate the primary disease, (2) reduce local and distant recurrence, (3) facilitate the treatment of metastases, (4) have the lowest possible morbidity, and (5) achieve the highest cure rate. The two major treatment "camps" are the total thyroidectomists and the less than total thyroidectomists. Those who argue against total thyroidectomy do so because they believe that this procedure does not afford a survival advantage and is associated with the possibility of the significant morbidity of permanent hypoparathyroidism and recurrent laryngeal nerve injury. Those who argue in favor of total thyroidectomy do so because (1) papillary carcinoma and its subtypes are typically multifocal; (2) there is a reduced incidence of local and distant recurrence; (3) it facilitates the use of 131 1; and (4) it allows the use of serum thyroglobulin to detect recurrence. To determine a survival advantage of any form of therapy in childhood thyroid carcinoma is difficult because the number of cases is relatively small and the current reported mortality is about 8%. If survival benefit is difficult to determine, then

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analyzing local and distant recurrences may be a better measure of the adequacy of initial treatment, including the role of total thyroidectomy. The extent of cervical lymph node dissection in childhood thyroid carcinoma is an important issue because of the consistently high incidence of nodal metastasis. Most series report a 71% to 90% incidence of cervical and upper anterior mediastinal metastases.4.II-14,61 Typically, carcinomas of the upper one third of the thyroid gland metastasize to the middle and upper jugular chain. Carcinomas in the lower two thirds may spread to the middle and lower jugular chain, the central compartment nodes (pretracheal and peritracheal nodes between the jugular veins), or the anterosuperior mediastinal nodes. To establish cervical metastasis, it is important to explore and sample lymph nodes in areas of likely spread. If involved nodes are found in the central compartment region, a complete ipsilateral central neck dissection from the level of the thyroid notch (Delphian node) to and including the anterior superior mediastinum should be performed. If jugular nodes are affected, the entire jugular chain should be explored, including the region of the lower spinal accessory nerve. All clinically involved nodes should be resected, including bilateral exploration and resection if indicated by the extent of the disease. What is typical in children is multinodal involvement,4,14,40,61 A classic radical neck dissection is virtually never indicated in childhood with DTC of follicular cell origin, Experience has shown that subsequent regional lymph node recurrence is related to the extent of initial disease as well as the scope of initial node dissection.' Patients who experience cervical lymph node recurrence within a year of thyroidectomy should probably be considered to have persistent or "missed" disease as a result of an inadequate exploration and resection, Frankenthaler and coworkers observed that DTC in young patients can involve any of the cervical and upper mediastinal nodal groups except the submental, submaxillary, and upper and lower

97

spinal accessory?' Schlumberger and colleagues found anterosuperior mediastinal involvement only in patients with involvement of the recurrent laryngeal nerve chain (peritracheal).14

Complications The increased incidence of complications associated with total thyroidectomy has been an argument against this procedure, especially if it does not improve survival. The two most feared complications of total thyroidectomy are permanent recurrent laryngeal nerve paralysis and permanent hypoparathyroidism. The incidence of these complications has been disturbingly high in several reports on childhood thyroid carcinoma. LaQuaglia and coworkers found that the probability of a major complication varied inversely with age. Children 6 years of age and younger had greater than a 60% chance of a major complication. Total or subtotal thyroidectomy in their series was associated with an 80% chance of a major complication in the same age group." Table 10-2 shows complication rates for total or near-total thyroidectomy in nine large series of patients with childhood thyroid carcinoma. Overall, the average rates were 12% for hypoparathyroidism and 6% for recurrent laryngeal nerve palsy. In contrast, the Michigan surgical group reported a zero incidence for these two complications in the 33 patients treated from 1971 to 1990. For the past 35 years, the University of Michigan's Department of Surgery has decided to treat all cases of DTC (whether in adults or children) uniformly with total thyroidectomy. Since 1971, nearly all thyroidectomies have been performed by members of Michigan's Division of Endocrine Surgery. This has resulted not only in a consistent approach but also in an excellent operative safety record. Other centers should be able to obtain the same results with a significant complication rate of about 2%. Total thyroidectomy should reduce the rate of recurrence in the thyroid bed to zero. Regional lymph node recurrence is related to the extent of initial disease and the scope of

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lymph node dissection. Pulmonary-distant recurrence is probably related to the biology and extent of disease at presentation and perhaps also to the extent of initial surgical therapy and the use of adjunctive 1311. Table 10-3 compares the use of total or near-total thyroidectomy and postoperative 131 1 with cervical, thyroid bed, and pulmonary-distant recurrences. The University of Michigan report by Harness and colleagues had the highest combined rate of total thyroidectomies (91%) and utilization of 1311 (73%) of the series shown in Table 10-3. The second highest combined use of total thyroidectomy (74%) and 1311 therapy (64%) was from Jarzab and associates." This group had the lowest incidence of recurrent cervical metastasis (6%) and the second lowest rate of distant pulmonary recurrence (6%). The University of Michigan group had zero recurrence in the thyroid bed." Similar results were reported by Mazzaferri and Jhiang in their report on the long-term impact of initial surgical and medical therapy in 1355 patients (primarily adults) with DTC. 62 Median follow-up was 15.7 years; 42% of patients were observed for 20 years and 14% for 30 years. They reported that patients with tumors 1.5 em or larger or with tumors that were multicentric, metastatic, or locally invasive disease had significantly improved long-term outcome-in terms of recurrence and cancer death-when initial therapy combines near-total or total thyroidectomy and 1311 remnant ablation or 1311 therapy for a residual local tumor. 62

ll-year-old boy with bronchiectasis and diffuse macronodularpulmonary metastasis, Figure 10-4 shows the 1311scintiscan of the lungs 6 weeks after total thyroidectomy. Uptake over the lungs was 17.4% at 24 hours. This patient eventually died 7 years later from progressive pulmonary metastasis despite aggressive 1311 therapy. The ability to "cure" patients of their pulmonary metastases is dependent on the initial extent of metastases. Schlumberger and colleagues, in their study of 283 patients (29 patients ranging in age from 4 to 19 years) treated with 131 1 for distant metastasis, found that complete remissions occurred in 64% of patients with normal radiographic examinations at discovery of metastasis and in only 8% of patients with initially abnormal radiographs." It is important to detect and treat distant metastasis early rather than late.

Radioiodine There is considerable experience with the use of 1311 as an adjunct to surgery in adult DTC. By comparison, there is less experience with this agent in children. Children are probably three times more sensitive to radiation than adults and are at higher risk for cancer over a longer projected life expectancy after 1311 therapy.v Yet, to date, only one case of a second cancer (hepatocellular cancer) has been reported in series reporting their long-term follow-up of children receiving 131 1 therapy. 55 In children, doses as high as 650 mCi have been used in an effort to eradicate pulmonary metastases/" In most series, the total dose of 1311 averages a little more than 200 mCi. 64 Pulmonary metastasis occurs with increased frequency in children. 4 .64 ,65 Figure 10-3 is a radiograph of the chest of an

FIGURE 10-3. Chest radiograph of ll-year-old boy with diffuse pulmonary metastasis and bronchiectasis.

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to 100%.4,11-14,40.64,65 Most deaths occur in children II years of age or younger at initial diagnosis. Late recurrences of childhood DTC have been reported up to 20 years after initial treatment." As a result, childhood DTC requires lifelong follow-up.

Summary

FIGURE 10-4. Iodine 131 scintiscan of lungs of the l l-year-old boy shown in Figure 10-3.

The best results for postoperative whole-body 131 1 scintigraphy are obtained after 4 to 6 weeks of hypothyroid status to achieve adequate endogenous thyroid-stimulating hormone (TSH) stimulation or through the use of recombinant human TSH (rhTSH). Initial trials with rhTSH in euthyroid patients have documented equivalent results with hypothyroid scans, and in some instances rhTSH scans have detected additional sites of 131 1 uptake not seen with hypothyroid scans." Selectivity in the use of 131 1has become more common over the last 30 years. Ablation of uptake in the thyroid bed only is not typically performed. Radioiodine can be used to treat residual microscopic disease, such as that around recurrent laryngeal nerves and in nonpalpable lymph nodes as well as pulmonary metastases. Not only does total thyroidectomy facilitate the detection and treatment of metastasis with 131 1 but also it allows the use of serum thyroglobulin as a sensitive indicator of recurrence. Normal thyroglobulin levels range from 0 to 60 ng/mL. Patients who have undergone total thyroidectomy and have no residual disease should have a thyroglobulin level of 5 ng/mL or less. The usefulness of this approach in childhood DTC was confirmed in a 1992 report.68 The patients in whom there is no evidence of focal uptake on diagnostic 131 1 scans, but who have increased serum thyroglobulin levels, may still be candidates for 131 1 therapy.

Long-Term Survival No single microscopic or ultrastructural feature of childhood DTC has emerged as a reliable means of predicting a fatal outcome. Adolescent and adult patients with DTC often have long periods observed from the time of initial diagnosis and treatment to the time of eventual recurrence and death. 69.7o Series reporting only 10- to 15-year follow-up periods are less meaningful because there have been documented instances of recurrence 15 to 25 years after initial treatment, and death may occur as long as 30 years after initial therapy." Despite presenting with initially more advanced disease, children with DTC have very good long-term survival. Survival rates vary in the literature from 86%

DTC in children and adolescents is an uncommon disease with a generally favorable prognosis, a high incidence of cervical metastasis, and an increased rate of pulmonary metastasis when compared with that in adults. Although the treatment ofDTC in children and adults remains controversial, total thyroidectomy is the best management option. It is safe when performed by a skilled and experienced endocrine surgeon. When used with appropriate cervical lymph node dissection, total thyroidectomy is essential not only for controlling cancer in the neck but for allowing 131 1 ablation therapy of microscopic regional and distant metastases. Children with thyroid carcinoma (differentiated or medullary) should be referred to centers with skilled and experienced endocrine surgeons. Thyroidectomies and neck dissections in children should not be performed in community hospitals or by surgeons who perform such procedures infrequently. To do so subjects these young patients to unnecessarily high rates of complications. Total thyroidectomy, appropriate neck dissection, selective use of postoperative 131 1, monitoring of serum thyroglobulin, and thyroid hormone replacement offer children and adolescents the best opportunity for recurrence-free long-term survival.

REFERENCES I. Ehrhardt O. Zur anatomie und klinik der struma maligna beitr klin. Chir 1902;35:343. 2. Hom RC. Carcinoma of the thyroid: Description of a distinct morphologic variant and a report of seven cases. Cancer 195I ;4:697. 3. Winship T, Rosvoll R. Thyroid carcinoma in children: Final report of a 20-year study. Clin Proc Child Hosp DC 1970;26: I I. 4. Harness JK, Thompson NW, McLeod MK, et al. Differentiated thyroid carcinoma in children and adolescents. World J Surg 1992; I6:547. 5. Boring CC, Squires TS, Tong T, et al. Cancer statistics, 1994. CA Cancer J Clin 1994;44:4. 6. Young JL, Percy CL, Asire AJ, et al. Cancer incidence and mortality in the United States, 1973-1977. Nat! Cancer Inst Monogr 1981;57:1. 7. Silverberg E. Cancer statistics 1977, from National Cancer Institute's National Cancer Survey. CA Cancer J Clin 1977;27:26. 8. Samuel AM, Sharma SM. Differentiated thyroid carcinomas in children and adolescents. Cancer 1990;67:2186. 9. Roudebush CP, De Groot D. The natural history of radiation-associated thyroid cancer. In: De Groot D, Frohman LA, Kaplan EL, Refetoff J (eds), Radiation-Associated Thyroid Carcinoma. New York, Grune & Stratton, 1977, p 97. 10. Duffy BJ, Fitzgerald PJ. Cancer of the thyroid in children: A report of 28 cases. J Clin Endocrinol Metab 1950;10:1296. I I. Ceccarelli C, Pacini F, Lippi F, et al. Thyroid cancer in children and adolescents. Surgery 1988;104:1143. 12. Goepfert H, Dichtel WJ, Samaan NA. Thyroid cancer in children and teenagers. Arch Otolaryngol 1984;110:72. 13. Buckwalter JA, Gurll NJ, Thomas CG Jr. Cancer of the thyroid in youth. World] Surg 1981;5:15. 14. Schlumberger M, De Vathaire F, Travagli JP, et al. Differentiated thyroid carcinoma in childhood: Long-term follow-up of 72 patients. J Clin Endocrinol Metab 1987;65:1088.

100 - - Thyroid Gland 15. Conard RA. Late radiation effects in Marshall Islanders exposed to fallout 28 years ago. In: Boice JD Jr, Fraumeni JF Jr (eds), Radiation Carcinogenesis: Epidemiology and Biological Significance. New York, Raven Press, 1984, p 57. 16. Akiba S, Lubin J, Ezaki H, et al. Thyroid cancer incidence among atomic bomb survivorsin Hiroshima and Nagasaki, 1958-1979(technical report, TR 5-91). Hiroshima, Japan, Radiation Effects Research Foundation, 1991. 17. Viswanathan K, Gierlowski TC, Schneider AB. Children thyroid cancer: Characteristics and long-term outcome in children irradiated for benign conditions of the head and neck. Arch Pediatr Adolesc Med 1994;1948:260. 18. Oleynic VA, Cheban AK. Thyroid cancer in children of Ukraine from 1981 to 1992. In: Robbins J (ed), Treatment of Thyroid Cancer in Childhood. Bethesda, MD, National Institutes of Health, 1994, p 45. 19. Astakhova LN, Vorontsova TV, Arozd VM. Thyroid nodule pathology in children of the Republic of Belarus following the Chernobyl accident. In: Robbin J (ed), Treatment of Thyroid Cancer in Childhood. Bethesda, MD, National Institutes of Health, 1994, p 35. 20. Gaitan E, Nilson NC, Poole GU. Endemic goiter and endemic thyroid disorders. World J Surg 1991;15:202. 21. Ozaki 0, Ito K, Kobayashi K, et al. Thyroid carcinoma in Graves' disease. World J Surg 1990;14:437. 22. Smith M, McHenry C, Jarosz H, et al. Carcinoma of the thyroid in patients with autonomous nodules. Am Surg 1988;54:448. 23. Ott RA, McCall AR, McHenry C, et al. The incidence of thyroid carcinoma in Hashimoto's thyroiditis. Am Surg 1987;53:442. 24. MacDougall JR, Kennedy JS, Thompson JA. Thyroid carcinoma following iodine 131 therapy: Report of a case and review of the literature. J Clin EndocrinoI1971;33:287. 25. McHenry C, Jarosz H, Calandra D, et al. Thyroid neoplasia following radiation therapy for Hodgkin's lymphoma. Arch Surg 1987; 122:684. 26. Stoffer SS, Van Dyke DL, Van den Bach J, et al. Familial papillary carcinoma of the thyroid. Am J Med Genet 1986;25:775. 27. Camiel MR, Mule lE, Alexander LL, Beninghoff DL. Association of thyroid carcinoma with Gardner's syndrome in siblings. N Engl J Med 1968;278:I056. 28. Smith WG, Kern BB. The nature of the mutation in familial multiple polyposis: Papillary carcinoma of the thyroid, brain tumors, and familial multiple polyposis. Dis Colon Rectum 1973;16:264. 29. Herrmann MA, Hay lD, Bartelt DH, et al. Cytogenetic and molecular genetic studies of follicular and papillary thyroid cancers. J Clin Invest 1991;88:1596. 30. Sarasin A, Bounacer A, Lepage F, et al. Mechanisms of mutagenesis in mammalian cells: Application to human thyroid tumors. C R Acad Sci III 1999;322:143. 31. Fenton CL, Lukes Y, Nicholson D, et al. The retlPTC mutations are common in sporadic papillary thyroid carcinomas of children and young adults. J Clin Endocrinol Metab 2000;85: 1170. 32. Nikiforov E, Rowland lM, Bove KE, et al. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 1997;57:1690. 33. Brousset P, Chaouche N, Leprat F, et al. Telomerase activity in human thyroid carcinomas originating from the follicular cells. J Clin Endocrinol Metab 1997;82:4214. 34. Moretti F, Nanni S, Pontecorvi A. Molecular pathogenesis of thyroid nodules and cancer. Baillieres Best Pract Res Clin Endocrinol Metab 2000;14:517. 35. Basolo F, Pinchera A, Fugazzola L, et al. Expression of p21 protein as a prognostic factor in papillary thyroid cancer [Abstract]. Eur J Cancer 1994;30A:171. 36. Tuttle RM PA, Francis G, Davis S, et al. Vascular endothelial growth facto (VEGF) and type 1 VEGF receptor (FIt-I) are highly expressed in Russian papillary thyroid carcinomas. In: Proceedings of the 12th International Thyroid Congress, Kyoto, Japan, 2000. 37. Ramirez R, Hsu D, Patel A, et al. Overexpression of hepatocyte growth factor/scatter factor (HGF/SF) and the HGF/SF receptor (cMET) are associated with a high risk of metastasis and recurrence for children and young adults with papillary thyroid carcinoma. Clin Endocrinol (Oxf) 2000;53:635. 38. Block MA. Well-differentiated carcinoma of the thyroid. Curr Probl Cancer 1979;3:3.

39. Hay lD. Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 1990;19:545. 40. Zimmerman D, Hay lD, Gough JR, et al. Papillary thyroid carcinoma in children and adults: Long-term follow-up of 1039 patients conservatively treated at one institution during three decades. Surgery 1988; 104:1157. 41. LiVolsi VA. Papillary neoplasms of the thyroid: Pathologic and prognostic features. Am J Clin Pathol 1992;97:426. 42. Russel WO, Ibanez M, Clark R, et al. Thyroid carcinoma: Classification, intraglandular dissemination, and clinicopathological study based upon whole gland sections of 80 thyroid glands. Cancer 1963;16: 1425. 43. Carcangiu ML, Zampi G, Rosai J. Papillary thyroid carcinoma: A study of its many morphologic expressions and clinical correlates. PatholAnnu 1985;20(Pt 1):1. 44. Rosai J, Zampi G, Carcangiu M. Papillary carcinoma of the thyroid. Am J Surg Pathol 1983;7:809. 45. Sierk AB, Askin FB, Reddick RL. Pediatric thyroid cancer. Pediatric Pathol 1990;10:877. 46. Furrnanchuk AW, Averkin Jl, Egloff B, et al. Pathomorphological findings in thyroid cancers of children from the Republic of Belarus: A study of 86 cases occurring between 1986 (post-Chernobyl) and 1991. Histopathology 1992;21:401. 47. Vickery AL, Carcangiu M, Johannessen lV, Sobrinho-Simoes M. Papillary carcinoma. Semin Diagn Pathol 1985;2:90. 48. Carcangiu ML, Bianchi S. Diffuse sclerosing variant of papillary thyroid carcinoma: Clinicopathologic study of 15 cases. Am J Surg Pathol 1989;13: 1041. 49. Sakamoto A, Kasai N, Sugano H. Poorly differentiated carcinoma of the thyroid. Cancer 1983;52:1849. 50. LiVolsi VA. Pathology of pediatric thyroid cancer. In: Robbins J (ed), Treatment of Thyroid Cancer in Childhood. Bethesda, MD, National Institutes of Health, 1994, p II. 51. LaQuaglia MP, Corbally MT, Heller G, et al. Recurrence and morbidity in differentiated thyroid carcinoma in children. Surgery 1988;I04: 1149. 52. Arganini M, Behar R, Wu TC, et al. Htirthle cell tumors: A twenty-fiveyear experience. Surgery 1986;100:1121. 53. Griem KL, Robb PK, Caldarell DD, Templeton AC. Radiation-induced sarcoma of the thyroid. Arch Otolaryngol Head Neck Surg 1989; 115:991. 54. Kirkland RT, Kirkland JL, Rosenberg HS. Solitary thyroid nodules in 30 children and report of a child with a thyroid abscess. Pediatrics 1973;51:85. 55. Harness JK, Thompson NW, Nishiyama RH. Childhood thyroid carcinoma. Arch Surg 1971;102:278. 56. Fowler CL, Pokorny WJ, Harberg FJ. Thyroid nodules in children: Current profile of changing disease. South Med J 1989;82:1472. 57. Giuffrida D, Scollo C, Pellegriti G, et al. Differentiated thyroid cancer in children and adolescents. J Endocrinol Invest 2002;25:18. 58. Newman KD, Black T, Heller G, et al. Differentiated thyroid cancer: Determinants of disease progression in patients younger than 21 years of age at diagnosis. Ann Surg 1998;227:533. 59. Jarzab B, Junak DH, Wloch J, et al. Multivariate analysis of prognostic factors for differentiated thyroid carcinoma in children. Eur J Nucl Med 2000;27:833. 60. Harness JK, Czako PE Ultrasound of the thyroid and parathyroid glands. In: Harness JK, Wisher DB (eds), Ultrasound in Surgical Practice: Basic Principles and Clinical Applications. New York, Wiley-Liss, 2001, p 237. 61. Frankenthaler RA, Sellin RV, Cangir A, Goepfert H. Lymph node metastasis from papillary-follicular thyroid carcinoma in young patients. Am J Surg 1990;160:341. 62. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1944;97:418. 63. National Council on Radiation Protection. Induction of thyroid cancer by ionizing radiation (NCRP Report No. 80). Bethesda, MD, National Council on Radiation Protection, 1985. 64. Becker DV, Zawzonico PB. Radioiodine therapy in children. In: Robbins J (ed), Treatment of Thyroid Cancer in Childhood. Bethesda, MD, National Institutes of Health, 1994, p 117. 65. Vassilopoulou-Sellin R, Klein MJ, Smith TH, et al. Pulmonary metastases in children and young adults with differentiated thyroid cancer. Cancer 1993;71:1348.

Childhood Thyroid Carcinoma - 66. Schlumberger M, Tubiana M, DeVathare F, et al. Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab 1986;63:960. 67. Meier CA, Braverman LE, Ebner SA, et al. Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma (phase III! study). J Clin Endocrinol Metab 1994;78:188. 68. Kirk JMW, Mort C, Grant DB, et al. The usefulness of serum thyroglobulin in the follow-up of differentiated thyroid carcinoma in children. Med Pediatr Oncol 1992;20:201.

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69. Tollefsen HR, DeCosse 11, Hunter RVP. Papillary carcinoma of the thyroid: A clinical and pathological study of 70 fatal cases. Cancer 1964;17:1035. 70. Tollefsen HR, Shah JP, Huvos AG. Follicular carcinoma of the thyroid. Am J Surg 1973;126:523. 71. Harness JK, McLeod MK, Thompson NW, et al. Deaths due to differentiated thyroid cancer: A 46-year perspective. World J Surg 1988;12:623.

Papillary Thyroid Carcinoma: Rationale for Hemithyroidectomy Yoshihide Fujimoto, MD, PhD • Takao Obara, MD, PhD • Takahiro Okamoto, MD, PhD

Current Considerations Papillary thyroid carcinoma is a rather common disease, at least in iodine-sufficient areas. Surgical treatment of this disease has remained controversial concerning the extent of thyroidectomy and the need for prophylactic lymph node neck dissection. The controversies persist because of the surgical complications associated with total or near-total thyroidectomy, which depend on the skill of the surgeon. On the other hand, because of the increased risk of recurrence and possibly cancer-related death after conservative surgery, there is a general consensus that postoperative thyroid-stimulating hormone (TSH) suppression therapy should be routinely given to all patients with papillary thyroid carcinoma. Attempts to determine prognostic factors, based on large retrospective studies of patients who underwent thyroidectomy for differentiated thyroid cancers, have been carried out at many institutions in North America,"? Japan.v" and Europe.r-" In 1979 15 and 1988,1 Cady and associates at the Lahey Clinic proposed a simple scoring system, AMES (age, distant metastasis, extrathyroid invasion, and size of the primary lesion), to predict the outcome of patients with differentiated thyroid carcinoma at the time of initial surgery. Hay and colleagues at the Mayo Clinic proposed another prognostic scoring system, AGES (age, histologic grade, extrathyroid invasion and distant metastasis, and size) in 1987. 16 In 1979, Byar and the European Organization for Research on Treatment of Cancer Thyroid Cancer Cooperative Group'? published yet another staging system, taking into account the following variables: age, sex, principal cell type, extrathyroidal invasion, and the presence of distant metastases. The International Union Against Cancer introduced the TNM staging system in 1987,18 and it was endorsed as the standard international staging system by the American Joint Committee on Cancer in 1988. 19 Statistically significant prognostic factors that are common to all these scoring systems are the presence of distant metastases and

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extrathyroid invasion. As for age, most patients with high-risk papillary thyroid carcinoma are late middle-aged or elderly persons at the time of initial diagnosis: 41 years or older for males and 51 years or older for females. There are, however, patients in all age groups who have low-risk papillary thyroid carcinoma, as demonstrated in our cohort at Tokyo Women's Medical University Hospital (Table 11-1). In our series from 1981 to 1989, distant metastases and local extrathyroid invasion were the important prognostic factors for high-risk papillary thyroid carcinoma, regardless of the patient's age. Many studies using these scoring or staging systems have shown that there are two distinctly different risk groups for patients with papillary thyroid carcinoma.P:" Hay" wrote an excellent review of all those prognostic scoring systems and compared them with each other. He reported that both the AGES and AMES systems allow the best discrimination between low-risk and high-risk papillary thyroid carcinoma. The mortality rate in the low-risk cancer group was 1% at 20 years following surgery, whereas it was 40% in the highrisk cancer group. This excellent outcome for low-risk patients demonstrates that low-risk papillary thyroid carcinoma is associated with an extremely low risk of cancer death. In iodinesufficient areas, low-risk cancers make up 85% to 90% of all papillary thyroid carcinomas. In our series at Tokyo Women's Medical University Hospital, the ratio of the low-risk to the high-risk groups is 92:8, and at an average 12-year follow-up the cancer-related death rates in the low-risk and high-risk groups were 0.5% and 35.1 %, respectively (Table 11-2). Because many of the results of retrospective, long-term follow-up studies reveal that low-risk papillary thyroid carcinomas are associated with a low cancer-mortality rate and that high-risk papillary thyroid carcinomas are associated with a high cancer morality rate,1,8,16,20-22 it seems rational to treat these two risk groups differently. Generally, even for patients with low-risk papillary thyroid carcinoma, curative resection is most important to prevent local recurrence. If the judgment of "low-risk cancer" at the initial operation is definite, then

Papillary Thyroid Carcinoma: Rationale for Hemithyroidectomy - -

we determine whether the papillary cancer lesion in a given patient localizes in one lobe or extends to the contralateral lobe. Only for the former, we choose hemithyroidectomy to prevent postoperative cancer recurrence .in the rernn~t thyroid. The differentiation between the umlateral and bilateral lesions may be possible by preoperative ultrasonography and intraoperative careful observation by surgeons. If we perform total thyroidectomy for all those patients, the procedure may carry increased surgical complications. . Concerning the need for TSH suppression therapy, there are two views. Most experts routinely administer thyroid hormone to patients for the rest of their lives to suppress pituitary '~1_ • 25 TSH secretion.P Others, such as our group, 24 'THUI.. ai, an d Boley and associates." do not use th~roid ho~one for TS~ suppression therapy in euthyroid patle~ts. Thl~ approach ,IS acceptable in patients who have low-risk papillary thyroid carcinoma that is macroscopically localized in only one lobe, but in most other patients TSH suppression therapy appears to be indicated.2.23·27 For high-risk patients with papillary thyroid carcinoma, surgeons should select a more aggressive surgical approach. This subject is discussed in more detail later. It is generally recognized that in iodine-rich areas like the United States and Japan, papillary thyroid carcinoma accounts for 80% or more of all thyroid cancers,28.29 and the ratio of low-risk to high-risk carcinoma is close to 9: 1,1.16 whereas in iodine-deficient areas papillary carcinoma constitutes 60% or less and the ratio of low-risk to high-risk carcinomas

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appears to be much higher. 30.31 Thus, the amou?t of i?dine intake may be a factor in the development of l?w-nsk papill~ thyroid carcinoma.30,32,33 There are three kinds of areas III terms of the amount of daily iodine intake, which is measured daily by urinary iodine excretion. Areas in which the a~erage urinary iodine excretion is 50 ug or le~s are c?ns.ldered t~ be iodine deficient." In most of the previously iodine-deficient areas of Europe, iodide has been added to table salt. Urinary iodine excretion has increased to 100 to 200 ug daily." The average daily iodine excretion in the United States is 500 to 700 Ilg 36 and that in Japan is as high as 1000 to 1500 Ilg.37 In most Western countries, supplemented iodine has been added to the water or diet so that some populations are in a transition from iodine-deficient to iodine-sufficient states. It appears that iodine deficiency should be a consideration when we treat patients with papillary thyroid carcinoma. . TSH suppression therapy has long been applied postoperatively as an effective modality to prevent recurrence or to prevent regrowth of unresected cancer t~ss?es.left ?ehind at ~eas, the initial operation.P However, at least III IOd~ne-nch large, long-term, retrospective follow-up studies of patients who underwent surgery for papillary thyroid carcinoma by Cady and others, 1,38 Vickery and colleagues." and our gr~up40 showed that TSH suppression therapy was not associated with improved survival in patients with low-risk carcinomas, probably because these patients have an exceedingly favorable prognosis even without TSH suppression.

Definition, Advantages, and Disadvantages of Hemithyroidectomy Hemithyroidectomy can be used in a patient with low-risk papillary thyroid carcinoma that is macroscopically l.ocalized in one thyroid lobe. In this procedure, the whole involved lobe, the isthmus, and occasionally the medial portion of the contralateral lobe are resected. When the medial third of the contralateral lobe is included in the resection, the thyroid operation is referred to as subtotal thyroidectomy in the United States" and in Japan. 8.24 We include patients who had subtotal thyroidectomy in our group of hemithyroidectomy patients. We have performed subtotal thyroidectomy and lobectomy (removal of one lobe without resection of the isthmus) in 71 % and 13%, respectively, among our group of 408 patients with low-risk papillary thyroid carcinoma (Table 11-3). The advantages of this surgical approach are that, when compared with total thyroidectomy, surgical complications including permanent hypoparathyroidism and bilateral recurrent laryngeal nerve palsy are lower, even when an inexperienced surgeon perforrns the operation. In patients treated in this manner, only one of the two recurrent nerves and two or three of the four parathyroid glands are at risk. Most patients are also euthyroid postoperatively, so that lifelong thyroid hormone replacement therapy is unnecess~ry. When we recently examined thyroid function by measunng serum thyroxine (T 4 ) , triiodothyronine (T 3), and TSH concentrations in 150 patients who had hemithyroidectomy, 95 (63%) of all patients examined were euthyroid, 31 (21 %) had subclinical hypothyroid (low T 4 and normal T 3 with abnormally high TSH), and 24 (16%) were hypothyroid.

104 - -

Thyroid Gland

indicator of persistent or recurrent disease because of the presence of a thyroid remnant and (2) distant metastases are often not detected by postoperative radioiodine scanning because of the presence of a thyroid remnant.

Rationale and Indications for Hemithyroidectomy

Although there are only a few long-term retrospective studies of patients with low-risk papillary thyroid carcinoma who had hemithyroidectomy as compared to patients who had total or near-total thyroidectomy,' tumor recurrence may occur at significantly higher rates after hemithyroidectomy than after near-total or total thyroidectomy.W? Russell.f Katoh,44 and their coworkers reported that thyroid carcinoma disseminates from the primary tumor site to all parts of the gland through intrathyroidal lymphatics in 87.5% and 78.1%, respectively. Despite this observation, the incidence of actual tumor recurrence in the contralateral lobe after hemithyroidectomy is surprisingly low (4.7% to 24%, mean recurrence about 7%).45 When hemithyroidectomy is carried out with strict indications, the recurrence rate is much lower only in those patients in whom preoperative ultrasonography does not demonstrate minute cancer lesions in the contralateral lobe and enlarged lymph nodes in the contralateral jugular chain, as demonstrated in our series. Only 2 (0.6%) of our 348 patients experienced recurrences in the thyroid remnant when these patients were monitored for an average of 12 years (Table 11-4). Two additional disadvantages of hemithyroidectomy are that (1) determination of serum thyroglobulin as a tumor marker in the postoperative follow-up period is not as sensitive an

Before 1945, thyroid cancers were more aggressive tumors in most other parts of the world except Japan. This is probably because in Japan there was high iodine intake as a result of the consumption of seaweed and seafood. In the United States, the addition of iodine to table salt, bread, and water was begun in the 1920s and 1930s, and in European countries it was added after the end of World War II. Currently, most of the Western countries have become iodine sufficient, and some even iodine rich, such as the United States. Whereas the biologic characteristics of thyroid cancers have remained virtually unchanged in Japan, there have been considerable changes in clinical and survival patterns in patients with thyroid cancers in the United States. 26,46 In iodine-rich areas, approximately 90% of all differentiated thyroid cancers of follicular cell origin are papillary thyroid carcinomas, and of these, approximately 90% are low-risk cancers." Using Cady's AMES scoring system, it is usually easy to determine whether a patient should be included in a low-risk or a high-risk category at the time of initial operation. I Hay and associates? in 1993 proposed a new prognostic scoring system, MACIS (metastases, age, completeness of resection, invasion, and size), which is applicable at the time of surgery by excluding histologic grade from the previous AGES classification system. The introduction of fine-needle aspiration biopsy has greatly facilitated the accurate preoperative diagnosis of papillary thyroid carcinoma. Therefore, surgeons should usually be able to determine whether a patient is at high or low risk at the time of the initial surgery based on either AMES, MACIS, or any other classifying system. Since this high- or low-risk information is 97% to 99% accurate, it should be useful in selecting the extent of thyroidectomy that will result in the best prognosis with the least risk of complications.

Papillary Thyroid Carcinoma: Rationale for Hernithyroideetomy - -

Hemithyroidectomy should be performed for low-risk papillary thyroid carcinoma that is macroscopically localized to one lobe to decrease the risk of local recurrence. We believe that even when a patient is in the low-risk papillary thyroid carcinoma group, total thyroidectomy or near-total thyroidectomy is preferable to hemithyroidectomy when the patient has (l) multicentric occurrence of cancer in both lobes or (2) markedly invasive cancer in both lobes, including the diffuse sclerosing variant of papillary carcinoma that occurs in young individuals.f Whether these cancers can be diagnosed at the time of hemithyroidectomy is controversial. Using preoperative or intraoperative ultrasonography and careful palpation of the

A

B

105

thyroid gland, experienced surgeons can usually know at the time of operation whether there is significant bilateral involvement. Lesions as small as 2 mm can be detected in the otherwise normal thyroid tissue by these methods. In Japan, preoperative ultrasonography has been widely used in many institutions. After a hemithyroidectomy is carried out, the resected thyroid specimen is longitudinally cut on the operating table as a routine procedure and the cut surface is macroscopically examined. Hemithyroidectomy is usually indicated when papillary thyroid carcinoma on the cut surface shows a well-circumscribed lesion without any associated satellite lesions (Fig. Il-lA) or with a small number of minute

c

FIGURE 11-1. Macroscopic views of the cut surfaces of surgical specimens obtained by hemithyroidectomy (A, B) or total thyroidectomy (C), showing various modes of intrathyroid papillary cancer spread. A, A sharply marginated primary lesion, measuring 3 x 2 em, is located in the left thyroid lobe and accompanied by four proven metastatic jugular chain nodes and one peritracheal node. The patient is a 43-yearold woman who is currently alive, well, and euthyroid without thyroid-stimulating hormone (TSH) suppression 10 years postoperatively. B, A 3 x 2-cm lesion was found in the right lobe with intrathyroid satellite lesions (arrowheads) associated with proved metastatic lesions in two jugular nodes and one peritracheal node. The patient was a 43-year-old woman who is alive, well, and euthyroid without TSH suppression 9 years after surgery. C, A diffusely infiltrating, whitish papillary carcinoma was found in the right lobe, and many tiny intrathyroid metastatic foci were found in the left lobe. Miliary lung metastases were noted on a chest radiograph at the time of operation. Total thyroidectomy and bilateral neck dissection followed by 1311 therapy were performed on the patient, a 30-year-old woman who is alive with disease 9 years after surgery, under TSH suppression therapy.

106 - - Thyroid Gland lesions only in areas close to the main lesion (Fig. 11-1B), and the contralateral lobe is normal to palpation. Intrathyroidal deposits of cancer are seen as whitish spots. When we have observed that papillary thyroid cancer tissue is known preoperatively to contain psammoma bodies, as in the case of the diffuse sclerosing variant, psammomatous shadows on a soft tissue roentgenogram of a resected specimen indicate intrathyroidal cancer spread." When intrathyroidal metastatic lesions are in close proximity to the surgical margin (Fig. 11-2), the remaining contralateral lobe should be removed. Previously, we occasionally failed to detect pulmonary metastases in young patients with papillary thyroid carcinoma because of normal chest radiographs at the time of the initial operation. Those patients subsequently experienced miliary lung metastases. They usually have diffusely invasive growth of cancer in the thyroid gland (see Fig. 11-1C ) and often have multiple lymph node metastases. Today, we recommend preoperative computed tomography scanning of the chest in such patients to detect lung metastases preoperatively. Those patients are then classified as high risk and are treated by total thyroidectomy. In our follow-up study, we also noted the postoperative development of lung metastasis in elderly patients, most of whom had a large primary tumor at the initial surgery. This result indicates the importance of tumor size as one of the criteria for classifying a high-risk patient who is elderly. Because of these observations, we currently perform more total thyroidectomies than in the past, although most lung metastases in elderly patients did not actually take up radioiodine. In our series at the Tokyo Women's Medical University Hospital, 408 patients with low-risk papillary thyroid carcinoma were treated from 1981 through 1989, a total thyroidectomy was done in 60 (15%), hemithyroidectomy including partial resection of the contralateral lobe in 343 (84%), and partial lobectomy in 5 (1%) (see Table 11-3). An average 12-year follow-up study in these patients was completed through August 15,2002, and these results are shown in Table 11-4. Of the 343 hemithyroidectomy patients, only 2 patients (0.5%) died of thyroid cancer. Two patients (0.5%) had recurrence in the remaining contralateral thyroid lobe. Local recurrence in the thyroidectomy bed and at the scar of open biopsy carried out elsewhere occurred in 5 patients and 1 patient, respectively. Cancer recurrence in lymph nodes was noted in a total of 31 patients (8.8%) who had undergone modified radical neck dissection and in 2 who had not undergone neck lymph node dissection. Lung metastasis was detected in 15 patients: 5 (8.5%) of 59 patients who had total thyroidectomy and 10 (2.9%) of 343 patients who had hemithyroidectomy. All 5 patients who had total thyroidectomy failed to have radioiodine uptake in the lung metastases. The 4 patients treated with hemithyroidectomy underwent completion total thyroidectomy, and only 1 of them was successfully treated with 1311. The other 3 patients did not have radioiodine uptake in the lung metastases. In the remaining 6 patients, a completion total thyroidectomy was not performed because of the patients' age, associated diseases, and/or concomitant recurrences.

FIGURE 11-2. Soft tissue roentgenogram of a thyroid specimen resected by subtotal thyroidectomy in a female patient with the diffuse sclerosing variant of papillary carcinoma. Note the presence of many psammomatous calcifications throughout the whole specimen, including the surgical cut end (arrow), which definitely indicates cancer remaining in the rest of the thyroid lobe.

Additional Considerations and the Need for Combined Lymph Node Neck Dissection Some papillary thyroid carcinomas invade the intrathyroidal lymphatic channels and spread intrathyroidally via the richly distributed lymphatic vessels.43,44 When Lipiodol Ultrafluid (2 mL of radiopaque material used for lymphography) is injected into the thyroid lobe, the material quickly enters the lymphatic network in the thyroid gland. The flow is directed upward to the upper pole of the thyroid lobe and within 30 minutes goes through the lymphatic vessels along the superior thyroid artery to the nodes located at the site where the internal and external carotid arteries originate from the common carotid artery (Fig. 11-3). These studies document that the whole thyroid gland has a very rich network of lymphatic vessels and that the lymphatic drainage is upward.'? The intrathyroidal lymphatics, draining lymphatics, and regional lymph nodes represent a thyroid-lymphatic organ unit. This is best demonstrated by two specific variants of papillary thyroid carcinoma. One of them is the diffuse sclerosing variant of papillary carcinoma, in which even a tiny primary lesion may cause involvement of a whole thyroid gland and bilateral jugular node metastases through intrathyroidal and extrathyroidal lymphatic vessels (Fig. 11-4) without any distant metastasis." The other example is a small papillary thyroid carcinoma located in the upper pole of the thyroid

Papillary Thyroid Carcinoma: Rationale for Hernithyroidectomy - -

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FIGURE 11-3. Thyroid lymphogram of a patient with simple

goiter taken 30 minutes after percutaneous injection of Lipiodol Ultrafluid, showing an abundant network of intrathyroid lymphatic channels and a rapid upward flow of the lymph from belowin the lobe. The contrast materialhas reachedthe upperand middlejugular nodes. (Courtesy of Nobukatsu Kasai, MD, Cancer Institute Hospital, Tokyo.) lobe, which often causes metastatic lymph node enlargement in the upper jugular chain (Fig. 11-5). Papillary thyroid cancer cells from the upper pole lesion easily enter the lymphatic vessels and spread to the regional lymph nodes. In most of these patients, the initial clinical finding is nodal enlargement in the submandibular region, and the primary lesion in the thyroid may be barely palpable or not palpable. We consider it necessary to remove regional cervical nodal metastases if one wants to perform an en bloc procedure. Although the presence of regional node metastases has only a small effect on the life expectancy of patients with low-risk papillary thyroid carcinoma, especially in iodinesufficient areas such as the United States and Japan,3,6,20,39,46 most endocrine surgeons recommend ipsilateral, or occasionally bilateral, modified radical neck dissection along with a central neck dissection in patients with clinically recognizable lymph node metastases. Prophylactic lymph node neck dissection is generally not recommended, except in children,5o,51 in Western countries. Although 80% to 90% of patients with papillary thyroid carcinoma have microscopic metastases in the regional nodes, the subsequent clinical appearance of lymph node metastases occurs in only about 7% to 15% of patients who have had no lymph node dissection. 20,46,52-54 Furthermore, if dissection is delayed, the survival rate is not decreased.' In Japan, previously, many patients presented with marked lymph node metastasis preoperatively, and most

FIGURE 11-4. Simple soft tissue roentgenogram of a thyroid

specimenresected from a patientwith the diffuse sclerosing variant of papillary carcinoma, showing a network of intrathyroid lymphatics, which was eventually constructed of numerous psammoma bodiespresentin cancer tissue growing in intrathyroid lymphatic vessels. postoperative local recurrences were due to cervical lymph node metastases. To decrease recurrences, in most Japanese institutions, modified neck dissection had been carried out almost routinely for patients with papillary thyroid carcinomas 1.5 em or larger.55 Today, the number of patients with incidentally found small papillary carcinoma without palpable lymph node metastases has increased because of the increased use of annual health examinations. We have found that, even with modified neck dissection, many patients complain of postoperative neck discomfort. Therefore, prophylactic lymph node dissection is less likely to be done in these patients than before.

Postoperative Adjuvant Therapy Because of the excellent prognosis of most patients with low-risk papillary thyroid carcinoma, it has been difficult to demonstrate any benefit from adjuvant therapy in the form of radioiodine or TSH suppression therapy. Vickery;'? Cady,I,38 and their associates concluded that the usual course of low-risk papillary carcinoma treated by conservative surgery is generally so benign that further beneficial effects of radioiodine, thyroid suppressive treatment, or total thyroidectomy have never been convincingly shown. In a report from the Mayo Clinic.j" where postoperative radioiodine ablation therapy has been used since 1976, Hay

108 - - Thyroid Gland

Treatment of High-Risk Papillary Thyroid Carcinoma

FIGURE 11-5. Cut surfaces of a surgically resected right thyroid

lobe and the right jugular chain nodes taken from a 52-year-old woman who had been aware of the enlarged lymph nodes for 4 years. At the operation, the node measured 4.5 em (curved arrow), and the primary lesion (straight arrow) in the upper pole of the right thyroid lobe measured 1.5 x I cm. The patient is currently alive andwell 12years after the operation, and she is euthyroid without thyroid-stimulating hormone suppression.

presented his own disappointing results in terms of prevention of tumor recurrence and mortality and also reviewed historic trends of this procedure, including published critical opinions against its effectiveness. Once TSH suppression therapy begins, patients must take the hormone daily for the rest of their lives. Such life-long therapy is not easy for either physician or patient, especially in developing countries. Hernithyroidectomy, leaving enough thyroid tissue to maintain normal thyroid function postoperatively, is easier for patients, unless TSH suppression therapy is required. Approximately 35% of our patients who underwent hemithyroidectomy have an elevated TSH level and have consequently been treated with L-thyroxine (25 to 150 ug daily) to normalize the serum TSH concentration. Although we adopted TSH suppression therapy in the 1950s and 1960s, when accurate determination of serum TSH concentration first became available in 1970, we were surprised to find poor drug compliance. We also noted no difference in the postoperative tumor recurrence rate or in the cancer mortality rate in patients with a suppressed serum TSH level and those with nonsuppressed TSH levels. 56,57 Since then, many institutions in Japan have used hernithyroidectomy to preserve the normal thyroid function after surgery, and if the patients are euthyroid, no thyroid hormone therapy is given. We adopted this strategy in 1970, and so far we have had satisfactory follow-up results,

Patients with high-risk papillary thyroid carcinomas may have local extrathyroid invasion and distant metastases. The cancer-related mortality rate is about 40% at 20 years after surgery." The main causes of death are either locally progressive cervical disease or distant metastases. Most experts from the United States and from European countries advocate total thyroidectomy followed by 1311wholebody scan and ablation with TSH suppression therapy more for high-risk than for low-risk patients. 12,16,4 J,52,S8 If the cancer invades into the adjacent structures and it is not possible to resect the tumor with negative margins, radioiodine treatment should be given. When there is no or inadequate uptake or progression of disease, external irradiation is used.20,52 Older patients with high-risk papillary thyroid carcinoma appear to be much less sensitive to both TSH suppression therapy and radioactive iodine therapy than younger patients with low-risk cancers. We, therefore, believe that high-risk patients should be treated more aggressively with total or near-total thyroidectomy and radical or modified ipsilateral neck dissection, including partial or sleeve resection of the trachea, if it is invaded. This therapy appears to increase patients' quality of life and may be curative. 59 -62

Summary We recommend a selective approach to the treatment of patients with papillary thyroid carcinoma. We include patients with direct extrathyroid invasion and distant metastases in our high-risk group, regardless of age. For low-risk patients, if a cancer is macroscopically localized in one lobe, we recommend hemithyroidectomy and, for those with clinical lymph node metastases, ipsilateral modified radical neck dissection with no postoperative radioiodine therapy or TSH suppression unless the patient is hypothyroid. For high-risk patients we recommend total thyroidectomy, resection of adjacent structures if invaded by cancer, and ipsilateral radical or modified neck dissection with postoperative TSH suppressive therapy,

REFERENCES I. Cady B, Rossi RL. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988;104:947. 2. De Groot LJ, Kaplan EL, McCormick M, et al. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 1990;71:414. 3. McConahey WM, Hay ill, Woolner LB, et al. Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: Initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc 1986; 61:978. 4. Samaan NA, Maheshwari YK, Nader S, et al. Impact of therapy for differentiated carcinoma of the thyroid: Analysis of 706 cases. J Clin Endocrinol Metab 1983;56: II3!. 5. Wanebo HJ, Andrews W, Kaiser DL. Thyroid cancer: Some basic considerations. Am J Surg 1981;142:474. 6. Harada T, Shimaoka K, Yakumaru K, et al. Prognosis of thyroid carcinoma. lnt Adv Surg Oncol 1981;4:83. 7. Ito J, Noguchi S, Murakami N, et al. Factors affecting the prognosis of patients with carcinoma of the thyroid. Surg Gynecol Obstet 1980;150:539.

Papillary Thyroid Carcinoma: Rationale for Hemithyroidectomy - 8. Noguchi S, Murakami N, Kuwamoto H. Classification of papillary cancer of the thyroid based on prognosis. World J Surg 1994;18:552. 9. Carcangiu ML, Zampi G, Pupi A, et al. Papillary carcinoma of the thyroid: A clinicopathologic study of241 cases treated at the University of Florence, Italy. Cancer 1985;55:805. 10. Hennequin P, Liehn JC, Delisle MJ. Multifactorial analysis of survival in thyroid cancer: Pitfalls of applying the results of published studies to another population. Cancer 1986;58:1749. II. Hoie J, Stenwig AE, Brennhord 10. Surgery in papillary thyroid carcinoma: A review of 730 patients. J Surg OncoI1988;137:147. 12. Schelfhout LJDM, Creutzberg CL, Hamming JF, et al. Multivariate analysis of survival in differentiated thyroid cancer: The prognostic significance of the age factor. Eur J Cancer Oncol 1988;24:331. 13. Tennval J, BiorklundA, Moller T, et al. Is the EORTC prognostic index of thyroid cancer valid in differentiated thyroid carcinoma? Cancer 1986;57: 1405. 14. Tubiana M, Schlumberger M, Rougier P, et al. Long-term results and prognostic factors in patients with differentiated thyroid carcinoma. Cancer 1985;55:794. 15. Cady B, Sedgwick CE, Meissner WA, et al. Risk factor analysis in differentiated thyroid cancer. Cancer 1979;43:810. 16. Hay ill, Grant CS, Taylor WF, et al. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: A retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 1987;102:1088. 17. Byar DP, Green SB, Dor P, et al. A prognostic index for thyroid carcinoma: A study of the EORTC Thyroid Cancer Cooperative Group. Eur J Cancer 1979;15:1033. 18. Hermaneck P, Sobin LH. TNM Classification of Malignant Tumours: International Union Against Cancer, 4th ed. New York, SpringerVerlag, 1987. 19. Beahrs OH, Henson DE, Hutter RVP, et al. Manual for Staging of Cancer: American Joint Commission in Cancer, 3rd ed, Philadelphia, JB Lippincott, 1988. 20. Hay ill. Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 1990;19:545. 21. Lorentz TG, Lau PWK, Lo CY, et al. Multivariate analysis of risk factors influencing survival in 110 ethnic Chinese with papillary thyroid carcinoma. World J Surg 1994;18:547. 22. Shah JP, Loree TR, Dharker D, et al. Prognostic factors in a differentiated carcinoma of the thyroid. Am J Surg 1992;164:658. 23. Clark OH. TSH suppression in the management of thyroid nodules and thyroid cancer. World J Surg 1981;5:39. 24. Fujimoto Y, Obara T, Ito Y, et al. Endocrine surgery in Japan and in our series. Endocrine Surg (Tokyo) 1988;5:423. 25. Takai S. Controversial issues regarding the management of papillary thyroid carcinoma. Thyroidol Clin Exp 1998;10:109. 26. Boley SJ, Cady B, Mazzaferri EL, et al. Symposium: Management of thyroid neoplasm. Contemp Surg 1993;43:369. 27. Clark OH. Total thyroidectomy. The treatment of choice for patients with differentiated thyroid cancer. Ann Surg 1982;196:361. 28. Ezaki H, Ebihara S, Fujimoto Y, et al. Analysis of thyroid carcinoma based on material registered in Japan during 1977-1986 with special reference to predominance of papillary type. Cancer 1992;70:808. 29. Rossi RL, Cady B. Differentiated carcinoma of thyroid gland. In: Cady B, Rossi RL (eds), Surgery of the Thyroid and Parathyroid Glands, 3rd ed. Philadelphia, WB Saunders, 1991, p 139. 30. Bacher-Stier C, Riccabonna G, Totsch M, et al. Incidence and clinical characteristics of thyroid carcinoma after iodine prophylaxis in an endemic goiter country. Thyroid 1997;7:733. 31. Scheumann GFW, Gimm 0, Wegener G, et al. Prognostic significance and surgical management of locoregional lymph node metastases in papillary thyroid cancer. World J Surg 1994;18:559. 32. Bubenhofer R, Hedinger C. Schilddriisenmalignome vor und nach Einfuhrung der Jodsalzprophylaxe, Schweiz Med Wochenschr 1977;107:733. 33. Krisch K. Schilddriisentumoren. Zur Morphologie maligner Schilddriisentumoren. Ein retrospective Studie anhand von 981 Fallen mit Beriicksichtigung des Einflusses der Jodsalz-Prophylaxe. Basel, Karger, 1983. 34. Belfiore A, Rosa GLL, Padova G, et al. The frequency of cold thyroid nodules and thyroid malignancies in patients from an iodine-deficient area. Cancer 1987;60:3096.

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35. Koutras DA. The present status of endemic goiter as a problem of the public health-Europe. In: Stanbury JB, Hetzel BS (eds), Endemic Goiter and Endemic Cretinism. New York, Wiley, 1980, p 79. 36. Oddie TH, Fisher DA, McConahey WM, et al. Iodine intake in the United States: A reassessment. J Clin Endocrinol Metab 1970;30:659. 37. Nagataki S. Thyroid function in the normal Japanese. Igakuno Ayumi (Progr Med) 1970;72:621. 38. Cady B, Cohen K, Rossi RL, et al. The effect of thyroid hormone administration upon survival in patients with differentiated thyroid carcinoma. Surgery 1983;94:978. 39. Vickery AL Jr, Wang C-A, Walker AM. Treatment of intrathyroidal papillary carcinoma of the thyroid. Cancer 1987;60:2587. 40. Fujimoto Y, Sugitani I. Postoperative prognosis of intrathyroidal papillary thyroid carcinoma: Long-term (35-45 year) follow-up study. Endocrine J 1998;45:475. 41. Mazzaferri EL, Young RL, Oertel JE, et al. Papillary thyroid carcinoma: The impact of therapy in 576 patients. Medicine 1977;56:171. 42. Grant CS, Hay ill, Gough IR, et al. Local recurrence in papillary thyroid carcinoma: Is extent of surgical resection important? Surgery 1988;104:954. 43. Russell WO, Ibanez ML, Clark RL, et al. Thyroid carcinoma: Classification, intraglandular dissemination, and clinicopathologic study based upon whole organ sections of 80 glands. Cancer 1963;16:1425. 44. Katoh R, Sasaki J, Kurihara H, et al. Multiple thyroid involvement (intraglandular metastasis) in papillary thyroid carcinoma: A clinicopathologic study of 105 consecutive patients. Cancer 1992;70:1585. 45. Clark OH. Thyroid nodules and thyroid cancer. In: Clark OH (ed), Endocrine Surgery on the Thyroid and Parathyroid Glands. SI. Louis, CV Mosby, 1985, P 56. 46. Mazzaferri EL. Papillary thyroid carcinoma: Factors influencing prognosis and current therapy. Semin OncoI1987;14:315. 47. Hay ill, Bergstralh EJ, Goellner JR, et al. Predicting outcome in papillary thyroid carcinoma: Development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993;114:1050. 48. Fujimoto Y, Obara T, Ito Y, et al. Diffuse sclerosing variant of papillary carcinoma of the thyroid: Clinical importance, surgical treatment, and follow-up study. Cancer 1990;66:2306. 49. Matoba N, Kikuchi T. Thyroidolymphography: A new technique for visualization of the thyroid and cervical lymph nodes. Radiology 1969;92:339. 50. Frankenthaler RA, Sellin RV, Cangir A, et al. Lymph node metastasis from papillary-follicular thyroid carcinoma in young patients. Am J Surg 1990;160:341. 51. Harness JK, Thompson NW, McLeod MK, et al. Differentiated thyroid carcinoma in children and adolescents. World J Surg 1992;16:547. 52. Cady B. Surgery of thyroid cancer. World J Surg 1981;5:3. 53. Mori Y, Takaya K, Miyata Y, et al. Induction of discriminant function concerning postoperative local recurrence or distant metastasis in 589 patients with differentiated thyroid cancer. Jpn J Surg 1993;23:777. 54. Noguchi S, Noguchi A, Murakami N. Papillary carcinoma of the thyroid: I. Development of metastasis. Cancer 1970;26: 1053. 55. Noguchi S, Murakami N. The value of lymph node dissection in patients with differentiated thyroid cancer. Surg Clin North Am 1987;67:251. 56. Fujimoto Y, Oka A, Uchida H, et al. Reevaluation of the effect of TSH suppression therapy on differentiated thyroid cancer. Shindan-toChiryo (Diagn Ther) 1968;56:473. 57. Fujimoto Y, Oka A, Tanaka K, et al. Plasma TSH levels in patients who underwent thyroidectomy for thyroid carcinoma: Reevaluation of TSH suppression therapy. Geka-Shinryo (Surg Clin) 1976; 118:792. 58. Mazzaferri EL. Management of solitary thyroid nodule. N Engl J Med 1993;328:553. 59. Fujimoto Y, Obara T, Ito Y, et al. Aggressive surgical approach for locally invasive papillary carcinoma of the thyroid in patients over forty-five years of age. Surgery 1986; 100:1098. 60. Ishihara T, Yamazaki S, Kobayashi K, et al. Resection of the trachea infiltrated by thyroid carcinoma. Ann Surg 1982;195:496. 61. Nakao K, Miyata M, Izukura M, et al. Radical operation for thyroid carcinoma invading the trachea. Arch Surg 1984;119:1046. 62. Yang C-C, Lee C-H, Wang L-S, et al. Resectional treatment for thyroid cancer with tracheal invasion. Arch Surg 2000;135:704.

Papillary Thyroid Carcinoma: Rationale for Total Thyroidectomy Orlo H. Clark, MD

Considerable controversy continues about whether all or part of the thyroid gland should be removed for patients with differentiatedthyroid cancer of follicular cell origin (papillary, mixed papillaryfollicular,follicular,and Hiirthle cell), because there are no controlled, prospective studies comparing the results of different methods of treatment (lobectomy, neartotal thyroidectomy, or total thyroidectomy). Patients with these thyroid cancers also generally have a good prognosis, with an overall mortality of about 20%, so that studies comparing survival must include large numbers of patients who are monitored for a long period. The rate of thyroidectomy complications, including vocal cord paralysis resulting from recurrent laryngeal nerve injury and hypoparathyroidism, should be low but ranges from less than 1% to more than 10%.1-4 Complications are reported to increase in patients having more extensive thyroid operations, especially when thyroidectomy is associated with central and modified radical neck dissection.v' Most surgeons and endocrinologists recommend thyroid lobectomy for patients with occult papillary thyroid cancers « 1 em) and for patients with minimally invasive follicular thyroid cancer, because these patients have little risk of dying from these tumors. Lobectomy with isthmectomy is also the treatment of choice for noncompliant patients who will not take thyroid hormone and for patients who do not have access to thyroid hormone. Other surgeons recommend a similar approach for patients determined to be at low risk by the AGES (age, grade, extent, size) (Table 12-1) or AMES (age, metastases, extent, size) classification, and more extensive resection (near-total or total) is recommended for high-risk patients and for patients with bilateral tumors (Table 12-2).6,7 Other surgeons recommend total thyroidectomy for all but very low risk patients with papillary and follicular cancers, as described previously, when this operation can be done safely «2% complication rate of recurrent laryngeal nerve injury or permanent hypoparathyroidisml.s'P A near-total thyroidectomy rather than a total thyroidectomy is recommended when

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the surgeon believes that the viability of the parathyroid glands or recurrent laryngeal nerve might be compromised; therefore, a little thyroid tissue is preserved to avoid injury to the parathyroid glands and recurrent nerve on the contralateral side of the cancer. The remnant tissue in these patients can subsequently be ablated with iodine 131. The smaller the remnant, the less radioiodine is required to ablate it. 13 It is difficult for me to understand, however, why one would recommend a near-total rather than total thyroidectomy when both recurrent laryngeal nerves have been clearly identified and the parathyroid glands are situated off the thyroid gland or have already been dissected off the thyroid gland. The advantage of total thyroidectomy over near-total thyroidectomy is that it eliminates the need to give an ablative dose of 1311 to destroy this remnant thyroid tissue, because all thyroid tissue has been removed. The 1311 that is given should therefore be effective in detecting or destroying possible metastatic disease. In my analysis of radioiodine therapy in 400 patients with thyroid cancer of follicular cell origin, about 65% of the patients' tumors took up enough 1311 for this treatment to be effective. Similar results have been reported by Schlumberger and associates." Recent investigations suggest that redifferentiation of some papillary thyroid cancers may improve the effectiveness of radioiodine therapy.P:" The purpose of this chapter is to describe the rationale for total thyroidectomy based on the pathophysiology of differentiated thyroid cancer and the short- and long-term results as well as the complication rate. Some surgeons also recommend total thyroidectomy for patients with benign thyroid problems such as Graves' disease and bilateral multinodular goiters because it eliminates the risk of recurrent disease.I':" Total thyroidectomy is also recommended by some surgeons for patients with thyroid nodules and a history of exposure to low-dose therapeutic radiation and for patients with familial papillary thyroid cancer, because these tumors are often multifocal with both benign and malignant tumors in the same thyroid gland.':":"

Papillary Thyroid Carcinoma: Rationale for Total Thyroidectomy - -

Papillary thyroid cancer, including mixed papillary follicular thyroid cancer and follicular variants of thyroid cancer, is the most common thyroid cancer (""80%); luckily, patients with this tumor have the best prognosis.Ui'? It is somewhat surprising that patients with this tumor, and especially young patients, do so well, because papillary thyroid cancers are often (:5:88.5%) multifocal within the thyroid gland and regional cervical lymph nodes are involved, at least microscopically, in up to 80% of these patienrs.P-" Some patients have poorly differentiated papillary thyroid cancers, including tall cell and columnar cell tumors, and these patients have a worse prognosis.F'" Follicular thyroid cancers account for about 10% of all thyroid cancers and are more common in patients from iodinedeficient areas (i.e., areas of endemic goiten." Follicular thyroid cancers are usually solitary tumors within the thyroid gland, and only about 10% are multifocal or involve the cervical lymph nodes. 12,25 Medullary thyroid cancers account for about 5% of all thyroid cancers; about 70% occur sporadically, and 30% are familial. These tumors are bilateral in most patients with familial medullary thyroid cancer and in patients with multiple endocrine neoplasia types 2A and 2B. Regional lymph nodes are present in 60% of patients with primary medullary thyroid tumors larger than 2 em." Htirthle cell thyroid cancers are included with follicular thyroid cancers in the World Health Organization classification. I believe, however, that they should be classified separately. Although they are of follicular origin and usually secrete thyroglobulin-like follicular cancers, Htirthle cell

111

carcinomas, in contrast to follicular carcinomas, usually do not trap radioiodine (only 10%), whereas most follicular carcinomas do. Also, about 30% are multifocal, whereas follicular cancers are usually solitary. In addition, they involve regional lymph nodules (30%), whereas follicular cancers usual~y do not (6%),27,28 A Hurthle cell variant of papillary thyroid cancer has also been identified. The remaining thyroid tumors, including anaplastic cancer, thyroid lymphoma, teratomas, squamous cell cancers, and carcinosarcomas, account for 1% to 2% of all thyroid cancers. These are aggressive tumors (see Chapter 44). About 80% of the anaplastic thyroid cancers also contain a differentiated thyroid cancer, suggesting a possible progression from differentiated to undifferentiated tumors." Recent experimental findings support this clinical observarion.l" Luckily, this occurs in only about I% of patients with differentiated tumors.'! . As mentioned, patients can be separated into low- and highnsk groups on the basis of patient age, grade of tumor, extent, and size of the tumor (AGES)7,32 or on age, metastases, extent, and size (AMES).6,33 Other factors also predict the behavior of a thyroid cancer, including (1) surgical resectability." (2) ploidy of the tumor.i-" (3) adenylate cyclase response to thyroid-stimulating hormone (TSH),36 (4) radioiodine uptake." and (5) epidermal growth factor (EGF) receptor leveJ.38,39 Other factors also include the presence of specific oncogenes or tumor suppressor genes such as gsp, ras, ret, and 'p'53 as w~ll as whether the patient has nonmedullary familial thyroid cancer. 40.43 Patients whose tumors cannot be completely resected.t' those with aneuploid DNA,35 those with a low adenylate cyclase response to TSH,36 those with a low or absent radioiodine uptake.'? and those whose tumors have more EGF binding have a worse prognosis.V-" Unfortunately, many of these factors or conditions, such as invasion, distant metastases, and resectability, are determined only postoperatively. Thus, the AGES and AMES classifications, as well as the TNM, MACIS (distant metastasis, patient age, completeness of resection, local invasion, tumor size) or European Organization for the Research and Treatment of Cancer (EORTC) classifications, which are used to separate patients into low- and high-risk groups, are postoperative, rather than preoperative, classifications.r' These classifications, however, do help predict tumor behavior, because the risk of death from thyroid cancer in low-risk patients is about 5%, whereas in the high-risk patients it is about 40%. Fortunately, most patients (""70%) are in the low-risk group. Despite the excellent outcome among most patients with thyroid cancer, I believe that if one can decrease the death rate from 5% to 2% or 3% and the rate of complications is less than 2%, one should perform a total thyroidectomy because not only is this operation associated with fewer recurrences but also several studies report improved survival. Grant and associates" reported that bilateral thyroid procedures decreased recurrence in both low-risk and high-risk patients and death and recurrence rates in high-risk patients. Cady and colleagues," who are advocates of lobectomy for low-ris~ patients with papillary thyroid cancer, reported that, usmg the AMES classification, 11% of their low-risk patients experienced recurrent tumors and 33% of these patients subsequently died of thyroid cancer.

112 - -

Thyroid Gland

Although some studies suggest that the survival rate is comparable in patients with thyroid cancer treated by either lobectomy or total thyroidectomy.f'" other studies, including those of Massin" Schlumberger," Defrroot," I Mazzaferri,s2,s3 Loh,s4 and their colleagues, document not only decreased recurrence but also improved survival when patients were treated by total or near-total thyroidectomy and postoperative 131 1 therapy, The benefits are similar to those obtained by not smoking or by coronary artery surgery for patients with three-vessel occluding coronary artery disease. ss-s7 The benefits of total thyroidectomy, in order of importance, are as follows: 1. Thyroid tissue is removed so that postoperative 131 1 scanning and ablative therapy can be effective. 2. Serum thyroglobulin levels are rendered more sensitive for detecting recurrent or persistent disease, 3, Intrathyroid cancer that is present in more than 50% of patients is removed. 4. The small risk of a differentiated thyroid cancer becoming an undifferentiated thyroid cancer is decreased. I also recommend completion total thyroidectomy, except for patients who have occult papillary or minimally invasive follicular thyroid cancers. When the initial thyroid operation was a total lobectomy, this completion thyroidectomy should not be associated with any higher risk of complications, as my colleagues and IS8 and others" have reported. The best time to perform a total thyroidectomy is also at the initial operation, when it can be done safely and there is less scarring. Some experts question whether a total thyroidectomy can be done because most patients have some uptake of radioiodine after total thyroidectomy. Among my own patients, about 25% have no uptake above background, and in most of the others the uptake is less than 1%. Higher uptake usually occurs in patients with residual disease. As reported by Leung,'? Park,60 and their coworkers, it is easier and takes less 131 1 to destroy small thyroid remnants than to destroy larger thyroid remnants. Recent studies support the use of ultrasonography prior to the initial operation or reoperation. Such studies frequently document multifocal or bilateral papillary thyroid cancers as well as regional lymph node metastases." The technique of total thyroidectomy that I use is similar to that described by Thompson and associates' and Perzik. 64 The side of the dominant or suspicious nodule is mobilized by (1) dividing the middle thyroid veins laterally; (2) dividing the inferior thyroid veins on the trachea in the midline as well as dividing the thyrothymic ligaments; (3) looking for a Delphian node and pyramidal lobe and dividing the fascia just superior to the thyroid isthmus; (4) mobilizing the tissues laterally and then medially along the upper portion of the thyroid; (5) dividing and ligating the superior thyroid vessels individually relatively low on the thyroid gland to avoid injuring the external laryngeal nerve; (6) sweeping the tissues laterally from the thyroid gland with blunt dissection, and dividing any remaining middle thyroid vein or veins; and (7) identifying the recurrent laryngeal nerve and upper parathyroid gland at the level of the cricoid cartilage where the nerve enters posterior to the cricothyroid muscle. The upper parathyroid glands are more consistent in position and more dorsal or posterior than the

lower parathyroid glands, and they are usually the easiest parathyroid glands to dissect from the thyroid on a vascular pedicle. The lower parathyroid glands are almost always situated anterior to the recurrent laryngeal nerves. Once the recurrent nerve has been identified, the dissection may proceed more quickly. No tissue that might be the recurrent nerve should be divided until the recurrent nerve has been definitively identified. When bleeding occurs in the region of the recurrent laryngeal nerve, it should be controlled by gentle pressure until one is sure that the nerve is not at risk. A similar technique is used on the other side after mobilization of the first lobe and after the thyroid mobilization across the midline of the trachea. All enlarged or abnormal lymph nodes adjacent to the thyroid should be removed, and a functional lateral neck dissection should be done when palpable nodes are present. After total thyroidectomy, the removed thyroid gland is inspected to be sure that it does not contain a parathyroid gland. If a parathyroid gland has been removed, it should be dissected off the removed thyroid, a small biopsy taken for frozen section confirmation, and the remnant kept in iced saline. If this proves to be a parathyroid gland, it should be autotransplanted in l-mm pieces in separate muscular pockets within the sternocleidomastoid muscle and marked with a suture or clip. Postoperatively, a sterile pressure dressing is applied and the patient is placed in a low Fowler's position (back and head elevated 20 degrees). Medications are ordered for nausea. In 300 consecutive patients having total thyroidectomy, my colleagues and I had no cases of unplanned permanent recurrent laryngeal nerve injury, and two patients «1 %) had permanent hypoparathyroidism.' Most of our patients after total or other thyroid operations are discharged on the first postoperative day.

Summary Surgeons performing thyroid surgery must learn how to perform a safe total thyroidectomy by training with an experienced thyroid surgeon. Numerous surgeons have demonstrated that total thyroidectomy can be done with minimal morbidity.I,8-10,17,63 The complication rate is higher in patients with extensive invasive tumors, marked lymphadenopathy, and in those requiring reoperation. When total thyroidectomy can be done safely, it is the treatment of choice for most patients with thyroid cancer because persistent or recurrent disease can be detected earlier by determining increased serum thyroglobulin levels and by scanning with radioiodine. When metastatic thyroid cancer is detected early, it can often be ablated with 1311.14,64,6S

REFERENCES I, Clark OH, Levin K, Zeng QH, et al. Thyroid cancer: The case for total thyroidectomy. Eur J Cancer Clin Oncol 1988;24:305, 2, Grossman RF, Tezelman S, Clark OH. Thyroid cancer: The case for total thyroidectomy revisited. In: Johnson JT, Didolkar MS (eds), Head and Neck Cancer, Vol III. Excerpta Medica International, Congress Series. Amsterdam, Elsevier, 1993, p 879, 3. Foster RS Jr. Morbidity and mortality after thyroidectomy. Surg GynecolObstet 1978;146:423. 4. Harness JK, Fung L, Thompson NW, et al. Total thyroidectomy: Complications and technique. World J Surg 1986;10:781.

Papillary Thyroid Carcinoma: Rationale for Total Thyroidectomy - 5. Thompson NW, Nishiyama RH, Harness JK. Thyroid carcinoma: Current controversies. Curr Probl Surg 1978;15: I. 6. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988;104:948. 7. Hay Il), Grant CS, Taylor WF, McConahey WM. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: A retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 1987;102:1088. 8. Clark OH. Total thyroidectomy: The treatment of choice for patients with differentiated thyroid cancer. Ann Surg 1982;196:361. 9. Attie IN, Moskowitz GW, Margouleff D, Levy LM. Feasibility of total thyroidectomy in the treatment of thyroid carcinoma: Postoperative radioactive iodine evaluation of 140 cases. Am J Surg 1979;138:555. 10. Thompson NW. Total thyroidectomy in the treatment of thyroid carcinoma. In: Thompson NW, Vinik AI (eds), Endocrine Surgery Update. New York, Grune & Stratton, 1983, p 71. II. Clark OH, Duh QY. Thyroid cancer. Med Clin North Am 1991;75:211. 12. DeGroot LJ, Kaplan EL, Shukla MS, et al. Morbidity and mortality in follicular thyroid carcinoma. 1 Clin Endocrinol Metab 1995; 80:2946. 13. Leung SF, Law MW, Ho SK. Efficacy of low-dose iodine 131 ablation of postoperative thyroid remnants: A study of 69 cases. Br 1 Radiol 1992;65:905. 14. Schlumberger M, Tubiana M, De Vathaire F, et al. Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab 1986;63:960. 15. Simon D, Kohrle J, Schmutzler C, et al. Redifferentiation therapy of differentiated thyroid carcinoma with retinoic acid: Basics and first clinical results. Exp Clin Endocrinol Diabetes 1996;104 (SuppI4):13. 16. Eigelberger MS, Wong MG, Duh QY, Clark OH. Phenylacetate enhances the antiproliferative effect of retinoic acid in follicular thyroid cancer. Surgery 200 I; 130: 931. 17. Reeve TS, Delbridge L, Cohen A, Crummer P. Total thyroidectomy: The preferred option for multinodular goiter. Ann Surg 1987;206:782. 18. Liu Q, Gianakakis L, Djuricin G, Prinz R. Total thyroidectomy for benign thyroid diseases. Surgery 1998;123:27. 19. Kikuchi S, Perrier N, Ituarte P et al. Accuracy of fine-needle aspiration cytology in patients with radiation-induced thyroid neoplasms. Br J Surg 2003;90:755. 20. Russell WD, Ibanez ML, Clark RL, et al. Thyroid carcinoma: Classification, intraglandular dissemination, and clinicopathological study based upon whole-organ sections of 80 glands. Cancer 1963;11:1425. 21. Noguchi S, Noguchi A, Murakami N. Papillary carcinoma of the thyroid: I. Developing pattern of metastasis. Cancer 1970;26: I053. 22. Kebebew E, Clark OH: Locally advanced differentiated thyroid cancer. Surg Oncol 2003; 12:91. 23. Putti TC, Bhuiya TA. Mixed columnar cell and tall cell variant of papillary carcinoma of thyroid: A case report and review of the literature. Pathology 2000;32:286. 24. Vigneri R. Studies on the goiter endemia in Sicily. 1 Endocrinol Invest 1988;11:831. 25. Emerick GT, Duh QY, Siperstein AE, et al. Diagnosis, treatment, and outcome of follicular thyroid carcinoma. Cancer 1993;72:3287. 26. Chong GC, Beahrs OH, Sizemore GW, Woolner LH. Medullary carcinoma of the thyroid gland. Cancer 1975;35:695. 27. Kushchayeva K, Duh QY, Kebebew E, Clark OH. Hiirthle cell cancer. World J Surg 2004;28:1266. 28. Yutan E, Clark OH. Hiirthle cell carcinoma. Curr Treat Options Oncol 2001 ;2:331. 29. Nishiyama RH, Dunn EL, Thompson NW. Anaplastic spindle cell and giant cell tumors of the thyroid gland. Cancer 1972;30: 113. 30. Miura D, Wada N, Chin K, et al. Anaplastic thyroid cancers cytogenetic patterns by comparative genomic hybridization. Thyroid 2003; 13:282. 31. Cohn KH, Backdahl M, Forsslund G, et al. Biologic considerations and operative strategy in papillary thyroid carcinoma: Arguments against the routine performance of total thyroidectomy. Surgery 1984;96:957. 32. Hay ro. Prognostic factors in thyroid carcinoma. Thyroid Today 1989;12:1. 33. Cady B, Rossi R, Silverman M, Wool M. Further evidence of the validity of risk group definition in differentiated thyroid carcinoma. Surgery 1985;98: 1l71.

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34. Hay ro. Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 1990;19:545. 35. Backdahl M, Carstensen J, Auer G, Tallroth E. Statistical evaluation of the prognostic value of nuclear DNA content in papillary, follicular, and medullary thyroid tumors. World J Surg 1986;10:974. 36. Siperstein AE, Zeng QH, Gum ET, et al. Adenylate cyclase activity as a predictor of thyroid tumor aggressiveness. World J Surg 1988;12:528. 37. Beierwaltes WH, Nishiyama RH, Thompson NW, et al. Survival time and "cure" in papillary and follicular thyroid carcinoma with distant metastases: Statistics following University of Michigan therapy. J Nucl Med 1982;23:561. 38. Duh QY, Siperstein AE, Miller RA, et al. Epidermal growth factor receptors and adenylate cyclase activity in human thyroid tissues. World 1 Surg 1990;14:410. 39. Clark OH, Duh QY. Thyroid growth factors and oncogenes. In: Benz CC, Liu ET (eds), Oncogenes and Tumor Suppressor Genes in Human Malignancies. Norwell, MA, Kluwer Academic, 1993, p 87. 40. Goretzki PE, Lyons J, Stacy-Phipps S, et al. Mutational activation of RAS and GSP oncogenes in differentiated thyroid cancer and their biological implications. World 1 Surg 1992;16:576. 41. Lemoine NR, Mayall ES, Wyllie FS, et al. Activated ras oncogenes in human thyroid cancers. Cancer Res 1988;48:4459. 42. Santoro M, Dathan NA, Berlingieri MT, et al. Molecular characterization of RETIPTC3, a novel rearranged version of the RET protooncogene in a human thyroid papillary carcinoma. Oncogene 1994;9:509. 43. Grossman RF, Tu SH, Duh QY, Siperstein AE, et al. Familial nonmedullary thyroid cancer. An emerging entity that warrants aggressive treatment. Arch Surg 1995;130:892. 44. Hay If), Thompson GB, Grant CS, et al. Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940-1999): Temporal trends in initial therapy and long-term outcome in 2,444 consecutively treated patients. World J Surgery 2002;26:879. 45. Grant CS, Hay Il), Gough IR, et al. Local recurrence in papillary thyroid carcinoma: Is extent of surgical resection important? Surgery 1988;104:954. 46. Cady B, Sedgwick CE, Meissner WA, et al. Risk factor analysis in differentiated thyroid cancer. Cancer 1979;43:810. 47. Wanebo Hl, Andrews W, Kaiser DL. Thyroid cancer: Some basic considerations. CA Cancer J Clin 1983;33:87. 48. Farrar WB, Cooperman M, lames AG. Surgical management of papillary and follicular carcinoma of the thyroid. Ann Surg 1980; 192:701. 49. Schroder DM, Chambors A, France Cl. Operative strategy for thyroid cancer: Is total thyroidectomy worth the price? Cancer 1986;58:2320. 50. Massin JP, Savoie lC, Garnier H, et al. Pulmonary metastases in differentiated thyroid carcinoma: Study of 58 cases with implications for the primary tumor treatment. Cancer 1984;53:982. 51. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. 1 Clin Endocrinol Metab 1990;71:414. 52. Mazzaferri EL, Young RL. Papillary thyroid carcinoma: A 10 year follow-up report of the impact of therapy in 576 patients. Am 1 Med 1981;70:511. 53. Mazzaferri EL, lhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am 1 Med 1994;97:418. 54. Loh KC, Greenspan F, Gee L, et al. Pathological tumor-node-metastasis (pTNM) staging for papillary and follicular thyroid carcinomas. 1 Clin Endocrinol Metab 1997;82:3553. 55. Wong JB, Kaplan MM, Meyer KB, Pauker SG. Ablative radioactive iodine therapy for apparently localized thyroid carcinoma: A decision analytic perspective. Endocrinol Metab Clin North Am 1990;19:741. 56. Kebebew E, Clark OH: Differentiated thyroid cancer: "Complete" rational approach. World J Surg 2000;24:942. 57. Esnaola NF, Cantor SB, Sherman SI, et al: Optimal treatment strategy in patients with papillary thyroid cancer: a decision analysis. Surgery 2001; 130:921. 58. Levin KE, Clark AH, Duh QY, et al. Reoperative thyroid surgery. Surgery 1992;111:604. 59. Attie IN, Bock G, Auguste LJ. Multiple parathyroid adenomas: Report of thirty-three cases. Surgery 1990;108:1014. 60. Park HM, Perkins OW, Edmondson lW, et al. Influence of diagnostic radioiodines on the uptake of ablative dose of iodine 131. Thyroid 1994;4:49.

114 - - Thyroid Gland 61. Kebebew E, Duh QY, Clark OH. Total thyroidectomy or thyroid lobectomy in patients with low-risk differentiated thyroid cancer: Surgical decision analysis of a controversy using a mathematical model. World Surg 2000;24:1295-1302. 62. Perzik S. The place of total thyroidectomy in the management of 909 patients with thyroid disease. Am J Surg 1976; 132:480. 63. Lennquist S. Surgical strategy in thyroid carcinoma: A clinical review. Acta Chir Scand 1986; 152:321.

64. Pacini F, Cetani F, Miccoli P, et al. Outcome of 309 patients with metastatic differentiated thyroid carcinoma treated with radioiodine. World J Surg 1994;18:600. 65. Casara D, Rubello D, Saladini G, et aI. Different features of pulmonary metastases in differentiated thyroid cancer: Natural history and multivariate statistical analysis of prognostic variables. J Nucl Med 1993;34:1626.

Follicular Neoplasms of the Thyroid Gerard M. Doherty, MD

In the normal thyroid gland, the basic functional unit is the follicle. Follicles are single-layer spheres of follicular cells surrounding a lake of viscous colloid that primarily stores thyroglobulin. Other cell types that are present in the thyroid gland are interposed between these follicular spheres. These cells include perifollicular cells, also called C cells, which secrete calcitonin, as well as some supportive fibrous tissue, vascular structures, and nerves. The most common tumors of the thyroid gland arise from the follicular cells, including both papillary tumors and follicular tumors. Papillary tumors are discussed elsewhere in this text; however, follicular cancers are probably best described in the ways in which they differ from papillary tumors. Papillary tumors consist of single layers of thyroid cells arranged around vascular stocks, forming papillations. A substantial minority of papillary tumors (-40%) also include laminated calcified spheres called psammoma bodies. Follicular tumors include neither of these characteristics. The tumor cells surround persistent spherical follicles that frequently contain a small amount of colloid compared with normal. The follicular cells are often bland in their cytologic appearance, although more aggressive lesions can have more abnormal-appearing cells. Notably, the tumors that are purely follicular do not have any of the papillations or psammoma bodies that are typical of papillary tumors. Tumors that have a mainly follicular appearance but also contain some papillations or psammoma bodies are classified as follicular variants of papillary cancer; their biologic behavior supports their inclusion as papillary cancers.

Incidence and Prevalence There are approximately 22,000 new cases of thyroid cancer, and 1400 people who die of thyroid cancer, in the United States each year.' Of these, approximately 15% to 20% are follicular neoplasms. Because of the difficulties in distinguishing follicular from papillary neoplasms in some marginal cases and because of changes in the definitions of follicular neoplasms over the past 20 years, exact proportions are difficult to determine. Of all follicular neoplasms

demonstrated by needle aspiration or biopsy, approximately 15% are cancers. Thus, 85% percent of the follicular lesions diagnosed in the United States each year are benign follicular adenomas. In Sweden, where reliable cancer statistics can be generated because of a fairly comprehensive national cancer registry, the incidence of follicular carcinoma of the thyroid appeared relatively stable between 1958 and 1981, at about I case per 100,000 women per year and 0.4 cases per 100,000 men per year.' This study also demonstrated the substantially increased risk of follicular thyroid cancer in areas with high frequency of an iodine-deficient diet. In addition, in the same review, there is a gradual increase in the overall incidence of thyroid cancer over time; almost all of this increase is accounted for by changes in the annual incidence of papillary thyroid cancer. The changes in thyroid cancer incidence over time is complex, however, as shown by a study in Tasmania that demonstrated an increasing incidence of papillary thyroid cancer and decreasing proportion of thyroid cancers that are follicular tumors over a 20-year interval coincident with the discontinuation of universal iodine supplements.' Autopsy studies have demonstrated the prevalence of unrecognized follicular thyroid neoplasms. In a detailed evaluation of 300 whole thyroid glands from people with no known thyroid disease, 13 had follicular adenomas (4.3% overall, 5% of men and 3% of women)." Follicular carcinoma was found in four thyroids (1.3% overall, 0.5% of men and 3% of women). In a separate study that evaluated only grossly evident lesions in 625 thyroid glands, only two follicular carcinomas, both in men, were identified (0.3% overall)." The difference between these studies probably lies in the thoroughness of evaluation of each thyroid gland; unsuspected follicular cancer probably exists in approximately 1% of the population. The spectrum of clinical follicular thyroid neoplasms includes follicular adenomas of various histologic types as well as follicular carcinomas. This chapter describes the differences between the follicular adenomas and carcinomas as well as the implications of those differences and presents a scheme for the management of follicular nodules of the thyroid.

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Follicular Adenoma Pathologic Features of Follicular Adenoma Follicular adenomas are benign tumors of the thyroid gland that grow in glandular or follicular patterns. They can occur in any portion of the thyroid and in any age group; they are more common in young adults. Adenomas are usually solitary and less than 3 em in size, although significant numbers of exceptions to these rules exist." The lesions tend to grow slowly within a capsule of surrounding compressed thyroid glandular tissue. Over time, they develop a dense capsule surrounding the lesion. Because of this they are more firm than the surrounding tissue. They become palpable when they reach 5 to 10 mm in size. On cut section, they vary from a soft grayish white tissue that bulges out above the cut surface to brown gelatinous tissue. On histologic examination, the follicular adenoma demonstrates the presence of follicles (Fig. 13-1). There can be marked variability in the follicles produced in one follicular adenoma compared with another. Some follicular tumors can be composed of nearly solid cords of tumor cells with rudimentary acinar formation. These are also sometimes called embryonal adenomas. Some follicular adenomas form extremely large dilated glandular structures with a large amount of colloid and only a very scant stroma. These follicular adenomas are sometimes called colloid nodules. Other patterns that are sometimes recognized include a variant with small well-formed acini very similar to normal thyroid tissue but with a large amount of hyalin collagenous fibrous tissue separating the follicles (fetal adenomas). Finally, adenomas with well-formed follicles but follicular cells that are considerably larger and more variable in size than usual thyroid follicular cells and that contain an abundant granular pink cytoplasm are called Hiirthle cell adenomas.' Hiirthle cell tumors are discussed in more detail in a separate chapter in this book. The origin of follicular adenomas and the stimuli that maintain them are as yet not clear. Investigations have supported the idea that most, if not all, follicular adenomas are of a monoclonal origin and represent true neoplasms. The evidence suggesting that follicular adenomas are monoclonal

FIGURE 13-1. Follicular adenoma of the thyroid. Note the well-formed acini and the intact tumor capsule. Original magnification x160.

neoplasms comes from cytogenetic or restriction fragment length polymorphism (RFLP) analysis.?"" Studies have focused on the growth advantages conferred by these molecular changes. These include activating mutations of the thyroidstimulating hormone (TSH) receptor.!':"

Clinical Features of Follicular Adenoma Adenomas tend to grow slowly, be unchanged for years at a time, and become symptomatic only late and rarely. They are typically discovered by palpation by the patient or physician on directed physical examination. If they are very inconveniently placed or are allowed to grow to a large size, the tumors can occasionally cause local symptoms such as dysphasia, voice changes, stridor, or pain. These symptoms may be brought on by bleeding or necrosis of the center portion of the lesion that causes a sudden increase in size. In that situation, the symptoms may be temporary and a portion of the lesion may become cystic. The vast majority of follicular adenomas are hypofunctional on radioiodine scan. If imaged in this fashion, they are seen as "cold" or "warm" (the same as normal thyroid) nodules. A small proportion of these nodules may be hyperfunctional, concentrating iodine avidly, which may suppress function in the remainder of the thyroid. They may occasionally produce thyrotoxicosis (toxic adenoma). Interestingly, once the neoplasm has differentiated as a follicular adenoma, it appears only rarely if ever to degenerate to carcinoma. There is little evidence in humans to suggest that adenomas transform into invasive carcinomas. Changes from hyperplasia to adenoma to invasive carcinoma are seen rarely in some people who have congenital goitrous hypothyroidism. This does not appear to be the typical course in most adults. The indications for removing a follicular adenoma are (1) evaluation for possible carcinoma, (2) treatment of toxic adenoma, and (3) resolution of local compressive symptoms.

Follicular Carcinoma Pathologic Features of Follicular Carcinoma Follicular carcinomas are the malignant counterparts to follicular adenoma. Follicular carcinomas come in two anatomic forms. The less aggressive but more difficult to diagnose variety is also called the angioinvasive encapsulated carcinoma or minimally invasive follicular carcinoma. These are usually small and seemingly encapsulated neoplasms of the thyroid gland that are grossly indistinguishable from follicular adenomas. Microscopically, however, they demonstrate invasive features that reveal them as carcinomas; with only minimal invasion, these tumors can have an excellent prognosis." The second variety is the follicular cancers, which are much larger and clearly grossly invasive; they may replace the entire thyroid lobe or extend outside the thyroid into adjacent soft tissues. Histologically, these tumors are adenocarcinomas with substantial range in the size and differentiation of the acinar follicles. Some carcinomas have only small incomplete gland formation with very little colloid evident. These resemble the embryonal pattern of follicular adenoma.

Follicular Neoplasms of the Thyroid - -

FIGURE 13-2. Follicular thyroid cancer with capsular invasion. This specimen demonstrates a broad tongue of tumor extending through the tumor capsule and abutting normal thyroid tissue. Large arrows, tumor capsule. Small arrows, normal thyroid follicles. Original magnification x160.

Others produce very well defined glands or follicles containing colloid. Occasionally, the differentiation of these tumors from normal thyroid architecture is difficult. This well-differentiated variety of follicular carcinoma has been misdiagnosed as lateral aberrant thyroid tissue in cervical lymph nodes (also known as benign metastasizing struma). The degree of invasiveness of the lesions is also variable. As noted, the microinvasive variety can be nearly indistinguishable from follicular adenoma. The salient characteristics are invasion of blood vessels in the tumor or invasion of the complete thickness of the tumor capsule (Figs. 13-2 and 13-3). In the more anatomically aggressive types of follicular cancer, this invasion can be grossly obvious and the diagnosis much more clear in spite of a benign histologic appearance of the follicles themselves. The follicular variant of papillary cancer is important to distinguish it from pure follicular cancer (Fig. 13-4). These tumors may be almost completely follicular; however,

FIGURE 13-3. Follicular thyroid cancer with vascular invasion. This tumor has areas of differentiated follicles along with the demonstrated tumor invasion into blood vessels. Large arrow, intravascular tumor. Small arrows, follicles. Original magnification x 300.

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A

B FIGURE 13-4. Follicular variant of papillary thyroid cancer. A, Low-power view of lesion shows an encapsulated follicular neoplasm that could be mistaken for a follicular adenoma. Original magnification x160. B, In a higher power view of the same lesion, the presence of several optically clear nuclei (Orphan Annie nuclei, arrow) defines the lesion as the follicular variant of papillary carcinoma. Original magnification x600.

if they contain any papillary structures, psammoma bodies, or optically clear nuclei (Orphan Annie nuclei), they should be classified as the follicular variant of papillary cancer. These tumors behave similarly to papillary carcinoma of the thyroid." The follicular variant of papillary cancer has frequently been misclassified in the past; thus, pathologic review is an important component of any retrospective series of follicular cancer," Another follicular variant contains cells that are large and have an abundant acidophilic cytoplasm with small pyknotic central nuclei; these are called Hiirthle cell carcinomas.!? They are discussed in a separate chapter of this text. Some pathologists have identified a subgroup of follicular tumors that contain an insular component.t-" This insular component is a near-solid portion of the tumor with nests of cells separated by capillaries. There is a small amount of follicular formation within the nests. Some tumors are composed of small amounts of insular component, whereas others are formed predominately of insular-type histology. The presence of this insular component correlates with a more aggressive clinical behavior, consistent with that of other widely invasive follicular thyroid cancers."

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These features of follicular cancer-the often cytologically benign cells and the sometimes minimal capsular or vascular invasion-usually make follicular cancer demonstrable only on permanent histologic sections. Fine-needle aspiration (FNA) cytology is limited because it assesses only small groups of cells and depends mainly on abnormalities of the individual cells (Fig. 13-5).Some criteria have been developed to improve the diagnostic accuracy of FNA for follicular lesions,such as the presence of microfollicles, necrotic debris, nuclear size, and the presence of nucleoli.22-24 In addition, immunocytologic techniques are being evaluated that may be useful.25 •26 In spite of these advances, there are still many indeterminate follicular neoplasms by FNA. Frozen section analysis has limitations for follicular tumors because the diagnosis of follicular cancer may rest on local capsular invasion, which can be difficult and time-consuming to assess on limited frozen section."

demonstrate a relatively benign-appearing follicular tumor; however, by its behavior it has defined itself as an invasive malignant variety. Thus, follicular cancers typically arise as a slowly growing solitary thyroid mass in a middle-aged to older person. About 25% of patients have extrathyroidal invasion at the time of presentation. Between 10% and 33% of patients have distant metastasis at the time of initial diagnosis. Most follicular cancers are nonfunctional ("cold") by radioiodine thyroid scan. Occasionally, a follicular cancer retains the ability to concentrate iodine to a degree similar to that of adjacent thyroid tissue ("warm") or even to a greater degree than the normal thyroid ("hot"). The rare "functional" thyroid cancer is nearly always a follicular carcinoma rather than a papillary tumor.

Clinical Features of Follicular Carcinoma

The prognosis of follicular carcinoma of the thyroid overall is slightly worse than that of papillary carcinoma of the thyroid. 29 -3 1 Some representative series are presented in Table 13-1. The overall survival for patients presenting with follicular carcinoma of the thyroid depends on the stage of the patient at presentation. In the series in Table 13-1, overall survival ranges from 43% at 10 years to 95%, with a mean lO-year follow-up. However, substantial differences exist in the proportion of patients who had demonstrable metastatic disease at presentation among the various series, and this can explain at least a large part of the variability in overall survival. Each of these series recognizes certain important prognostic factors that can be easily clinically defined. The presence of metastases at initial diagnosis was associated with a very poor 5-year survival. Although these patients can be treated or palliated by radioiodine therapy with some benefit, the overall survival and outcome for patients with distant metastases are grim. The cause of death is typically progression of distant metastases.v-" Age at the time of initial diagnosis appears to be a very important prognostic factor that was recognized in each of the series noted in Table 13-1. Although the exact age cutoff varied from series to series, as would be expected when assigning an abrupt cutoff to retrospective analysis of a continuous variable, somewhere between 40 and 60 years of age appeared to be a substantial transition point for patients presenting with this tumor. Overall, older patients have a worse prognosis with follicular carcinoma. Besides age and the presence of metastases, important prognostic factors appeared to be the degree of invasion (microinvasive versus widely invasive) and in one series the degree of tumor cell differentiation. Using this information about the risk of death from follicular thyroid cancer in various clinical situations, one can develop a system for identifying those at substantial risk. In such a system, age and the degree of invasion present in the tumor appear to be the important variables for patients with localized tumor at presentation. Thus, for young patients with minimally invasive tumors, one can be relatively reassuring about their good outcome in spite of the occasional exception. On the other hand, an elderly patient with evidence of a widely invasive follicular carcinoma of the thyroid would have a much more guarded outlook and in fact would have a predicted 8% survival after 10 years of follow-up, according to the data from the Mayo Clinic.

Although follicular thyroid cancers can occur in any age group, the median age of groups with follicular cancers is typically higher than that of groups with papillary cancers. Typically, the median age at presentation is in the sixth decade of life. As with papillary cancer, the female-male ratio is between 2: I and 5: 1. The typical presentation of a patient with follicular carcinoma of the thyroid is similar to that of a patient with follicular adenoma. Most patients present with a solitary thyroid nodule. In contrast to patients with follicular adenoma, patients with follicular thyroid cancers are more likely to have local symptoms. These can include difficulty swallowing, dysphonia, stridor, or pain. Patients can also present with evidence of distant metastases, most typically metastases in the bone, lung, brain, or liver. Apparently because of their propensity for vascular invasion, follicular tumors often metastasize by hematogenous pathways and only rarely by cervical lymph nodes, as would be more typical of papillary cancer," Biopsy at these distant sites may

FIGURE 13-5. Fine-needle aspiration specimen from a follicular thyroid neoplasm. Note the bland and uniform cytologic appearance of the cells. Defining features for follicular cancer, such as vascular or capsular invasion, can, of course, not be assessed in this type of specimen. Original magnification x600.

Prognosis of Follicular Carcinoma

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Treatment of Follicular Carcinoma: Surgery Substantial controversy surrounds the selection of therapy for patients with follicular carcinoma of the thyroid. Some authors have recommended unilateral operations, typically lobectomy and isthmusectomy, for patients who are in good prognostic groupS.34,35 This would include lesions that are confined to the thyroid, smaller in size, and in younger patients. Others have contended that it is important to remove all or nearly all of the thyroid tissue in order to achieve certain desirable goalS. 35-37 First, although most patients who fall into the good prognostic groups do well, a few do poorly, and at this point the disease course cannot be predicted, There are data to suggest that a more complete removal of the thyroid improves overall prognosis even for the patients who are in the low-risk groups if their tumor is over I em in size.38,39 Further, more complete removal of the thyroid tissue allows ablation of the remaining normal thyroid tissue more easily using 131 1 and may allow better therapeutic use of 1311. This in tum decreases recurrence and may also decrease the death rate from tumor.39,40 More complete removal of the thyroid improves the value of postablation l3l1 whole-body scanning and also allows the clinician to follow serum thyroglobulin levels as a tumor marker.'? Finally, all patients with well-differentiated thyroid cancer should be treated with thyroxine replacement for life regardless of the extent of their surgery, and there is no functional physiologic value to leaving a contralateral thyroid lobe in place." Total or near-total thyroidectomy at the

initial operation is a very safe procedure in the hands of an experienced thyroid surgeon.i' For all of these reasons, many respected thyroid surgeons and endocrinologists prefer a more extensive operation, even for patients in good prognostic groups with follicular carcinoma of the thyroid. The role of reoperation to remove remaining thyroid tissue in a patient who has had less than total thyroidectomy (completion thyroidectomy) for follicular cancer is controversial.36,42,43 The frequency with which this issue arises should be minimized by careful initial surgery and gross intraoperative evaluation, As previously mentioned, patients can have a very benign histologic appearance of the follicular cancer in the thyroid gland. However, if the patient has metastasis to lymph nodes near the thyroid or has evidence of local soft tissue invasion outside the thyroid glands, the patient should clearly have a total or near-total thyroidectomy. Frozen section analysis of the thyroid gland itself is not often helpful in making this decision; the utility of frozen section analysis of follicular thyroid lesions has been assessed by a randomized clinical trial." However, careful gross evaluation, attention to the clinical situation, and judicious use of frozen section analysis of abnormalities away from the primary tumor may make the need for total thyroidectomy apparent at the initial operation." The most common indication for completion thyroidectomy is a frozen section analysis of a thyroid lesion that is interpreted as benign follicular adenoma. On subsequent permanent pathology, areas of invasion are identified and the diagnosis is changed to follicular carcinoma. In this

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situation, the surgeon is faced with the decision of whether to go back and remove the contralateral thyroid gland for completion of the thyroidectomy or to leave the contralateral gland in place. Studies have demonstrated that completion thyroidectomy can be done safely by experienced surgeons and that cancer can be found in the contralateral thyroid in a significant proportion of these patients. 36,42 There are no data to demonstrate that the completion thyroidectomy has an effect on recurrence or survival because no one has studied this topic prospectively. In my opinion, the decision should be individualized. If the patient is in a very good prognostic group, such as a 35-year-old woman with a l-cm follicular tumor that has minimal invasion of the capsule only, it is reasonable to maintain the patient with thyroxine suppression and not perform completion thyroidectomy. If, however, the patient has any risk factors that might indicate a more significant risk for tumor recurrence and mortality, I would suggest reoperation for completion of the thyroidectomy. For the patients in the worse prognostic groups and for those with previous neck irradiation, complete removal of the thyroid gland is more clearly indicated. Radiation exposure increases the risk of multicentric disease, and patients with follicular tumors after radiation exposure are at a particularly increased risk for recurrence.f Complete removal of the thyroid gland removes gross or occult contralateral disease and allows the therapeutic use of 1311, which can treat local, regional, and distant follicular carcinoma. Most surgeons avoid procedures that might alter function for the patient in the presence of a well-differentiated follicular tumor. For example, radical neck dissection or laryngectomy would rarely be indicated given the efficacy of 1311 therapy for disease that is not resectable by less mutilating means. In patients with metastases, therapy should begin with thyroidectomy. This is the quickest way to make the patient hypothyroid and allow total-body 1311 scanning. Patients who have a single demonstrable resectable metastasis should have resection, as this may lead to cure or prolonged survival. Multiple metastases are best treated by radioactive iodine therapy and occasionally adjuvant chemotherapy or external beam irradiation. Local therapies to relieve symptoms from bone metastases are palliative."

Treatment of Follicular Carcinoma: Adjuvant Therapy Suppression of pituitary TSH release with exogenous thyroid hormone replacement is an important therapy for follicular thyroid cancer." Because TSH acts as a growth factor for some thyroid cancers, it appears to be reasonable to manage all patients having follicular carcinoma of the thyroid with oral thyroxine replacement for life, although the demonstration of efficacy for all groups is lacking.'? The use of thyroxine to suppress TSH to very low levels can be accompanied by osteoporosis or evidence of thyrotoxicosis, including cardiac arrhythmias. Because of this potential toxicity, patients for whom thyroxine replacement is used in an adjuvant setting should have their TSH suppressed to a level of 0.2 to 0.4 mU/mL. Patients who have demonstrable metastatic cancer should be treated with higher doses to suppress TSH to an undetectable level as long as this is not associated with adverse side effects, such as cardiac effects.

Therapy of follicular carcinoma of the thyroid with radioiodine is currently recommended for most patients.P''" Only those with the very best prognosis, such as patients younger than 30 with very small lesions, unless they have had radiation exposure, are excluded from treatment. Radioiodine treatment is used in an adjuvant setting in all other patients who can have their disease completely resected and as a treatment modality in patients with metastatic disease. Patients are managed with suppressive hormone therapy immediately after thyroidectomy. It is most convenient to use liothyronine (T 3) in this setting because of its shorter half-life than thyroxine. After the patient has recovered from surgery, the liothyronine is discontinued for at least 7 days and the TSH level measured. Once the TSH level has achieved the supraphysiologic range (>25 units/ml.), maximal stimulation of any residual thyroid tissue or thyroid cancer can be assumed. Patients are given a small dose of 1311 and a total-body scan performed to survey for areas of uptake. A substantial proportion of patients have residual uptake in the cervical region in spite of total anatomic thyroidectomy. This residual uptake in what is usually normal thyroid tissue can be subsequently ablated with an appropriate dose of 1311. After this dose (typically -30 mCi) has been administered, the patient can be started on thyroxine replacement. If there were no demonstrable extracervical metastatic lesions on the initial scan, the patient should be rescanned in 6 months to 1 year. If, however, the patient has had metastatic disease defined on the initial radioiodine scan, the patient should be treated with a substantial dose of radioiodine, typically 75 to 250 mCi. This cycle of radioiodine scanning and treatment for metastatic lesions can be repeated every 6 to 9 months as appropriate given the patient's physiologic status and tumor response. The efficacy of radioiodine in an adjuvant setting is variable. A study from Young and colleagues demonstrated clear improvement in the overall recurrence rate in patients with disease initially confined to the neck who were treated with surgery, radioiodine, and hormonal therapy compared with patients treated with only surgery and hormonal therapy." Overall, survival was improved; however, there may be subgroups that are at very low risk that do not benefit from radioiodine ablation. One of these groups was evaluated retrospectively in a study from the University of British Columbia. In 71 patients with follicular thyroid cancers and minimal invasion, this group saw no difference in survival or disease-free survival between the 46 patients who underwent hormonal suppression only and the 17 patients who had radioiodine ablation and hormonal suppression." With the data currently available, radioiodine ablation should be recommended for most patients with follicular carcinoma of the thyroid; however, there may be low-risk groups who will be more clearly defined in future studies as not benefitting from such treatment.

Management of Follicular Neoplasms A scheme for the management of patients with follicular neoplasms is presented in Figure 13-6. The typical euthyroid patient with a solitary nodule should be evaluated with

Follicular Neoplasms of the Thyroid - -

Solitary No Evidence of • Euthyroid Thyroid' Nodule Metastases Fineneedle aspiration

High Risk Size>3 em Age> 60 yr History of neck radiation Suspicious cytology

• Thyroxine suppression • Foilowsize each6 months

~

+

l

'--1

I No Growth I ~

Operation Thyroidlobectomy and isthmusectomy

FIGURE 13-6. Management scheme for patients with follicular neoplasms.

FNA of the nodule. Cytology cannot usually distinguish between follicular adenoma and follicular carcinoma because the diagnosis of carcinoma depends upon histologic features (vascular or capsular invasion) that are not demonstrable by FNA. The diagnosis then is follicular neoplasm. Patients who are at low risk for having thyroid carcinoma rather than adenoma, as well as low risk for a poor outcome if they do have carcinoma, can be managed conservatively. Conservative management consists ofTSH suppression with exogenous thyroxine to decrease the growth stimulus for the neoplasm. The value of suppression as a technique for distinguishing between carcinoma and adenoma has been questioned, and the potential downside of oversuppression (osteoporosis in particular) has been recognized. However, it seems reasonable to suppress TSH to a moderately low level (0.3 to 0.6 mU/mL) while patients are being observed conservatively. This is done not to decide that lesions that shrink are not cancers, as 2 of 19 follicular cancers shrank with suppression therapy in the University of California series," but to remove growth stimulation during the prolonged follow-up. If the lesion does grow during follow-up, the patient should have a thyroid lobectomy and isthmusectomy. Patients with thyroid nodules should be observed indefinitely for evidence of growth. Intermediate-risk patients include those whose lesions are I to 3 em in size and those who are older than 40 years. The patients should have a functional (1 231 or 99mTc04) scan to assess the nature of the nodule. Patients with functional nodules are unlikely to harbor cancer in that lesion; they can join the low-risk follow-up group with thyroxine suppression. Patients who have nonfunctioning nodules should have thyroid lobectomy and isthmusectomy for diagnosis, not only because they are at higher risk of having follicular

121

cancer but also because they are at higher risk of having an aggressive tumor if they do have thyroid cancer. Low-risk patients who are averse to the inherent risk of delaying treatment of a cancer, which is possible in the more conservative plan of follow-up, can be included with this group and assessed with a functional scan. The high-risk group includes patients who are older than 60 years and those with nodules greater than 3 em in size. These patients are at higher risk of having cancer in the nodule and of having an aggressive cancer. In addition, patients who have a history of neck irradiation, or whose cytology is suspicious for cancer (because of atypia or necrosis, for example), have a higher risk of cancer. These patients should have a diagnostic thyroid lobectomy and isthmusectomy without further evaluation because of their higher risk. The scheme outlined here is one of several possible designs for managing patients with follicular thyroid neoplasms. More important than the algorithm itself are the data that underlie it. If the clinician understands these data, individual algorithms can be constructed for each patient and new information incorporated into future plans.

REFERENCES 1. Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5. 2. Pettersson B, Adami H-O, Wilander E, Coleman MP. Trends in thyroid cancer incidence in Sweden, 1958-1981, by histopathologic type. lnt J Cancer 1991;48:28. 3. Burgess JR, Dwyer T, McArdle K, et al. The changing incidence and spectrum of thyroid carcinoma in Tasmania (1978-1998) during a transition from iodine sufficiency to iodine deficiency. J Clin Endocrinol Metab 2000;85:1513. 4. Bisi H, Fernandes VSO, Asato De Camargo RY, et al. The prevalence of unsuspected thyroid pathology in 300 sequential autopsies, with special reference to the incidental carcinoma. Cancer 1989;64:1888. 5. Martinez-Tello FJ, Martinez-Cabruja R, Fernandez-Martin J, et al. Occult carcinoma of the thyroid. Cancer 1993;71:4022. 6. Davis NL, Gordon M, Germann E, et al. Clinical parameters predictive of malignancy of thyroid follicular neoplasms. Am J Surg 1991;161:567. 7. LiVolsi VA. Current concepts in follicular tumors of the thyroid. In: LiVolsi VA, DeLellis RA (eds), Pathobiology of the Parathyroid and Thyroid Glands. Baltimore, Williams & Wilkins, 1994, p 118. 8. Antonini P, Levy N, Caillou B, et al. Numerical aberrations, including trisomy 22 as a sole anomaly, are recurrent in follicular thyroid adenomas. Genes Chromosomes Cancer 1993;8:63. 9. Hicks DG, LiVolsi VA, Neidich JA, et al. Clonal analysis of solitary follicular nodules in the thyroid. Am J PathoI1990;137:553. 10. Roque L, Castedo S, Gomes P, et al. Cytogenetic findings in 18 follicular thyroid adenomas. Cancer Genet Cytogenet 1993;67:1. II. Aust G, Steinert M, Kiessling S, et al. Reduced expression of stromalderived factor 1 in autonomous thyroid adenomas and its regulation in thyroid-derived ceils. J Clin Endocrino! Metab 200 1;86:3368. 12. Persani L, Lania A, Alberti L, et al. Induction of specific phosphodiesterase isoforms by constitutive activation of the cAMP pathway in autonomous thyroid adenomas. J Clin Endocrinol Metab 2000; 85:2872. 13. Tonacchera M, Agretti P, Chiovato L, et al. Activating thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiter. J Clin Endocrinol Metab 2000;85:2270. 14. Tonacchera M, Vitti P, Agretti P, et al. Functioning and nonfunctioning thyroid adenomas involve different molecular pathogenetic mechanisms. J Clin Endocrinol Metab 1999;84:4155. 15. Hishinuma A, Takamatsu J, Ohyama Y, et al. Two novel cysteine substitutions (C1263R and C1995S) of thyroglobulin cause a defect in intracellular transport of thyroglobulin in patients with congenital goiter and the variant type of adenomatous goiter. J Clin Endocrinol Metab 1999;84: 1438.

122 - - Thyroid Gland 16. van Heerden JA, Hay ID, Goellner JR, et al. Follicular thyroid carcinoma with capsular invasion alone: A nonthreatening malignancy. Surgery 1992;112:1130. 17. Tielens ET, Sherman SI, Hruban RH, Ladenson PW. Follicular variant of papillary thyroid carcinoma. Cancer 1994;73:424. 18. Lin HS, Komisar A, Opher E, Blaugrund SM. Follicular variant of papillary carcinoma: The diagnostic limitations of preoperative fineneedle aspiration and intraoperative frozen section evaluation. Laryngoscope 2000;110:1431. 19. Evans HL, Vassilopoulou-Sellin R. Follicular and Hurthle cell carcinomas of the thyroid: A comparative study. Am J Surg Pathol 1998; 22:1512. 20. Ashfaq R, Vuitch F, Delgado R, Albores-Saavedra J. Papillary and follicular thyroid carcinomas with an insular component. Cancer 1994;73:416. 21. Pilotti S, Collini P, Mariani L, et al. Insular carcinoma: A distinct de novo entity among follicular carcinomas of the thyroid gland. Am J Surg Patho 1997;21:1466. 22. Gardner HAR, Ducatman BS, Wang HH. Predictive value of fineneedle aspiration of the thyroid in the classification of follicular lesions. Cancer 1993;71:2598. 23. Harach HR, Zusman SB. Necrotic debris in thyroid aspirates: A feature of follicular carcinoma of the thyroid. Cytopathology 1992;3:359. 24. Montironi R, Braccischi A, Scarpelli M, et al. Well differentiated follicular neoplasms of the thyroid: Reproducibility and validity of a "decision tree" classification based on nucleolar and karyometric features. Cytopathology 1992;3:209. 25. DeMicco C, Basko V, Garcia S, et al. Fine-needle aspiration of thyroid follicular neoplasm: Diagnostic use of thyroid peroxidase immunocytochemistry with monoclonal antibody 47. Surgery 1994;116:1031. 26. Saggiorato E, Cappia S, De Giuli P, et al. Galectin-3 as a presurgical immunocytodiagnostic marker of minimally invasive follicular thyroid carcinoma. J Clin Endocrinol Metab 2001;86:5152. 27. Kingston GW, Bugis SP, Davis N. Role of frozen sections and clinical parameters in distinguishing benign from malignant follicular neoplasms of the thyroid. Am J Surg 1992;164:603. 28. Iwasaki H, Matsumoto A, Ito K, et al. Prediction of distant metastasis in follicular adenocarcinoma of the thyroid. World J Surg 1990; 14:425. 29. Akslen LA, Haldorsen T, Thoresen SO, Glattre A. Survival and causes of death in thyroid cancer: A population-based study of 2479 cases from Norway. Cancer Res 1991;51:1234. 30. Balan KK, Raouf AH, Critchley M. Outcome of 249 patients attending a nuclear medicine department with well differentiated thyroid cancer; a 23 year review. Br J RadioI1994;67:283. 31. Hoie J, Stenwig AE. Long-term survival in patients with follicular thyroid carcinoma. The Oslo experience: Variations with encapsulation, growth pattern, time of diagnosis, sex, age, and previous thyroid surgery. J Surg Oncol 1992;49:226. 32. Beasley NJ, Walfish PG, Witterick I, Freeman JL. Cause of death in patients with well-differentiated thyroid carcinoma. Laryngoscope 2001;111:989.

33. Kitamura Y, Shimizu K, Nagahama M, et al. Immediate causes of death in thyroid carcinoma: Clinicopathological analysis of 161 fatal cases. J Clin Endocrinol Metab 1999;84:4043. 34. Cady B, Rossi R, Silverman M, Wool M. Further evidence of the validity of risk group definition in differentiated thyroid carcinoma. Surgery 1985;98: 1171. 35. Cady B, Sedgwick CE, Meissner WA, et al. Risk factor analysis in differentiated thyroid cancer. Cancer 1979;43:810. 36. De Jong SA, Demeter JG, Lawrence AM, Paloyan E. Necessity and safety of completion thyroidectomy for differentiated thyroid carcinoma. Surgery 1992;112:734. 37. Emerick GT, Duh Q-Y, Siperstein AE, et al. Diagnosis, treatment, and outcome of follicular thyroid carcinoma. Cancer 1993;72:3287. 38. Harness JK, Thompson NW, McLeod MK, et al. Follicular carcinoma of the thyroid gland: Trends and treatment. Surgery 1984;966:972. 39. Samaan NA, Schultz PN, Hickey RC, et al. The results of various modalities of treatment of well differentiated thyroid carcinomas: A retrospective review of 1599 patients. J Clin Endocrinol Metab 1992;75:714. 40. Young RL, Mazzaferri EL, Rahe AJ, et al. Pure follicular thyroid carcinoma: Impact of therapy in 214 patients. J Nucl Med 1980;21 :735. 41. Ley PB, Roberts JW, Symmonds RE Jr, et al. Safety and efficacy of total thyroidectomy for differentiated thyroid carcinoma: A 20-year review. Am Surg 1993;59: 110. 42. DeGroot LJ, Kaplan EL. Second operations for "completion" of thyroidectomy in treatment of differentiated thyroid cancer. Surgery 1991;110:936. 43. Shaha AR, Jaffe BM. Completion thyroidectomy: A critical appraisal. Surgery 1992;112:1148. 44. Udelsman R, Westra WH, Donovan PI, et al. Randomized prospective evaluation of frozen-section analysis for follicular neoplasms of the thyroid. Ann Surg 2001;233:716. 45. Schneider AB, Recant W, Pinsky SM, et al. Radiation-induced thyroid carcinoma. Ann Intern Med 1986;105:405. 46. Smit JW, Vielvoye GJ, Goslings BM. Embolization for vertebral metastases of follicular thyroid carcinoma. J Clin Endocrinol Metab 2000;85:989. 47. Davis NL, Gordon M, Germann E, et al. Efficacy of 1311 ablation following thyroidectomy in patients with invasive follicular thyroid cancer. Am J Surg 1992;163:472. 48. Jorda M, Gonzalez-Campora R, Mora J, et al. Prognostic factors in follicular carcinoma of the thyroid. Arch Pathol Lab Med 1993;117:631. 49. Brennan MD, Bergstralh EJ, van Heerden JA, McConahey WM. Follicular thyroid cancer treated at the Mayo Clinic, 1946 through 1970. Initial manifestations, pathologic findings, therapy and outcome. Mayo Clin Proc 1991;66:II. 50. Mueller-Gaertner HW, Grzac HT, Rehpenning W. Prognostic indices for tumor relapse and tumor mortality in follicular thyroid carcinoma. Cancer 1991;67:1903. 51. Crile G Jr, Pontius KI, Hawk WA. Factors influencing the survival of patients with follicular carcinoma of the thyroid gland. Surg Gynecol Obstet 1985;160:409.

Hurthle Cell Adenoma and Carcinoma Herbert Chen, MD, FACS • Robert Udelsman, MD, MBA, FACS

Few topics in endocrine surgery have been as controversial as Hiirthle cell neoplasms of the thyroid. Hiirthle cell neoplasms (adenomas and carcinomas) are "solitary masses in the thyroid comprised of Hiirthle cells exclusively, or at least over 50% so comprised, and confined by a capsule found in a gland not otherwise overcome by chronic thyroiditis.'" They comprise 3% to 10% of all epithelial thyroid tumors and have been reported to account for 15% to 20% and 2% to 8% of all follicular and papillary cancers, respectively.' Hurthle cell tumors are well differentiated and tend to be more aggressive than routine follicular thyroid cancers but less so than sporadic medullary thyroid cancers. Since their initial description, there has been debate about their origin, clinical behavior, classification, diagnosis, surgical management, and prognosis. Part of the difficulty in characterizing the behavior of these tumors is due to the relative low incidence of malignant Hiirthle cell lesions; therefore, experience obtained in any single institution is limited. In this chapter, we discuss the controversy surrounding Hiirthle cell neoplasms and outline our current management.

Historical Background The term Hiirthle cell tumor is a misnomer. In 1894, Hiirthle described intrafollicular cells of the thyroid in a normal dog that actually were parafollicular C cells.' True Hiirthle cells were first described in 1898 in a patient with thyrotoxicosis by Askanazy." In 1907, Langhans reported the first Hiirthle cell tumor, and Ewing, in 1919, described a true Hiirthle cell tumor and miscredited Hiirthle as the original discoverer.' Therefore, these tumors are occasionally referred to as Askanazy cell tumors or Langhans tumors; however, they are most commonly referred to as Hiirthle cell neoplasms.

Origin and Classification Controversy exists regarding the presumed origin of Hiirthle cells. Most believe that they originate from thyroid follicular cells. This conclusion is supported by the following: (1) histology from a single thyroid gland can show the

transition from follicular cells to Hiirthle cells; (2) Hiirthle cells can secrete thyroglobulin similar to thyroid follicular cells; (3) a high concentration of Hiirthle cells is seen in inflammatory diseases of the thyroid; and (4) a functional thyroid-stimulating hormone (TSH) receptor-adenylate cyclase system is present in Hiirthle cell neoplasms." There are some investigators, however, who suggest that Hiirthle cells are of parafollicular origin. This is based on the fact that Hiirthle cell cancers more often metastasize to lymph nodes, are less likely to trap radioactive iodine, and have a distinct oncogene expression profile as compared to follicular cancers.' The confusion surrounding the description of Hiirthle cell tumors continues today. The nomenclature is not standardized; Hi.irthle cell tumors (adenomas and carcinomas) are also referred to as oncocytomas, oxyphilic tumors, Askanazy cell tumors, Langhans tumors, and follicular Hiirthle cell tumors. In 1988, the World Health Organization formally classified Hiirthle cell carcinoma as an oxyphilic variant of follicular carcinoma. However, since then, several investigators have presented convincing evidence that these tumors should be classified separately as Hiirth1ecell carcinomas.

Clinical Characteristics Histology Hiirth1e cells are large polygonal, eosinophilic cells with pleomorphic, hyperchromatic nuclei and fine granular, acidophilic cytoplasm, representing an abundance of mitochondria (Fig. 14-1). The individual cells are 10 to 15 urn in diameter and can vary in shape and size from small dumbbells to bizarre giant cells. Hiirthle cell neoplasms are encapsulated collections of Hiirthle cells (Fig. 14-2). Therefore, the presence of nonencapsulated Hiirth1e cells does not signify a neoplastic process, because they are commonly associated with Hashimoto's thyroiditis, Graves' disease, and nodular goiters as well as with well-differentiated thyroid cancers. Hiirthle cell tumors continue to be classified as variants of follicular neoplasms. However, Hiirthle cell carcinomas

123

124 - -

Thyroid Gland

Risk Factors Up to 39% of patients with Htirthle cell neoplasms in one study reported previous childhood head and neck radiation. II Previous radiation exposure has also been correlated with an increase in bilaterality and multicentricity of Htirthle cell tumors, as well as an increased incidence of contralateral non-Htirthle cell malignant thyroid lesions. No genetic syndromes have been reported to be associated with Htirthle cell tumors. Other than radiation exposure and age, no other risk factors have been associated with Htirthle cell neoplasms.

Presentation

FIGURE 14-1. Fine-needle aspiration of a thyroid nodule showing an abundance of polygonal-shaped Hiirthle cells. Note the pleomorphic hyperchromatic nuclei and granular cytoplasm.

generally behave in a more aggressive manner, metastasizing more frequently, and are less likely to respond to radioactive iodine." In addition, Htirthle cell variants of papillary thyroid cancer have been reported with increasing frequency." These tumors behave in a manner more similar to Htirthle cell carcinomas, metastasizing and recurring more frequently than papillary carcinomas. Therefore, most believe that Htirthle cell tumors should be classified as a distinct category, with subgroups of follicular and papillary variants.

Demographics Htirthle cells neoplasms have a peak incidence in the fifth to sixth decades. With advancing age there is an increased chance of a malignancy. 10 There is a female preponderance, with reported ratios ranging from 2:1 to 10:1. However, male patients with Htirthle cell neoplasms have a higher relative incidence of carcinoma.

FIGURE 14-2. A Htirthle cell adenoma (A). Note the presence of a thin capsule (C) without any signs of capsular invasion. Most of this neoplasm is composed of Htirthle cells.

Most patients with Htirthle cell neoplasms present with a solitary thyroid nodule. Approximately 80% of these lesions are nonfunctioning and are therefore "cold" on nuclear scans. Approximately 5% to 60% (in most series, 10% to 35%) of Htirthle cell neoplasms are carcinomas. In patients presenting with malignant lesions, 70% to 80% are confined to the gland, 11% have lymph node metastasis, and 15% have distant metastasis, most commonly to bone or lung. Patients may also present with advanced local disease manifested by esophageal or airway obstructive symptoms.

Diagnosis Histopathology In 1974, Thompson and colleagues reported a series of 25 patients with Htirthle cell neoplasms in which 75% of these whose lesions were initially described as benign (i.e. adenomas) subsequently died of Htirthle cell carcinoma." This led to the suggestion that gross and histopathologic examination of Htirthle cell neoplasms could not reliably predict clinical behavior and that all lesions should be treated as malignant or potentially malignant. Since then, however, several studies have shown that histologic criteria can reliably differentiate between Htirthle cell adenomas and carcinomas. Grant and colleagues in 1988 reviewed 272 surgically resected Htirthle cell neoplasms at the Mayo Clinic that were deemed to be histologically benign and found that only 1 had an incorrect diagnosis manifested by tumor recurrence, with a mean follow-up of 4 years.13 The criteria currently used to diagnose Htirthle cell carcinoma are capsular or vascular invasion, invasion of adjacent structures, lymph node metastases, and distant metastases. Moreover, Carcangiu and associates found similar results in reviewing 153 cases of Htirthle cell neoplasms." In their study, patients were grouped into three categories: benign (90), indeterminate (35), and malignant (28). Malignant lesions had to demonstrate fullthickness capsular invasion, vascular invasion, or invasion into adjacent tissue. Indeterminate lesions had minimal capsular invasion, solid versus follicular growth pattern, marked nuclear atypia, and extensive necrosis. With up to 22 years of follow-up, no tumor recurrences or cause-specific death was seen in the benign or indeterminate groups. From these and other studies.v-" one can conclude that histologic examination can differentiate benign from malignant Htirthle cell neoplasms and that the sine qua non of Htirthle cell carcinoma is full-thickness capsular and/or vascular invasion (Figs. 14-3 and 14-4).

Htirthle Cell Adenoma and Carcinoma - - 125

>.

o

80%

c: ctl c: 60%

.Ql (ij

E 40%

'0

Q)

Cl c: 20%

ctl

s:

o

0%

1 em or less

>1 em and <4 em

4em or greater

Tumor size

FIGURE 14-3. A Hurthle cell carcinoma invading through fullthickness capsule(C).The tumor(T) is presenton both sides of the capsule and extends almostbeyondthe thyroidcapsule.

Fine-Needle Aspiration Fine-needle aspiration (FNA) can reliably detect Hiirthle cell neoplasms (see Fig. 14_1).16.18 FNA can also be helpful in differentiating Hiirthle cell neoplasms from non-neoplastic lesions with Hiirthle cells present. Hiirthle cell tumors are associated with a high percentage of Hiirthle cells; nests of Hiirthle cells; cellular dyshesion; large nucleoli; nuclear pleomorphism; significant nuclear enlargement; and the absence of macrophages, plasma cells, or lymphocytes. 19 Although reliable histologic criteria for malignancy exist, FNA cannot accurately distinguish Hiirthle cell adenomas from carcinomas.W' Since FNA cannot determine the presence of full-thickness capsular and/or vascular invasion, several studies have focused on determining if any cellular features seen on FNA are associated with malignancy. Unfortunately, cellular atypia, including nuclear size, nuclear mitoses, cellular pleomorphism, necrosis, and percentage of Hiirthle cells, does not have a relationship to malignancy. 10 Molecular profiling for expression of ras, p53, mdm-Z, p21, cyclin DI, Bcl-2, and other markers associated with

Number of patients (n)

n

=6

n

= 34

n

= 17

FIGURE 14-5. Tumor size is predictive of malignancy. With increasing size, the chanceof malignancy increases. (FromChenH, Nicol TL, Zeiger MA, et al: Hiirthle cell neoplasms of the thyroid: Are there factors predictive of malignancy? Ann Surg 1998; 227:542.)

malignancy have failed to show any correlation with Hiirthle cell carcinomas,?,22,23 DNA aneuploidy has been associated with increased recurrence and distant metastasis in patients with Hiirthle cell carcinoma; however, Hiirthle cell adenomas are also often aneuploid.P Finally, size of a Hiirthle cell neoplasm has been shown to correlate with malignant potential (Fig. 14-5). In a series of 57 consecutive Hiirthle cell neoplasms, tumors 1 cm or less were found to be malignant in 17% of cases." However, 65% of tumors at least 4 em in diameter proved to be malignant. Thus, other than size, no cytologic characteristics can reliably predict malignancy. Therefore, the cornerstone of diagnostic studies remains careful histologic evaluation.

Frozen Section Evaluation Intraoperative frozen section evaluation has traditionally been used to assess indeterminate thyroid lesions. There have been no studies specifically addressing the use of frozen section evaluation in the management of Hiirthle cell neoplasms. However, because follicular thyroid carcinomas and Hiirthle cell carcinomas both are diagnosed solely by the presence of capsular and/or vascular invasion, studies addressing follicular lesions appear applicable. In a review of 125 consecutive patients with follicular thyroid lesions, including a small number of Hiirthle cell neoplasms.. who underwent surgical exploration, frozen section evaluation was of minimal value, rendering no additional diagnostic information 87% of the time." Although providing diagnostic information in 13% of patients, in only 3.3% did frozen section correctly modify the surgical procedure. Notably, in 5% of patients, the frozen section was incorrect and potentially led to misguided interventions. Therefore, frozen section evaluation should play only a minor role in the management of Hiirthle cell neoplasms.

Management FIGURE 14-4. Vascular invasion by Htirthle cell carcinoma (H). An endothelial-lined blood vessel (V) structure is completely occluded by tumor cells (T).

Patients presenting with Hiirthle cell neoplasms usually have had a solitary thyroid nodule evaluated by FNA. In our

126 - - Thyroid Gland experience, 35% of these lesion ultimately prove to be malignant, although in some series, up to 60% have been reported to be cancers.t-" Accordingly, we recommend surgical exploration for patients in whom the FNA demonstrates a Hiirthle cell neoplasm.

Surgical Procedure A careful exploration is always undertaken to detect the presence of obvious malignant disease-i.e., tumor invasion into adjacent structures, metastatic nodal disease-as well as contralateral nodular thyroid disease. We advocate onestage total or near-total thyroidectomy if obvious malignant disease or contralateral nodular disease is present or if the patient has a history of childhood head and neck irradiation. This is based on the fact that there is an increased incidence of multifocal disease as well a 50% chance of a concomitant papillary cancer associated with previous head and neck irradiation. II Furthermore, Carcangiu and associates have shown that local recurrence of Hurthle cell carcinoma is correlated with the extent of surgery, with recurrence rates for nodulectomy, thyroid lobectomy, and total thyroidectomy of 75%, 40%, and 15%, respectively.'? In addition, some patients, understanding the 35% risk of carcinoma, may elect to have an initial total thyroidectomy rather than having a completion thyroidectomy should cancer be found. For the routine patient with a single dominant nodule, surgical management should consist of an ipsilateral lobectomy and isthmusectomy. Surgical procedures involving less than a lobectomy, in our opinion, have no role in the

management of neoplastic lesions. Some surgeons advocate intraoperative frozen section evaluation to assess capsular and/or vascular invasion." If frozen section reveals a benign process such as thyroiditis or goiter, or a Hiirthle cell neoplasm lacking capsular or vascular invasion, the surgery is terminated. If capsular or vascular invasion is present, then total or near-total thyroidectomy is performed. Although this is theoretically an acceptable approach, because frozen section is inherently unreliable in detecting capsular/vascular invasion," one can argue for omitting frozen section evaluation. Although some recommend random lymph node sampling in all cases." we typically do not excise lymph nodes unless they are enlarged. If disease is found outside the thyroid-i.e. soft tissue invasion or lymph node metastasis-resection of all gross/microscopic disease is performed. Because surgical resection is usually the only curative treatment option for Hiirthle cell carcinoma, every effort should be made to resect all disease. This includes a modified radical neck dissection for positive cervical lymph node metastasis. We occasionally advocate more radical surgery for advanced Hurthle cell carcinoma, including resection of the larynx, trachea, skin, soft tissue, cervical lymph nodes, and esophagus (Fig. 14-6). In patients who underwent an initial lobectomy/isthmusectomy whose final pathology was diagnostic of carcinoma, we generally perform a completion thyroidectomy as soon as possible after the initial surgery. In patients with only partial capsular invasion, the decision is not as clear. Several studies, however, have illustrated that these lesions do not behave in a malignant manner.v!':" This has also been our experience. Although some advocate completion

FIGURE 14-6. A patient with very aggressive Htirthle cell carcinoma. A, MRI demonstrates a large thyroid mass. B, CT scan of the neck depicts almost complete airway obstruction by tumor. C, A barium swallow study illustrates esophageal deviation and obstruction secondary to the mass. This patient's operative management included total thyroidectomy, total laryngectomy, bilateral modified radical lymph node dissections, esophagectomy, and gastric pull-up reconstruction.

c

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thyroidectomy in this case, we would favor close clinical follow-up and life-long thyroid suppression. In patients with the diagnosis of Hiirthle cell adenoma, no further operative intervention is warranted. However, close clinical follow-up is recommended. There have been reports of recurrence with Hiirthle cell adenomas.P but this is a rare occurrence.

Radioactive Iodine and Other Modalities Hiirthle cell carcinomas generally fail to concentrate 131 1 and, therefore, in most patients, radioablation does not offer a therapeutic benefit. As a result, the only curative treatment for Hiirthle cell carcinoma is surgical resection. However, there have been case reports of metastatic tumors that have 131 I uptake. In 4 of 7 patients with pulmonary metastases from Hiirthle cell carcinoma, 131 1 uptake by the metastatic tumors was present." Although there have also been reports of resolution of pulmonary metastases with 131 1 treatment, it is important to note that uptake does not always correlate with tumor responsiveness. However, because results from other modalities of treatment for metastatic disease have been dismal, each patient's case must be individually considered in evaluating the role for 1311. In most patients, it is unlikely that BII has a therapeutic benefit. In another series, two patients, who had pulmonary metastases responsive to 131 1 treatment, also had extraordinarily elevated serum thyroglobulin levels.'? Others have also reported regression of Hiirthle cell carcinoma metastases with 131 1 in tumors that apparently secreted thyroglobulin." Hiirthle cell adenomas and carcinomas are known to be able to secrete thyroglobulin. We have also had two patients with pulmonary and hilar lymph node metastases, respectively, who responded to 131 1 therapy." Based on these reports, some advocate 131 1 scans in patients with elevated thyroglobulin levels 4 to 6 weeks after total thyroidectomy, and treatment if positive. Other modalities of treatment have no efficacy in the primary treatment of Hiirthle cell carcinoma. These tumors are not responsive to various regimens of chemotherapy. Extemalbeam radiation to the soft tissue in the neck has shown no effect of survival." However, it does have a role for palliation of bony metastasis.

Postoperative Follow-Up Our philosophy is based on the belief that total or neartotal thyroidectomy is the treatment of choice for welldifferentiated thyroid cancers including Hiirthle cell carcinomas. After thyroidectomy, we advocate 131 1 ablation if any residual uptake is present. This offers the advantage of screening for recurrence by thyroglobulin levels. After ablation, thyroglobulin levels should be checked at 6-month intervals initially. If thyroglobulin levels are elevated, the patients should be withdrawn from thyroid hormone and a scan performed. If positive, the patient should be treated with therapeutic doses of 1311. If the 131 1 scan is negative, then we use other modes of imaging, including neck ultrasound, computed tomography scan or magnetic resonance imaging of the neck and chest, and positron-emission tomography (PET) scans. In a recent meta-analysis for the detection of Hiirthle cell carcinoma by PET, the reported sensitivity, specificity, positive predictive value, negative predictive

value, and accuracy were 92%,80%,92%,80%, and 89%, respectively.F Another emerging method to detect Hiirthle cell carcinoma recurrence is octreotide scintiscanning. Gorges and associates recently reported their experience with 29 patients with recurrent Hiirthle cell cancers.P They found that in patients with thyroglobulin greater than 10 ng/ml., 95 % had positive IIIIn-octreotide scans. If any of these studies localize recurrent disease, surgical resection is considered.

Prognosis The lO-year survival rates for the classes of well-differentiated thyroid cancers are papillary, 95%; follicular, 85%; and Hiirthle cell, 70%. The cause-specific 20-year mortality for Hiirthle cell carcinomas has been reported to range from 20% to 35%.34Prognosis generally depends on extent of disease at the initial diagnosis and the possibility of resection. The most favorable prognosis is associated with disease confined to the thyroid gland itself. A strong correlation has been demonstrated between tumor DNA aneuploidy and decreased survival in Hiirthle cell carcinomas." However, adenomas often have an aneuploid DNA status and do not recur or metastasize. Therefore, aneuploidy is not an unfavorable prognostic factor. Studies that have focused strictly on Hiirthle cell cancers have failed to identify useful prognostic factors such as age at diagnosis, tumor size, histologic grade, and tumor growth pattern. 10 None of these factors have been found to be associated with survival advantage. There is universal agreement, however, that adequate surgical resection (at least total lobectomy) is the treatment of choice of all Hiirthle cell carcinomas.

Summary Hiirthle cell tumors comprise 3% to 10% of thyroid tumors, whereas Hiirthle cell cancer makes up I % to 3% of all thyroid cancers. They hematogenously metastasize to bone, lung, brain, and lymph nodes. FNA can reliably diagnose Hiirthle cell neoplasms, but it cannot determine malignancy, which occurs in 35% of patients. Frozen section analysis is rarely useful. Treatment is primarily surgical consisting of total or near-total thyroidectomy. Ablation with 131 1 plays a limited role. The 10-year survival rate for patients with Hiirthle cell cancer is 70%.

REFERENCES I. Bronner MP, Clevenger CV, Edmonds PR, et al. Flow cytometric analysis of DNA content in Hiirthle cell adenomas and carcinomas of the thyroid. Am J Clin Pathol 1988;89:764. 2. Hundahl SA, Cady B, Cunningham MP, et at. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the united states during 1996: U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation Study. Cancer 2000;89:202. 3. Hiirthle K. Beitrage sur kenntnis des sekretionsvorganges in der schilddruse. Arch Ges Physiol 1894;56: 1. 4. Askanazy M. Pathologish-anatomische bitrage zur kenntnis des morbus basedowii, insbesondere uder die dabei auftretende muskelerkrankung. Deutsches Arch Klin Med 1898;61:118.

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5. Langhans T. Uber die epithelialan formen der malignen struma. Virchows Arch 1907;189:69. 6. Clark OH, Gerend PL. Thyrotropin receptor-adenylate cyclase system in Hiirthle cell neoplasms. 1 Clin Endocrinol Metab 1985;61:773-778. 7. Hoos A, Stojadinovic A, Singh B, et al. Clinical significance of molecular expression profiles of Hiirthle cell tumors of the thyroid gland analyzed via tissue microassays. Am 1 Pathol 2002; 160:175. 8. Chen H, Nicol TL, Zeiger MA, et al. Hurthle cell neoplasms of the thyroid: Are there factors predictive of malignancy? Ann Surg 1998;227:542. 9. Herrera MF, Hay ID, Wu PS, et al. Hiirthle cell (oxyphilic) papillary thyroid carcinoma: A variant with more aggressive biologic behavior. World 1 Surg 1992;16:669. 10. Carcangiu ML, Bianchi S, Savino D, et al. Follicular Hiirthle cell tumors of the thyroid gland. Cancer 1991;68:1944. II. Arganini M, Behar R, Wu TC, et al. Hiirthle cell tumors: A twenty-five-year experience. Surgery 1986;100:1108. 12. Thompson NW, Dunn EL, Batsakis lG, Nishiyama RH. Hiirthle cell lesions of the thyroid gland. Surg Gynecol Obstet 1974;139:555. 13. Grant CS, Barr D, Goellner lR, Hay ID. Benign Hiirthle cell tumors of the thyroid: A diagnosis to be trusted? World 1 Surg 1988;12:488. 14. Bronner MP, LiVolsi VA. Oxyphilic (Askanazy/Hiirthle cell) tumors of the thyroid: Microscopic features predict biologic behavior. Surg Pathol 1988;1: 137. 15. Stojadinovic A, Hoos A, Ghossein RA, et al. Hiirthle cell carcinoma: A 60-year experience. Ann Surg Oncol 2002;9: 197. 16. Mclvor NP, Freeman Jl., Rosen I, Bedard yc. Value of fine-needle aspiration in the diagnosis of Hurthle cell neoplasms. Head Neck 1993;15:335. 17. McHenry CR, Rosen IB, Walfish PG, Bedard Y. Influence of fine-needle aspiration biopsy and frozen section examination on the management of thyroid cancer. Am 1 Surg 1993;166:353. 18. Udelsman R, Chen H. The current management of thyroid cancer. Adv Surg 1999;33: I. 19. Gonzalez Jl., Wang HH, Ducatman BS. Fine-needle aspiration of Hiirthle cell lesions: A cytomorphologic approach to diagnosis. Am 1 Clin Pathol 1993; 100:231. 20. Kini SR, Miller 1M, Hamburger JI. Cytopathology of Hiirthle cell lesions of the thyroid gland by fine-needle aspiration. Acta Cytol 1981;25:647.

21. Chen H, Udelsman R. Follicular, Hiirthle cell, and anaplastic thyroid cancer. In: Bland K (ed), The Practice of General Surgery. Philadelphia, WB Saunders, 2001, p 1053. 22. Johnson TL, Lloyd RV, Burney RE, Thompson NW. Hiirthle cell thyroid tumors: An immunohistochemical study. Cancer 1987;59:107. 23. Flint A, Davenport RD, Lloyd RV,et al. Cytophotometric measurements of Hiirthle cell tumors of the thyroid gland: Correlation with pathologic features and clinical behavior. Cancer 1988;61:110. 24. Chen H, Nicol TL, Udelsman R. Follicular lesions of the thyroid: Does frozen section evaluation alter operative management? Ann Surg 1995;222: 101. 25. Cooper DS, Schneyer CR. Follicular and Hiirthle cell carcinoma of the thyroid. Endocrinol Metab Clin North Am 1990;19:577. 26. McLeod MK, Thompson NW. Hiirthle cell neoplasms of the thyroid. Otolaryngol Clin North Am 1990;23:441. 27. Rosen IB, Luk S, Katz 1. Hiirthle cell tumor behavior: Dilemma and resolution. Surgery 1985;98:777. 28. Sugino K, Ito K, Mimura T, et al. Hiirthle cell tumor of the thyroid: Analysis of 188 cases. World 1 Surg 2001;25:1160. 29. Samaan NA, Schultz PN, Haynie TP, Ordonez NG. Pulmonary metastasis of differentiated thyroid carcinoma: Treatment results in 101 patients. 1 Clin Endocrinol Metab 1985;60:376. 30. Bondeson L, Bondeson AG, Ljungberg O. Treatment of Hiirthle cell neoplasms of the thyroid. Arch Surg 1983;118: 1453. 31. Caplan RH, Abellera RM, Kisken WA. Hiirthle cell neoplasms of the thyroid gland: Reassessment of functional capacity. Thyroid 1994;4:243. 32. Plotkin M, Hautzel H, Krause Bl, et al. Implication of 2-18fluor-2deoxyglucose positron-emission tomography in the follow-up of Hiirthle cell thyroid cancer. Thyroid 2002;12:155. 33. Gorges R, Kahaly G, Muller-Brand 1, et al. Radionuclide-Iabeled somatostatin analogues for diagnostic and therapeutic purposes in nonmedullary thyroid cancer. Thyroid 2001;11:647. 34. Hay ID, Klee GG. Thyroid cancer diagnosis and management. Clin Lab Med 1993; 13:725. 35. Erickson LA, lin L, Goellner lR, et al. Pathologic features, proliferative activity, and cyclin D[ expression in Hiirthle cell neoplasms of the thyroid. Mod Pathol 2000;13: 186.

Medullary Thyroid Carcinoma Jeffrey F. Maley, MD • Nina Shervin, MD

Background Medullary thyroid carcinoma (MTC) occurs in sporadic and hereditary clinical settings and displays a variety of clinical behaviors ranging from moderately aggressive to extremely indolent. The discovery of the gene responsible for hereditary MTC has shed light on the biologic basis for this range of clinical presentations. MTC was described in 1959 by Hazard, Hawk, and Crile. 1 MTC is a tumor of the thyroid C cells, also known as the parafollicular cells (Fig. 15-1). These cells are of neural crest derivation. Other neural crest-derived tumors include melanomas, pheochromocytomas, and neuroblastomas. C cells are dispersed throughout the thyroid gland, with the highest concentration in the upper poles. C cells secrete calcitonin, a hormone involved in calcium metabolism. Calcitonin is a sensitive and specific marker for the presence of MTC. It has been invaluable in the screening of individuals predisposed to the hereditary forms of the disease and in the follow-up of patients who have been treated. MTC cells have been noted to express and secrete a variety of substances in addition to calcitonin. Some of these are carcinoembryonic antigen (CEA), histaminase, neuron-specific enolase, calcitonin gene-related peptide, somatostatin, thyroglobulin, thyrotropin-stimulating hormone, adrenocortical releasing hormone, gastrin-related peptide, serotonin, chromogranin, substance P, and propriomelanocortin. MTC is often associated with a proliferative lesion, C-cell hyperplasia. It is likely that C-cell hyperplasia is a precursor of MTC. MTC constitutes approximately 5% to 10% of all thyroid cancers. MTC occurs as unifocal or multifocal clonal populations of tumor cells. Regional lymphatic spread occurs to perithyroidal lymph nodes, paratracheallymph nodes, nodes of the jugular chain, and upper mediastinal nodes.' Nodal metastases are often found along the recurrent laryngeal nerves in the paratracheal regions and may be present where these nerves branch and insert into the larynx. Nodes may be in close association with the parathyroid glands. MTC may remain confined to the neck for long periods of time. In more advanced stages, metastases are found in liver, lungs, bone, and sometimes brain and subcutaneous tissues (Fig. 15-2). Histologic features of aggressiveness include vascular invasion, lymphatic invasion, invasion of the thyroid capsule, and extranodal spread of tumor in lymph node metastases.

The disease can be locally aggressive, and local structures may be invaded by the primary tumor or by tumor in nodal metastases. In the neck, the structures most commonly invaded include the trachea, recurrent laryngeal nerve, and strap muscles. Invasion of the trachea in the neck or mediastinum can cause death.

Clinical Presentation MTC may be sporadic or familial. In sporadic MTC, tumors are usually single and unilateral. There is no family history and no other endocrinopathies are present. Sporadic MTC arises as a mass in the neck, and metastases to lymph nodes in the neck are usually present at the time of diagnosis. Familial forms of MTC are the multiple endocrine neoplasia (MEN) type 2A and 2B syndromes and the related disorder of familial non-MEN MTC (FMTC) (Table 15-1, Fig. 15-3).3-5 In these autosomal dominant inherited disorders, the tumor is multifocal, bilateral, and there is an early age of onset. In MEN 2A, patients develop multifocal, bilateral MTC associated with C-cell hyperplasia. Approximately 42% of affected patients develop pheochromocytomas, which may also be multifocal and bilateral; these tumors occur in the setting of diffuse adrenal medullary hyperplasia. Hyperparathyroidism develops in 10% to 35% of patients and is due to hyperplasia, which may be asymmetrical, with one or more glands becoming enlarged." Cutaneous lichen amyloidosis has been described in some patients with MEN 2A7 and Hirschsprung's disease is infrequently associated with MEN 2A.8-IO In MEN 2B, 40% to 50% of patients develop pheochromocytomas, and all individuals develop neural gangliomas, particularly in the mucosa of the digestive tract, conjunctiva, lips, and tongue.t'! MEN 2B patients also have megacolon, skeletal abnormalities, and markedly enlarged peripheral nerves. MEN 2B patients do not have hyperparathyroidism. MTC develops in all patients at a very young age (infancy) and appears to be the most aggressive form of hereditary MTC, although its aggressiveness may be related more to the extremely early age of onset than the biologic virulence of the tumor. MTC in MEN 2B is rarely cured. FMTC is characterized by the development of MTC without any other endocrinopathies. 12 MTC in these patients

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FIGURE 15-1. Photomicrograph of a focus of medullary thyroid

carcinoma surrounded by normal thyroidfollicles in a patient with multiple endocrine neoplasia type 2A.

has a later age of onset and a more indolent clinical course than MTC in patients with MEN 2A and MEN 2B. Occasional patients with FMTC live to their seventh and eighth decades without clinical evidence of MTC (symptoms or a lump in the neck), although biochemical testing and histologic evaluation of the thyroid always demonstrate MTC. In families affected by hereditary forms of MTC, biochemical and genetic screening of at-risk family members have resulted in the routine detection of MTC before a mass is palpable in the neck. In those cases, metastases are rarely detectable at the time of thyroidectomy. 13,14 MTC, however, is a common cause of death in patients who are not diagnosed early. The pattern of spread and metastasis is similar in hereditary and sporadic forms of MTC. Individuals at risk for MEN 2A, MEN 2B, and FMTC may be screened for MTC by measurement of calcitonin levels. IS Pheochromocytomas may be detected by measurement of plasma metanephrines. Alternatively, 24-hour urine collection for catecholamines, metanephrines, and vanillylmandelic acid may be done. Hyperparathyroidism is detected by measurement of serum calcium and parathyroid hormone levels. Now that the gene responsible for hereditary forms of MTC is known (the RET protooncogene), accurate genetic testing allows early identification of mutant gene carriers,

FIGURE 15-2. Distant metastatic disease in patients with

medullary thyroid carcinoma. Top left, Lymphangitic pulmonary spread in childwithmultiple endocrine neoplasia type 2B (MEN 2B) and medullary thyroid carcinoma (MTC). Bottom left, Solitary brainmetastasis in patientwithMEN 2A and MTC. Right, Multiple skeletal metastases in patientwith sporadic MTC. (FromMoley IF, Lairmore TC, Phay IE, et al. Hereditary endocrinopathies, Curr Probl Surg 1999;36:653.) which obviates the need to continue biochemical testing of family members who have not inherited the mutation (Table 15-2). Control of MTC in those found to have inherited the mutation is more effective because surgical intervention is carried out before there is clinical or biochemical evidence of tumor. In patients who present with a mass in the neck, the diagnosis of MTC is made by fine-needle aspiration cytology and measurement of serum calcitonin. If a patient is found to have MTC, careful physical examination should be performed to look for signs of MEN 2B. Patients should be questioned about family history of thyroid, adrenal, or

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FIGURE 15-3. Featuresof patients with hereditary medullary thyroid carcinoma (MTC). A, Bisected thyroid gland from a patient with multiple endocrine neoplasia type 2A (MEN 2A) showing multicentric, bilateral foci of MTC. B. Adrenalectomy specimen from patient with MEN 2B demonstrating pheochromocytoma. C, Megacolon in patient with MEN 2B. D. Midface and tongue of patient with MEN 2B showing characteristic tongue notching secondary to plexiform neuromas. (A, Courtesy of S.A. Wells, MD. B. C, and D, Courtesy of R. Thompson, MD.)

c parathyroid disease as well as Hirschsprung's disease. A family history of hypertension and sudden unexplained deaths may indicate the presence of undiagnosed pheochromocytomas. Symptoms of hoarseness, dysphagia, stridor, and hemoptysis indicate a locally invasive tumor. Physical examination should attempt to delineate the size and location of the mass, fixation to local structures, unilaterality versus bilaterality, and presence of regional nodal metastases. All patients with a preoperative diagnosis of MTC, whether detected by screening or finding of a palpable mass, should

D undergo measurement of CEA and plasma calcitonin levels. Screening for hyperparathyroidism and pheochromocytoma is important, even in those who are thought to have sporadic MTC. Sizemore and colleagues found that 19% of patients thought to have sporadic MTC were eventually found to be index cases of MEN 2A.16 Genetic testing for mutations in the RET protooncogene should be done in all patients with a diagnosis of MTC. 14 •17.18 At-risk family members should also be screened by genetic testing or by stimulated calcitonin testing.

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Blood levels of calcitonin may be measured in the basal state or after the administration of the secretagogues calcium and pentagastrin." After basal levels have been obtained, intravenous calcium (2 mg/kg/min) is infused, followed immediately by pentagastrin (0.5 ug/kg per 5 seconds), and then blood is drawn for measurement of plasma calcitonin levels at 1,3, and 5 minutes. Recently, pentagastrin has not been made in the United States; however, European-made pentagastrin has been obtained and approved for use at Washington University in St. Louis (investigational new drug number 61,205) and at Duke University.

Factors Influencing Prognosis As discussed in the previous section, the age of onset and clinical course of MTC are different in FMTC, MEN 2A, and MEN 2B. As is the case in most cancers, nodal status and tumor stage are associated with outcome.19-21 MTC often has an indolent clinical course, with approximately 75% lO-year overall survival and 50% 15-year overall surviva1. 22.23 Patients with high levels of calcitonin secondary to MTC may experience symptoms of flushing and diarrhea. The presence of such symptoms is associated with a poor prognosis.e' Other features that may correlate with clinical outcome include plasma calcitonin levels, CEA levels, DNA ploidy, and calcitonin and somatostatin immunohistochemistry. In a study of 94 patients, a high preoperative stimulated calcitonin level (> 10,000 pg/mL) was associated with a worse outcome." Those who presented with lower calcitonin levels were less likely to have nodal metastatic disease at operation than patients with high levels. CEA is elevated in more than 50% of patients with MTC.26 Elevated levels of CEA have been reported to be associated with the presence of metastatic disease, although this is not always the case.27,28

Surgical Treatment-Palpable Disease In this section, the surgical approach to the patient with a palpable tumor is addressed. A later section addresses the surgical approach to patients identified as RET mutation carriers by genetic screening. The surgical treatment of MTC is influenced by several factors. First, the biology and behavior of MTC are very different from those of

differentiated thyroid cancer. MTC cells do not take up iodine, and radioactive iodine therapy is ineffective. Unlike differentiated thyroid cancer, MTC does not respond to thyroid suppression. Surgery is the only effective therapeutic modality for MTC. Second, MTC is multicentric in 90% of patients with hereditary forms of the disease and in 20% of patients with the sporadic form. Fourth, nodal metastases are present in more than 70% of patients with palpable disease (Tables 15-3 and 15_4).29,21.30 Lastly, the ability to measure postoperative stimulated calcitonin levels allows the adequacy of surgical extirpation to be assessed. Total thyroidectomy is the appropriate treatment of the primary tumor, accompanied by a central node dissection in patients with a palpable thyroid tumor. In this operation, all thyroid tissue and all nodal tissue from the level of the hyoid bone superiorly to the innominate vessels inferiorly are removed. After the parathyroid glands are identified, central nodal tissue on the anterior surface of the trachea is removed, exposing the superior surface of the innominate vein behind the sternal notch. Fatty and nodal tissue between the carotid sheaths and the trachea is removed, including paratracheal nodes along the recurrent nerves. On the right, the junction of the innominate and right carotid arteries is exposed, and on the left, nodal tissue is removed to a comparable level behind the head of the left clavicle. A systematic approach to the removal of all nodal tissue in the central neck has been reported to improve recurrence and survival rates when compared retrospectively with procedures in which only grossly involved nodes were removed."

Management of the Parathyroids Controversy exists over the optimal management of the parathyroid glands in operations for MTC. Some surgeons prefer to leave the parathyroid glands in situ, ensuring that the vascular pedicle is preserved. 18,32-36 Our approach, in patients with established palpable MTC, is to remove the parathyroids and transplant them because complete thyroidectomy and central node dissection invariably cause devascularization of the glands." The blood supply to the parathyroids is intimately associated with the posterior capsule of the thyroid and with the central perithyroidal lymph nodes. Attempts to leave the parathyroids in place result in either leaving thyroid tissue and central nodes in the neck or leaving devascularized parathyroids. Furthermore, if the need for reoperation in the central compartment arises,

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the risk of subsequent hypoparathyroidism is negligible if the patient has a functioning autograft. Finding and preserving parathyroids in a scarred, previously operated neck are difficult, and the risk of hypoparathyroidism after such procedures is significant. Therefore, we advocate parathyroidectomy with autotransplantation as part of total thyroidectomy for established, palpable MTC (we do not recommend routine parathyroidectomy with autotransplantation for young MEN 2 patients having preventative thyroidectomy after genetic testing, as will be discussed later).'? Parathyroid glands to be autotransplanted are removed and placed in cold saline. The glands are sliced into 1- by 3-mm fragments and autotransplanted into individual muscle pockets (two fragments per pocket-approximately 15 pockets). We use the sternocleidomastoid muscle in patients with sporadic MTC, FMTC, and MEN 2B and the nondominant forearm in patients with MEN 2A (because they may develop graft-dependent hyperparathyroidismlocalization of the source of hyperparathyroidism and surgical removal of the hyperfunctional tissue are greatly simplified if the grafts are in the forearm). In patients with MEN 2A who have hyperparathyroidism at the time of operation, at least 100 mg of parathyroid tissue should be transplanted, and residual tissue should be viably frozen." The autografts generally function well within 4 to 6 weeks, at which time calcium supplementation of patients can be stopped.

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(see Table 15-3). In patients with bilateral intrathyroidal tumors, nodal metastases were present in 78% of central level VI nodal groups, in 71% of level II through V nodes ipsilateral to the largest intrathyroidal tumor, and in 49% of level II through V nodes contralateral to the largest intrathyroidal tumor (see Table 15-4). This is an alarmingly high incidence of nodal involvement. In this series, intraoperative palpation of nodes was not an accurate predictor of the presence or absence of metastases. The sensitivity of intraoperative assessment by the surgeon was only 64%, and the specificity was 71%.40 Therefore, reliance on intraoperative assessment would miss involved nodes 36% of the time. The strategy of resecting only "clinically involved nodes" may be effective in differentiated thyroid cancer, for which effective adjuvant therapy is available; however, no effective adjuvant treatments for MTC are available. On the basis of the results, our recommendation for patients who present with palpable MTC is total thyroidectomy, parathyroidectomy with autotransplantation, central neck dissection, and unilateral or bilateral dissection of level II through V nodes (Fig. 15-4).

Management of Regional Nodes Regional node metastases are present in the majority of patients with palpable MTC. Because these tumors do not take up iodine, nodal metastases cannot be ablated with radioactive iodine. Surgical node clearance is the only effective strategy for eliminating these deposits. 2 1.3 1,39 In a report in 1999, we evaluated the incidence and pattern of nodal metastatic spread in patients with palpable MTC (see Tables 15-3 and 15-4).40 In this series, 73 patients with palpable MTC underwent thyroidectomy with concurrent or delayed central and bilateral cervical node dissection. The number and location of lymph node metastases in the central (levels VI and VII) and bilateral (levels II through V) nodal groups were noted and were correlated with the size and location of the primary thyroid tumor. In patients with unilateral intrathyroidal tumors, nodal metastases were present in 81% in central level VI, in 81% in ipsilateral levels II through V, and in 44% in contralateral levels II through V nodal groups

FIGURE 15-4. Total thyroidectomy and central (levels VI and VII) and bilateral level II through V node dissections from a thin young male with multiple endocrine neoplasia type 2B and bilateral palpable thyroid masses (parathyroids not shown). Microscopic metastases were present in all nodal groups. (From Moley IF, Lairmore TC, Phay JE, et al. Hereditary endocrinopathies. CUff Probl Surg 1999;36:653.)

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As with any specialized procedure undertaken for an unusual clinical problem, these operations should be performed by surgeons familiar with the disease and with expertise in the techniques described.

Genetic Testing for Hereditary MTC Germline defects in the RET protooncogene are responsible for MEN 2A, MEN 2B, and FMTC. 4 1-43 RET encodes a transmembrane growth neurotrophic receptor with tyrosine kinase activity. In MEN 2A and FMTC, gain-offunction mutations within codons specifying cysteine residues in the extracellular ligand-binding domain of the RET gene product are most commonly found (see Table 15-2). In MEN 2B, a mutation is found in the intracellular tyrosine kinase domain. Changes in protein structure and function that result from these mutations predispose to neoplasia by a dominant oncogenic mechanism." Loss-of-function mutations in different regions of the same gene have been found in patients with Hirschsprung's disease. A small percentage of patients with MEN 2A have Hirschsprung's disease.v '? All patients with MEN 2B have megacolon and constiparion.v'
Preventive Surgery for Multiple Endocrine Neoplasia Type 2 Gene Carriers Individuals with MEN 2A, 2B and FMTC are virtually certain to acquire MTC at some point in their lives (usually before age 30 years). Therefore, at-risk family members who are found to have inherited the RET gene mutation are candidates for thyroidectomy regardless of their calcitonin levels. It has been shown in several series that RET mutation carriers often harbor foci of MTC in the thyroid gland even when stimulated calcitonin levels are normal. I4 , IS,33,34,45-47 In a series from Washington University in St. Louis reported in 1994, Wells and coauthors described the performance of preventive surgery in asymptomatic RET mutation carriers." Families of patients with MEN 2A were screened with genetic and biochemical testing. Thirteen children found to be asymptomatic RET mutation carriers were treated with total thyroidectomy, central lymph node dissection, and parathyroid autotransplantation (six with normal plasma calcitonin levels and seven with elevated levels). After surgery, patients received thyroid, calcium, and vitamin D supplementation. Approximately 8 weeks after the operation, the oral calcium and vitamin D were stopped. 1\\'0 weeks later the serum calcium concentration was within the normal range in each patient. All patients had microscopic foci of MTC or C-cell hyperplasia. In 1996, Wells and colleagues reported an updated series including 49 patients with similar results.f Lips and colleagues, in a series from the Netherlands reported in 1994, identified 14 young members of families affected by MEN 2A who had normal calcitonin testing but who were found to be MEN 2A gene carriers by DNA testing. IS Thyroidectomy was performed on 8 of these 14, and foci of MTC were identified in all 8. At Washington University in St. Louis, we have performed 85 such procedures to date. All patients had central neck node dissection and parathyroidectomy with autotransplantation. Two patients were found to have nodal metastases (one despite a normal stimulated calcitonin level), and calcitonin levels remain elevated in two. Three patients continue to receive calcium supplementation. There were no recurrent laryngeal nerve injuries. Follow-up testing is being carried out in all of these patients to determine the long-term outcome of such procedures. The finding of carcinoma in the glands of many young patients with normal stimulated calcitonin testing indicates that the operation is often therapeutic, not prophylactic. There is some urgency, therefore, to apply this genetic test to other at-risk individuals and to perform thyroidectomy on those who test positive genetically. The ideal age for performance of thyroidectomy in patients found to be genetically positive has not been determined unequivocally. We believe that 6 years of age is a reasonable time to perform surgery in patients with MEN 2A and FMTC. Patients with MEN 2B should undergo thyroidectomy during infancy because of the aggressiveness and earlier age of onset of MTC in these patients. Follow-up over the next decades

Medullary Thyroid Carcinoma - - 135 will determine whether there is a significant rate of recurrence after preventive thyroidectomy. At present, it is advisable to observe these patients with stimulated plasma calcitonin levels every 1 to 2 years. These patients must also continue to be observed for the development of pheochromocytomas and hyperparathyroidism.

Nonsurgical Treatment of the Patient with Persistent or Recurrent Medullary Thyroid Carcinoma Radiation Therapy

Persistent or Recurrent Hypercalcitoninemia After primary surgery for MTC, persistent or recurrent elevation of the basal or stimulated calcitonin levels indicates the presence of residual or recurrent tumor. Although longer follow-upof reported series is needed, it is likely that thyroidectomy is curative in children with MEN 2A and FMTC in whom the diagnosis of MTC is made by genetic testing or by detection of an elevated calcitonin level after previous negative yearly testing.lv" Patients in whom the diagnosis of hereditary MTC is made at an older age, however, when calcitonin levels are already high or a palpable tumor is present, are more likely to have residual disease after thyroidectomy. In one series, approximately 50% of these patients had persistent elevations of calcitonin levels postoperatively." In patients who present with a mass in the neck (this includes virtually all patients with sporadic MTC), lymph node metastases are present in more than 50%, and persistent elevation of calcitonin levels occurs in 50% to 100%.50,51 In one study of patients who presented with palpable tumors, 15 of 18 patients (83%) with hereditary disease and 11 of 20 patients (55%) with sporadic tumors had persistent disease as indicated by elevated calcitonin levels postoperatively. 50 The clinical course of patients with MTC who have positive nodes has been addressed in several studies. MTC can be a very indolent disease. Many patients with persistently high levels of calcitonin after thyroidectomy and node dissection continue to do well without evidence of disease for many years. In a study of 18 patients, 16 of whom had persistently elevated calcitonin levels after "adequate surgery," Block and coworkers found that calcitonin levels remained stable for up to 6 years and recommended observation in the absence of overt clinical disease. 52 These observations and this approach have been supported by other groups.v-" Other studies have indicated a poorer outcome in these patients. In a Norwegian study of 84 cases of MTC, it was noted that more than 50% of patients who presented with cervical node metastases eventually died of the disease.'? In a series of 139 patients operated on for MTC at Mayo Clinic, it was found that 59% of the patients with positive cervical lymph nodes experienced progression of disease.v In a subsequent report from Mayo Clinic, 66% of nodepositive patients with hereditary MTC died, and none of the patients with positive nodes had normal calcitonin levels after a median follow-up of 15.7 years." The variable outcome of patients with positive lymph nodes is explained by differences in the biologic virulence of the tumor, the extent of spread at the time of treatment, and the adequacy of surgical extirpation.

The thyroid C cells do not concentrate iodine, and reports of radioactive iodine treatment of metastatic MTC have indicated a lack of significant effect." Several reports have advocated the use of external beam radiation therapy for MTC.55-58 These retrospective studies involved small numbers of patients, and it is difficult to determine whether or not radiation treatment had a significant effect. Other studies have not supported the use of radiation therapy in MTC.23.24.59 In the report by Samaan and colleagues, 202 patients were studied retrospectively. Even though the authors believed that the characteristics of the two groups were comparable, it was found that the patients who received external beam radiation therapy had a worse outcome those who did not." A study from France in 1992 reported a series of 59 patients with MTC, all of whom received external beam radiation therapy to the neck and upper mediastinum after surgery.'" Of these 59 patients, 44 had positive nodes and 11 had residual tumor after surgery. After radiation therapy to a mean dose of 54 Gy, 18 patients (30%) experienced clinically evident local recurrences. Thirty-five patients were still alive (median follow-up, 65 months), and 24 had no clinical evidence of disease, although calcitonin levels were not available for all patients. These data indicate a high rate of clinically significant local recurrence, and without post-treatment calcitonin levels it is impossible to determine the actual response rate. Postradiation scarring, fibrosis, and vasculitis make further surgery for removal of metastatic deposits much more difficult and dangerous in the radiated patient. Further studies are needed to define the role of radiation therapy in this disease.

Chemotherapy In patients with advanced or metastatic MTC, chemotherapeutic regimens have not been extensively studied because of the relative rarity of the disease. Existing reports, however, have not shown any consistent benefit from either singleagent or combination chemotherapy regimens. Doxorubicin (Adriamycin) as a single agent was not noted to alter the progression ofMTC. 61A study of combination chemotherapy, using doxorubicin, cisplatin, and vindesine, resulted in one partial remission and three minor responses of 20 patients treated/? Another study used a combination of dacarbazine (dimethyl triazeno imidazole carboxamide, DTIC) and 5-fluorouracil (5_FU).61 In the five patients treated, there were three partial responses that lasted less than a year.63 In a study by Schlumberger and coworkers, combinations of 5-FU and streptozocin and 5-FU and dacarbazine were given alternately to 20 patients with metastatic MTC. Three partial responses and 11 long-term stabilizations were observed.P"

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The use of low-dose interferon-a was reported in two patients with MTC. 64,65 Both of these patients showed improvement in symptoms and in calcitonin level after treatment, Neither had a complete response, Juweid and colleagues reported the results of a phase I clinical trial in which 12 patients were treated with highdose 1311-MN-14F(abh anti-CEA monoclonal antibody combined with autologous hematopoietic stem cell rescue (AHSCR).66 Toxicity was acceptable, and one partial response was reported. Schott and coauthors reported treatment of seven patients with MTC by immunotherapy with calcitonin-pulsed dendritic cells."? One significant response was seen in this preliminary study. Chemoembolization of liver metastases from patients with MTC has been effective in reducing the size of lesions and in ameliorating symptoms (author, unpublished data). Studies with tyrosine kinase inhibitors have shown in vitro activity, and clinical trials to test these agents are under way.68-70

Localization of Persistent or Recurrent Medullary Thyroid Carcinoma Computed Tomography and Ultrasonography A number of methods have been used to localize residual or recurrent disease in patients with persistent or recurrent calcitonin elevation after surgery for MTC. Careful physical examination may reveal adenopathy in the jugular and paratracheal regions. Patients with advanced metastatic disease may acquire subcutaneous tumors of the trunk and extremities. Imaging studies that have been reported to be successful in localization include ultrasonography with fine-needle biopsy, computed tomography (CT) scanning, magnetic resonance imaging (MRI), selective venous catheterization (SVC), and nuclear imaging studies. Van Heerden and colleagues reported on high-resolution (lO-MHz) ultrasonography with ultrasound-guided fine-needle aspiration biopsy in patients with a negative clinical examination.P In a study of 47 patients with elevated calcitonin levels after primary surgery for MTC, Raue and associates evaluated ultrasonographic examination of the neck as well as physical examination, CT scan, SVC, fine-needle biopsy, and combinations of these modalities in localization of metastatic MTC.71 After reoperation in 14 patients, calcitonin levels were normalized in 2 patients. In a subsequent study they reported that SVC correctly localized tumor tissue in 89% of patients compared with 38% with CT scan and only 28% with ultrasonography."

Selective Venous Catheterization SVC facilitates detection of occult foci of metastatic MTC by determining basal or stimulated calcitonin levels in samples of venous blood drawn from sites in the neck, chest, and abdomen. This technique was used successfully by Norton and coworkers in seven patients." They reported that SVC correctly localized tumor to a surgically resectable

area of the neck in every case. In a study by Mrad and colleagues," localized disease in the neck was identified by SVC in six patients. In two patients the calcitonin levels were normal after operation guided by SVC data." In a study from France in 1994, SVC was performed in 19 patients, and calcitonin elevations suggestive of distant metastases were found in 5 patients." All five eventually acquired clinically apparent distant disease, recommending the usefulness of this technique in identifying distant metastases. In another series from Norway, elevated hepatic vein stimulated calcitonin levels were believed to indicate the presence of hepatic metastases. In this series, however, only three patients were demonstrated to have hepatic metastases by other means, and the significance of this finding is unclear," In our series, eight patients with hepatic vein calcitonin gradients were not found to have evidence of liver metastases by CT scanning and laparoscopy with liver biopsy." These patients underwent resection of metastatic MTC in the neck and two of the eight had subsequent normalization of stimulated calcitonin levels, indicating that the hepatic vein elevations may have been spurious. We no longer routinely use SVC in patients with occult MTC. The technique of SVC varies depending on the institution. At our institution, catheters are simultaneously placed in the right and left jugular veins and also in the left innominate vein and in a hepatic vein. Peripheral blood is drawn from a femoral catheter. After obtaining baseline values from these locations, a standard injection of calcium and pentagastrin is performed. Samples for calcitonin levels are drawn at I, 3, and 5 minutes from each of these locations. Values obtained are compared with simultaneously obtained baseline and stimulated peripheral values. Other authors do not use calciumpentagastrin stimulation during SVC but rather use sample basal levels from multiple sites in the neck, chest, and abdomen and determine gradients by comparing these with peripheral levels."

Nuclear Imaging Studies A number of different radiopharmaceuticals have been described to localize metastatic MTC. Thallium 201 (l0ITl) chloride and technetium 99m dimercaptosuccinic acid (99mTc DMSA) have been shown to be useful in evaluating hypercalcitoninemic patients. 78-8o Iodine 131 metaiodobenzylguanidine (MIBG) scintigraphy can be used to image MTC but is not consistent.v-" Octreotide scans with indium III CII In) have been used to localize metastatic disease, but these scans do not detect small liver metastases.Pv" Monoclonal anti-CEA antibodies labeled with iodine 131 ( 1311) or iodine 123 C231), 1111n, and 991l1Tc have been evaluated for localization of MTC. 85,86 Juweid and colleagues reported the largest series with 26 patients, but only 9 of those were identified as patients with occult disease.f'" Single-photon emission CT (SPECT) with labeled monoclonal anti-CEA antibodies was compared with ultrasonographic examination and CT scan, and in four of nine patients imaged metastatic foci were confirmed by operative results.f" The value of monoclonal antibodies in localization of occult MTC remains to be proved. Anticalcitonin monoclonal antibodies have also been evaluated in a small number of cases but have never gained broad attention."

Medullary Thyroid Carcinoma - -

In addition, studies have examined the imaging of cholecystokinin B receptors, which have been demonstrated in a high percentage of MTCs in vitro in patients with MTC. 90,91 Radioimmunoguided surgery is a technique designed to facilitate the intraoperative detection of metastases. After systemic administration of tumor-specific radiolabeled monoclonal antibodies, a hand-held gamma counter is used to scan the operative field. Areas of increased activity are explored, and soft tissue and nodes from these areas are resected. In five patients in whom immunoscintigraphy using an anti-CEA monoclonal antibody was applied, all previously identified metastases could be visualized. According to the authors, the technique detected tumor foci missed by intraoperative inspection and palpation in three of five patients. Radioimmunoguided surgery did not identify two small (10 mm x 10 rom) lesions that were resected and found to contain microscopic cancer." In a case report, intraoperative scanning after III In pentetreotide administration was used to localize metastatic sites. Plasma calcitonin levels fell remarkably after surgery but were not reduced to normal values.f Although these results are promising, surgical cures were not noted, and a compartment-oriented resection or observation may also be considered in asymptomatic patients." Fluorodeoxyglucose (FDG) positron emission tomography (PET) has been evaluated by our group in the staging of MTC. From January to December 1996, 10 consecutively treated patients (7 men and 3 women) with elevated serum calcitonin levels after primary operative treatment for MTC were included in the study. FDG-PET images were compared with CT and MRI images, and suspected metastatic foci were assessed by correlation with intraoperative and histopathologic findings.?" FDG-PET imaging proved to be more sensitive but less specific in detecting cervicomediastinal metastatic lesions compared with CT or MRI, respectively. Two patients with liver metastases detected by laparoscopy only, however, had no evidence of abnormal liver FDG uptake on PET imaging."

Diagnostic Laparoscopy MTC metastatic to the liver often has a miliary appearance, with multiple small (1 to 3 mm), white, raised nodules on the liver surface, which are easy to see with the laparoscope but may not be detected by CT scan, MRI, or other imaging techniques. We have routinely used diagnostic laparoscopy to look for liver metastases in patients with elevated calcitonin levels after primary surgery for MTC (Fig. 15-5).77 In a series of 41 patients, liver metastases were demonstrated in 8 patients, 7 of whom had negative CT imaging. In an update of this series, 136 patients had direct inspection of the liver by laparoscopy (126) or open procedure (10). Liver metastases were identified in 29 patients (21.3%).77

Surgical Treatment of Recurrent or Persistent Medullary Thyroid Cancer Because of the lack of success reported for other modalities in the treatment of persistent or recurrent MTC, surgical

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B FIGURE 15-5. A, Computed tomography (CT) of liver from patient with multiple endocrine neoplasia type 2A, recurrent medullary thyroid carcinoma (MTC), and elevated calcitonin levels. There is no evidence of liver metastases on the scan. B, Laparoscopic view of liver from the same patient showing multiple small raised whitish lesions on andjust beneath the surface of the liver, confirmed to be metastatic MTC by biopsy. These small, multiple metastases are often not seen with routine CT scanning or other imaging modalities, including nuclear scanning. (From Tung WS, Veseley TM, Moley IF. Laparoscopic detection of hepatic metastases in patients with residual or recurrent medullary thyroid cancer. Surgery 1995;118:1024.)

reintervention has been used by several groups to attempt to control the disease. MTC is often indolent and remains in the neck for long periods of time. It is possible that removal of residual or recurrent disease in the neck will result in cure in some cases and arrest the course of the disease in others. Several groups have reported their experience with reoperation for persistent or recurrent MTC in the neck.29.73.95.96 A significant reduction in stimulated calcitonin levels after reoperation was reported in many patients, and normalization of calcitonin levels was noted in some. In 1986, Tisell and colleagues reported a series of 11 MTC patients with persistent hypercalcitoninemia after previous apparently adequate surgery.97 Tisell performed what he called a "microdissection." This involves a meticulous dissection of all lymph node and fatty tissue of the central and lateral zones of the neck, including the thyroid bed, both recurrent nerves, and nodes in the lateral neck, extending from the level of the mastoid process down to the innominate vein and subclavian arteries and out laterally to the level of the

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spinal accessory nerve. In several cases, a median sternotomy and resection of upper mediastinal nodes were also performed. In this series, the calcitonin levels were normalized in four patients and significantly lowered in three. We reported two series of cervical reoperations for MTC: from 1990 to 1993 98 and from 1993 to 1996. 99 In the first series, 37 operations were done in 32 patients. The patients had previously undergone total thyroidectomy and most of the patients also had previous lymph node dissections. All patients had elevated stimulated calcitonin levels. Localization studies, including selected venous catheterization, CT scanning, and physical examination, were successful in localizing tumor in half the cases. Operative morbidity was low and there were no deaths. In 28 of the 35 operations, discharge from the hospital occurred 2 to 5 days postoperatively. In nine cases (group 1), calcitonin was reduced to undetectable levels following reoperation. In 13 cases (group 2), postoperative calcitonin levels were decreased by 40% or more. In 10 cases (group 3), postoperative calcitonin levels were not improved. Patients' sex, disease, number of nodes previously resected, preoperative calcitonin levels, and preoperative localization study results were not significantly different among the three groups and therefore unlikely to predict outcome for reoperation. Previously resected tumors from patients in group 3, however, were more likely to have demonstrated invasive features (invasion of adjacent structures, extranodal or extracapsular spread) than tumors from patients in groups 1 and 2 (P < .05, Fisher's exact test)." In this series, reoperation resulted in normalization of calcitonin levels in 28% of patients and a decrease in calcitonin levels by 40% or more in another 42% of patients. The results also suggested that determination of the degree of invasiveness of the primary tumor may help in selecting patients likely to benefit from reoperative surgery for recurrent medullary thyroid cancer. In the second series, we sought to improve our results through better selection of patients likely to benefit from

reoperation.?? This was achieved by obtaining a systematic metastatic work-up including routine staging laparoscopy, described earlier. One hundred and fifteen patients with persistent elevation of calcitonin after primary surgery for MTC were evaluated. After metastatic work-up, which revealed distant disease in 25% of these patients, and discussion of the options (including observation in patients without gross cervical disease), 52 patients elected to undergo cervical reoperation. Seven patients had paIliative procedures and 45 patients had cervical re-exploration with curative intent. In the seven patients who had paIliative cervical operations, one patient had persistent postoperative hypocalcemia. There were no other complications in that group. In the 45 patients who underwent reoperation with curative intent, there were no postoperative deaths and no transfusions were required. Complications included thoracic duct leak in four patients (8.9%) and hypocalcemia (2 patients [4%] at follow-up of 3 months and 2 years). Careful identification and exposure of the recurrent laryngeal nerves (RLNs) were done through a previously undissected area by the lateral, backdoor, or anterior approach. There were no permanent recurrent nerve injures."? In the 45 patients who had reoperation with curative intent, the mean decrease in postoperative stimulated calcitonin level was 73.1% (see Fig. 15-4). In 22 of 45 patients (48%), the postoperative stimulated calcitonin level dropped more than 90% compared with the preoperative value (Fig. 15-6). Seventeen (38%) had postoperative stimulated calcitonin levels that were within the normal range (group 1), and six (13%) had no significant decrease in stimulated calcitonin levels (group 3). The remaining patients had a greater than 35% reduction in stimulated calcitonin levels (group 2). As in our earlier series, tumor invasiveness was the only parameter correlated with failure to reduce postoperative calcitonin levels to the normal range (P < .05, Fisher's exact test)." These results indicate an improvement in outcome after reoperation for persistent or recurrent MTC. In the second

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30 20 10 0 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45

Patients

FIGURE 15-6. Postoperative change in peak stimulated calcitonin levels. The shaded bars indicate the postoperative stimulated calcitonin levels of the 45 patients who underwent curative cervical reexploration and dissection. The postoperative calcitonin level is expressed as a percentage of the preoperative calcitonin level. One hundred percent indicates no change in calcitonin level, and 10% indicates that the stimulated calcitonin level fell by 90%. 'Postoperative levels were higher than preoperative levels. (From Moley JF, DeBenedetti MK. Patterns of nodal metastases in palpable medullary thyroid carcinoma: Recommendations for extent of node dissection. Ann Surg 1999;229:880.)

Medullary Thyroid Carcinoma - -

series (1992 to 1996),38% (17 of 45) of patients had normal postoperative stimulated calcitonin levels, compared with 28% (9 0["32) in the first series. Only 13% (6 of 45) of patients had no decrease in calcitonin levels following reoperation, compared with 31% (10 of 32) in the first series (P = .07, Fisher's exact test). This improvement occurred through better preoperative selection of patients and the institution of routine laparoscopic liver examination preoperatively, which identified metastases in 10 patients, 9 of whom had normal CT or MR imaging of the liver and who would otherwise have undergone neck reoperation with curative intent. In this series of 115 patients, 24 decided not to have surgical intervention."? If a patient with elevated calcitonin levels has had an adequate previous operation and results of imaging studies are negative, an expectant approach with routine yearly screening is appropriate in many cases.P We do, however, believe that it is important to observe these patients closely with routine CT or MRI of the neck and chest. If central recurrence develops, resection prevents death from airway or great vessel invasion in some patients. Tumor debulking may afford some patients relief from symptoms caused by local disease in the neck or from tumor-induced flushing and diarrhea. We treated six patients with severe, disabling diarrhea who had preoperative stimulated calcitonin levels greater than 25 ng/mL, in whom surgery reduced calcitonin levels and abolished the diarrhea (author, unpublished results). These reports support the use of reoperation in patients with persistently elevated calcitonin levels after surgery for MTC. Although patients with highly invasive tumors are not as likely to benefit from this approach, these operations can be done safely in the majority of cases and may result in long-term survival benefit and prevention of recurrence complications in the neck. Long-term follow-up of these patients is needed to confirm the presumed benefit derived from these operations.

Summary and Conclusions MTC is a tumor of the thyroid C cells that occurs in sporadic and hereditary clinical settings. Measurement of plasma calcitonin is a sensitive marker for the presence of this tumor. Hereditary forms of MTC, including MEN 2A, MEN 2B, and FMTC, are associated with mutations in the RET protooncogene. Genetic testing can identify mutant gene carriers, and preventive thyroidectomy should be done in patients found to have inherited a mutant gene. Surgical treatment for palpable MTC is total thyroidectomy with central and lateral functional neck dissection. Recurrent or residual MTC may be localized by ultrasonography, CT scanning, MRI, nuclear scanning, or SVc. Reoperation with systematic node dissection in patients with localized or occult MTC and no evidence of distant metastases has resulted in normalization of calcitonin levels in a significant number of patients. Radiation and chemotherapy have not been shown to be consistently effective in the treatment of MTC, and the treatment of patients with widely metastatic disease is unsatisfactory. Clinical trials of newer chemotherapeutic agents may identify more effective regimens.

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53. Van Heerden 1, Grant CS, Gharib H, et aJ. Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg 1990;212:395. 54. Saad M, Guido 1, Samaan N. Radioactive iodine in the treatment of medullary carcinoma of the thyroid. 1 Clin Endocrinol Metab 1983;57:124. 55. Halnan K. The non-surgical treatment of thyroid cancer. Br 1 Surg 1975;62:769. 56. Brierley ID, Tsang RW. External radiation therapy in the treatment of thyroid malignancy. Endocrinol Metab Clin North Am 1996;25: 141. 57. Simpson W. Radiotherapy in thyroid cancer. Can Med Assoc 1 1975;113:115. 58. Steinfeld A. The role of radiation therapy in medullary carcinoma of the thyroid. Radiology 1977;123:745. 59. Williams E, Brown C, Doniach 1. Pathological and clinical findings in a series of 67 cases of medullary carcinoma of the thyroid. 1 Clin Pathol 1966;19:103. 60. Nguyen T, Chassard lL, Lagarde P, et al. Results of postoperative radiation therapy in medullary carcinoma of the thyroid: A retrospective study by the French Federation of Cancer Institutes-The Radiotherapy Cooperative Group. Radiother Oncol 1992;23:1. 61. Husain M, Alsever RN, Lock IP, et aJ. Failure of medullary carcinoma of the thyroid to respond to doxorubicin therapy. Horm Res 1978;9:22. 62. Scherubl H, Raue F, Ziegler R. Combination chemotherapy of advanced medullary and differentiated thyroid cancer. Phase II study. 1 Cancer Res Clin Oncol 1990;116:21. 63. Orlandi F, Caraci P, Berruti A, et aJ. Chemotherapy with dacarbazine and 5-fluorouracil in advanced medullary thyroid cancer. Ann Oncol 1994;5:763. 64. Schlumberger M, Abdelmoumene M, Delisle Ml, Couette IF. Treatment of advanced medullary thyroid cancer with an alternating combination of 5 FU-streptozocin and 5 FU-dacarbazine. Br 1 Cancer 1995;71:363. 65. Grohn P, Kumpulainen E, lakobsson M. Response of medullary thyroid cancer to low-dose alpha-interferon therapy. Acta Oncol 1990;29:950. 66. luweid ME, Hajjar G, Stein R, et aJ. Initial experience with high-dose radioimmunotherapy of metastatic medullary thyroid cancer using tJII-MN-14F(ab)2 anti-carcinoembryonic antigen MAb and AHSCR. 1 Nucl Med 2000;41 :93. 67. Schott M, Feldkamp 1, Klucken M, et aJ. Calcitonin-specific antitumor immunity in medullary thyroid carcinoma following dendritic cell vaccination. Cancer Immunolimmunother 2002;51 :663. 68. Cohen MS, Hussain HB, Moley IF. Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors. Surgery 2002; 132:960. 69. Carlomagno F, Vitagliano D, Guida T, et aJ. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 2002;62:7284. 70. Carlomagno F, Vitagliano D, Guida T, et aJ. The kinase inhibitor PPlblocks tumorigenesis induced by RET oncogenes. Cancer Res 2002;62: 1077. 71. Raue F, Winter 1, Frank-Raue K, et aJ. Diagnostic procedure before reoperation in patients with medullary thyroid carcinoma. Horm Metab Res Suppl 1989;21:31. 72. Frank-Raue K, Raue F, Buhr HI, et aJ. Localization of occult persisting medullary thyroid carcinoma before microsurgical reoperation: High sensitivity of selective venous catheterization. Thyroid 1992;2: 113. 73. Norton 1, Doppman 1, Brennan M. Localization and resection of clinically inapparent medullary carcinoma of the thyroid. Surgery 1980;87:616. 74. Mrad M, Gardet P, Roche A, et aJ. Value of venous catheterization and calcitonin studies in the treatment and management of clinically inapparent medullary thyroid cancer. Cancer 1989;63: 133. 75. Abdelmoumene N, Schlumberger M, Gardet P, et aJ. Selective venous sampling catheterisation for localisation of persisting medullary thyroid carcinoma. Br 1 Cancer 1994;69: 1141. 76. Gautvik KM, Talle K, Hager B, et aJ. Early liver metastases in patients with medullary carcinoma of the thyroid gland. Cancer 1989;63: 175. 77. Tung WS, Veseley TM, Moley IF. Laparoscopic detection of hepatic metastases in patients with residual or recurrent medullary thyroid cancer. Surgery 1995;118: 1024.

Medullary Thyroid Carcinoma - - 141 78. Bigsby RJ, Lepp EK, Litwin DE, et al. Technetium 99m pentavalent dimercaptosuccinic acid and thallium 20 I in detecting recurrent medullary carcinoma of the thyroid. Can J Surg 1992;35:388. 79. Ohnishi T, Noguchi S, Murakami N, et al. Detection of recurrent thyroid cancer: MR versus thallium-201 scintigraphy. AJNR Am J Neuroradiol 1993;14:105!. 80. Udelsman R, Ball D, Baylin SB, et al. Preoperative localization of occult medullary carcinoma of the thyroid gland with single-photon emission tomography dimercaptosuccinic acid. Surgery 1993;114:1083. 81. !toh H, Sugie K, Toyooka S, et al. Detection of metastatic medullary thyroid cancer with 1311-MIBG scans in Sipple's syndrome. Eur J Nucl Med 1986;11:502. 82. Skowsky WR, Wilf LH. Iodine 131 metaiodobenzylguanidine scintigraphy of medullary carcinoma of the thyroid (erratum in South Med J 1991;84:816, 937). South Med J 1991;84:636. 83. Kwekkeboom DJ, Reubi JC, Lamberts SW, et al. In vivo somatostatin receptor imaging in medullary thyroid carcinoma. J Clin Endocrinol Metab 1993;76:1413. 84. Krausz Y, Ish-Shalom S, Dejong RB, et al. Somatostatin-receptor imaging of medullary thyroid carcinoma. Clin Nucl Med 1994;19:416. 85. O'Byrne KJ, Hamilton D, Robinson I, et al. Imaging of medullary carcinoma of the thyroid using IIIIn-labeled anti-CEA monoclonal antibody fragments. Nucl Med Commun 1992;13:142. 86. Peltier P,Curtet C, Chatal JF, et al. Radioimmunodetection of medullary thyroid cancer using a bispecific anti-CEAlanti-indium-DTPA antibody and an indium-l l I-labeled DTPA dimer, J Nucl Med 1993;43:1267. 87. Juweid ME, Sharkey RM, Behr T, et al. Targeting and initial radioimmunotherapy of medullary thyroid carcinoma with 13lI-labeled monoclonal antibodies to carcinoembryonic antigen. Cancer Res 1995;55(Suppl):5946s. 88. Juweid M, Sharkey RM, Behr T, et al. Improved detection of medullary thyroid cancer with radio-labeled antibodies to carcinoembryonic antigen. J Clinical OncoI1996;14:1209.

89. Manil L, Boudet F, Motte P. Positive anticalcitonin immunoscintigraphy in patients with medullary thyroid carcinoma. Cancer Res 1989;49:5480. 90. Kwekkeboom DJ, Bakker WH, Kooij PP, et al. Cholecystokinin receptor imaging using octapeptide DTPA-CCK analogue in patients with medullary thyroid carcinoma. Eur J Nucl Med 2000;27:1312. 9!. Behr TM, Jenner N, Behe M, et al. Radiolabeled peptides for targeting cholecystokinin-B/gastrin receptor-expressing tumors. J Nucl Med 1999;40: 1029. 92. Waddington WA, Kettle AG, Heddle RM, Coakley AJ. Intraoperative localization of recurrent medullary carcinoma of the thyroid using indium-III pentetreotide and a nuclear surgical probe. Eur J Nuc1 Med 1994;21:363. 93. Musholt TJ, Moley JF. Management of persistent or recurrent medullary thyroid carcinoma. Prob Gen Surg 1997;14:89. 94. Musholt TJ, Musholt PB, Dehdashti F, Moley JF. Evaluation of tluorodeoxyglucose-positron emission tomographic scanning and its association with glucose transporter expression in medullary thyroid carcinoma and pheochromocytoma: A clinical and molecular study. Surgery 1997;122: 1049; discussion, 1060. 95. Block M, Jackson C, Tashjian A. Management of occult medullary thyroid carcinoma: Evidenced only by serum calcitonin level elevations after apparently adequate neck operations. Arch Surg 1992;113:368. 96. Buhr H, Kallinowski F, Raue F, et al. Microsurgical neck dissection for occultly metastasizing medullary thyroid carcinoma: Three year results. Cancer 1993;72:3685. 97. Tisell L, Hansson G, Jansson S, Salander H. Reoperation in the treatment of asymptomatic metastasizing medullary thyroid carcinoma. Surgery 1986;99:60. 98. Moley JF, Wells SA, Dilley WG, Tisell LE. Reoperation for recurrent or persistent medullary thyroid cancer. Surgery 1993;114:1090. 99. Moley J, Dilley W, DeBenedetti M. Improved results of cervical reoperation for medullary thyroid carcinoma. Ann Surg 1997;225:734.

Localization Tests in Patients with Thyroid Cancer Shiro Noguchi, MD, PhD, FJCS, FACE

Differentiated Thyroid Cancer of Follicular Cell Origin The minimal test for determining the diagnosis of a thyroid nodule is fine-needle aspiration cytology with or without ultrasonography. Use of these two tests enables one to discriminate benign from malignant thyroid tumors in about 85% of patients. The remaining 15% of thyroid malignancies are follicular cancer, Htirthle cell cancer, and some follicular variants of papillary thyroid cancer. Various imaging techniques are used for detecting regional and/or distant metastasis and identifying local invasion of adjacent structures.

Ultrasonography for Papillary Cancer Since the advent of high-resolution ultrasonography, it is sometimes possible to establish the diagnosis of papillary cancer with only ultrasonography, and fine-needle aspiration cytology is used to confirm the diagnosis.!:" Papillary cancer is most frequently thyroid cancer (""80%). The presence of calcification, irregular shape, absence of a halo and hypoechogenicity, and local invasion suggest it is a malignant nodule. Calcification is identified as multiple, small hyperecho genic spots in a hypoechogenic area (Figs. 16-1 and 16-2). They are usually due to superimposed psammoma bodies. Larger papillary thyroid cancers often degenerate, and complex cyst formation is common. These partially cystic areas are usually located at the peripheral part of the tumor (Fig. 16-3). A protrusion of solid tumor into the cyst can frequently be seen. Lymph node metastases or recurrence in lymph nodes is also identified with ultrasonography. Lymph nodes greater than 9 mm in diameter, those with a longitudinal-transverse diameter ratio of less than 2.0, and those with a round configuration are likely to contain metastatic cancer (Fig. 16-4).5.7 When one or more suspicious nodes are identified by ultrasonography, fine-needle aspiration cytology is usually recommended for confirmation of diagnosis. Ultrasonography is an accurate and sensitive localization test for diagnosing cervical metastases, but unfortunately it is

142

not useful for identifying metastases in the retroclavicular area and mediastinum. Thus, when serum thyroglobulin levels are increased, other localization tests are necessary, such as magnetic resonance imaging (MRI) or radioiodine whole-body scanning (WBS), the latter for the patient who has previously had a total or near-total thyroidectomy. The search for enlarged lymph node metastases in the neck has become easier because of ultrasonography; however, microscopic metastases are also present in about 80% of patients with papillary thyroid cancer who have no evident cervical metastases on clinical examination.f-? These small metastases mayor may not be visualized with ultrasonography." In patients with papillary thyroid cancer, the importance of nodal metastasis on survival is controversial. Some studies suggest that the presence of clinically evident lymph node metastases in patients with papillary and follicular cancer has an adverse effect on survival. 11·16 Extracapsular invasion of nodal metastases of thyroid cancer is associated with a poorer survival rate in patients with papillary microcarcinoma." Other studies suggest that lymph node metastases are associated with increased recurrence rate, but survival is not affected.":" Since cervical lymph node is the most frequent site for recurrent tumor, ultrasonography of the neck is helpful for the management of patients with papillary thyroid cancer.

Radioiodine Scintigraphy Iodine 131 ( 1311) is a favored scanning agent for following patients after total or near-total thyroidectomy for thyroid cancer of follicular cell origin because 1311 can be used therapeutically. Many studies have examined the sensitivity and specificity of a low dose (370 MBq, or lower) and high dose of 131 1 (2.9 GBq, 80 mCi, or more) for the detection of disease. 22. 34 The sensitivity ranges from 40% to 84% depending on the dose of 1311, the age of the patient, tumor differentiation, and tumor location. The specificity is high and the range is narrow, from 90% to 100% (Fig. 16-5). The sensitivity for detecting lung metastases is reported to vary from 42% to 60%, and for bone metastasis it varies from

Localization Tests in Patients with Thyroid Cancer - -

143

ultrasonography, 18F-2-fluoro-2-deoxY-D-glucose positronemission tomography (FDG-PET), or Tc 99m sestamibi are often used alone or in combination to document the presence and site of persistent or recurrent disease. 1231 is a pure lower energy (l59-keV) gamma emitter, whereas 131 1 is a high-energy (364-keV) gamma and beta emitter. 1231has better resolution imaging properties than 131 I because 1231 does not emit beta particles; therefore, a larger dose of 1231 can be administered with a lower risk of stunning, which reduces subsequent therapeutic efficacy." Image quality after radioiodine administration is good in terms of resolution and low background at 24 hours. The recommended dose of 1231 is 56 MBq; there is little incremental advantage of sensitivity after scanning using larger doses. The concordance with 131 1 is almost identical with post-therapy scan.37.38 The overall sensitivity of 1231 is 93% when compared with 1311.

Scintigraphy with Alternative Nucleotides THALLIUM 201 CHLORIDE

B FIGURE 16-1. Papillary cancer. A and B, Many small hyperechoic spots are seen in the hypoechoic region.

54% to 60%.26,35 The sensitivity for detecting lymph node metastasis is only about 22%26; luckily, ultrasonography, computed tomography (CT), MRI, Tc 99m sestamibi, and thallium can usually detect cervical lymph node metastases. The sensitivity may change depending on the definition of tumor presence. Serum thyroglobulin levels, 20lTI scan, neck

Thallium 201 eOIT!) was first used in the early 1980s for detecting metastases from both well-differentiated thyroid cancer and recurrent medullary cancer in 1980s.39. 44 It accumulates in the tumor and gives a positive image by contrasting with the negative image by radioiodine and remains in the tumor longer than it does in normal thyroid (Fig. 16-6). Tc 99m sestamibi became available around 1987, and many investigators compared the results of 20lTI scintigraphy to Tc 99m sestamibi. Although these two imaging isotopes gave comparable results, Tc 99m sestamibi results were slightly better and clearer than those with 20lTI in patients with differentiated thyroid cancer.45,46 For patients with medullary cancer 99mTc(V)-dimercaptosuccinic acid (Tc 99m DMSA) appeared to be somewhat more accurate than 20lTI for routine clinical use." 20lTI imaging is most useful after total or near-total thyroidectomy and 131 1 ablative therapy in patients with rising or elevated serum thyroglobulin levels. In addition, about 10% of hypothyroid patients with verified thyroid cancer and positive 20lTI scan have a low serum thyroglobulin leve1. 48,49 20lTI imaging has an additional advantage in that it can be done in the patients who are

FIGURE 16-2. Papillary cancer. Arrow I, right carotid artery; arrow 2, primary tumor; arrow 3, trachea; arrow 4, esophagus; and arrow 5, left carotid artery.

1

2

3

4

5

144 - -

Thyroid Gland

negative 131 1 scan in a patient with an elevated serum thyroglobulin level. 28,49 20lTI scanning is helpful for detecting cervicomediastinal nodal metastases but is not accurate for detecting a normal thyroid remnant or pulmonary metastasis. Overall, 20lTI is the most commonly used radioactive pharmaceuticals for patients with thyroid cancer, other than 1311. TECHNETIUM 99M SESTAMIBI

FIGURE 16-3. Papillary thyroid cancer with cystic degeneration.

receivmg thyroid hormone. Discontinuation of thyroid hormone medication stimulates increased thyroid-stimulating hormone (TSH) secretion, which can stimulate thyroid tumor uptake of radioiodine and tumor growth. Imaging with 20lTI also requires only one visit, in contrast with scanning with 131 1 using human recombinant TSH, which requires several visits. The sensitivities reported for 20lTI vary depending on the dose of 20lTI and the timing of imaging after injection of the isotope. When imaging is done 15 to 20 minutes after injection, sensitivities ranging from 74% to 94% have been reported.23.27.50 Reported specificities range from 84% to 97%.27,49 In a large retrospective series including 326 patients, 20lTI scintigraphy demonstrated abnormal findings in 39 patients who had negative 131 1 studies." Among these patients, 26 were confirmed histologically and 5 radiologically, and 8 had no definite confirmation. The sensitivity was 94% and the specificity was 98%. There is a large discordance between 20lTI and 131 1 studies in patients with remaining normal thyroid tissue, because the sensitivity oeolTI is poor when normal thyroid remains, whereas 131 1 uptake is high in this tissue.t' After ablation with 1311, 20lTI has a sensitivity of 94% and a specificity of 96%.23 The sensitivity of 20lTI is equivalent or superior to low-dose 131 1 but less sensitive than high-dose 1311. 20lTI is particularly useful in the setting of a

Scanning with Tc 99m sestamibi in thyroid cancer patients has been compared to radioiodine." with 201TI,45 with Tc 99m terrofosmin, and with MRI.52 Tc 99m sestamibi, like 20ITI, does not require discontinuing thyroid hormone and requires only one visit. This is an advantage of Tc 99m sestamibi over 1311. Imaging with non iodine radiopharmaceuticals is independent of TSH stimulation, but TSH stimulation improve the quality of images. Contemporary gamma cameras are optimized for imaging at the emission energy of 99mTc (140 keY) rather than much higher emission energies of 1311 (364 keY) or the lower emission energy of 20lTI (69 to 81 keY). Tc 99m sestamibi has the advantage of the availability of a kit-based radiopharmaceutical with same-day imaging. The other advantage ofTc 99m sestamibi over 20lTI is a short physical half-life of 6 hours, whereas 20lTI has a physical half-life of 73 hours. Therefore, Tc 99m sestamibi can be administered in a larger dose (20 to 25 mCi), resulting in better images and lower radiation exposure to the patient.

Invasion of Papillary Cancer to Adjacent Organs Involvement of the recurrent laryngeal nerve by tumor cannot be determined preoperatively unless vocal cord palsy is evident on direct laryngoscopy. However, the size and position of the primary tumor provide some information. Among our 3148 patients with papillary thyroid cancer larger than 10 mm in maximum dimension, there was a direct correlation between adhesion/invasion of the recurrent laryngeal nerve. Thus, involvement occurred in 9.2% of tumors 10 to 14 mm, 17.3% of tumors 15 to 24 mm, and 33.0% of tumor more than 25 mm in maximum diameter. Using the same size criteria, as determined by frozen section, invasion/adhesion occurred within the esophagus in 2.7%,9.2%, and 21.4%. respectively. CT, MR!, conventional esophagography, and esophagoscopy may help predict the

FIGURE 16-4. Lymph node metastasis

with calcification (A) and with cystic degeneration (B).

A

B

Localization Tests in Patients with Thyroid Cancer - - 145

A

c

FIGURE 16-5. Lung metastases. A, With conventional chest radiograph, no metastases were seen. B, With high-dose 1311

scintigraphy, extensive metastases were shown. C, With helical CT,multiple small shadows of metastases wereseen in one patient.

B

presence of invasion of thyroid cancer into the esophagus; however, these modalities are insufficient for a precise diagnosis and determination of exact depth of invasion. Recently, endoscopic ultrasonography was reported to be superior to MRI and esophogography in terms of accuracy and specificity regarding esophageal invasion." Invasion of the trachea is also difficult to determine preoperatively. Using the same size criteria, adhesion/invasion to the trachea was observed in 17%, 29%, and 40%, respectively; however, when the tumor was close to Berry's ligament, it

was hard to differentiate. These figures therefore could be an overestimation. Tumor size is a well-known predictor of tumor behavior. 54•55 MRI helps determine extent of tracheal invasion. Characteristic findings include a soft tissue signal in the tracheal cartilage, intraluminal mass, and degree of tumor circumference around the trachea abutting 180 degrees or more.>' An anterior part of the trachea is most likely to be invaded by thyroid cancer in primary cases; however, in cases of recurrence, invasion can occur in any part of the trachea. Endoscopic documentation of

146 - - Thyroid Gland

A

B

FIGURE 16-6. Thallium scan, showing early image (A) and delayed image (B). The arrow in B indicates tumor localization.

laryngotracheal invasion was recently reported. The major findings included mucous membrane swelling, dilated capillaries, localized reddening, localized swelling, edema, and erosion (Fig. 16-7). Intraluminal tumor is rare." When these findings are present, resection of a part of the trachea followed by end-to-end anastomosis or partial resection with preservation of the recurrent laryngeal nerve is recommended rather than shaving the tumor off the surface of the trachea.T"

A

B

c

D

Follow-Up of Patients Who Lost Differentiation Markers Although the serum thyroglobulin level is the most sensitive and useful marker for follow-up of patients with differentiated thyroid cancer, especially in patients after total thyroidectomy, in some patients serum basal thyroglobulin levels are not increased and fail to increase when TSH levels are increased. Thyroglobulin in this small group does not

FIGURE 16-7. A, Stage I thyroid cancer that extended through the capsule of the thyroid gland and abutted the external perichondrium. B, Stage 2 thyroid cancer that invaded between the rings of cartilage or destroyed the cartilage. C, Stage 3 thyroid cancer that extended through the cartilage or between the cartilaginous plates into the lamina propria of the tracheal mucosa. D, Stage 4 thyroid cancer that extended through the entire thickness of and expanded the tracheal mucosa.

Localization Tests in Patients with Thyroid Cancer - - 147 serve as a useful marker for recurrence. Some thyroid cancers also dedifferentiate, particularly with advanced disease and age. 131 1 ablation is less effective in these patients. 7,45,48,52,59-61 Since the most common site of recurrence is in the neck lymph nodes, ultrasonography would be selected first for local disease and 20lTI or Tc 99m sestamibi for WBS. For lung metastases with small miliary foci, helical CT is better than WBS. External-beam radiation can be helpful for treatment of high-risk patients with persistent or recurrent disease. Redifferentiation with retinoic acid and other agents may be helpful.F

Image Diagnosis of Medullary Cancer All patients with a preoperative diagnosis of medullary cancer of the thyroid should be tested for a ret protooncogene germline point mutation and also be screened for pheochromocytoma and hyperparathyroidism (see other chapters regarding medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism). Medullary cancer secretes calcitonin and carcinoembryonic antigen (CEA) and occasionally neuron-specific enolase, serotonin, chromogranin, gastrin-releasing peptide, substance P, pro-opiomelanocortin-derived products, and somatostatin. Among them, calcitonin and CEA are used as tumor markers for following patients for persistent disease or recurrent disease. Calcitonin is the most sensitive biochemical marker for predicting the presence of tumor. A steep slope with rapidly rising CEA levels indicates that the patients have rapidly progressive tumor. A normal CEA level or a flat slope indicates that patients may be cured or they have only slowly progressive disease.63,64 Decrease of the calcitonin/CEA ratio indicates dedifferentiation of medullary thyroid cancer.

Ultrasonography Medullary cancer is a considerably rare disease, constituting only 4% to 9% of all thyroid cancers. Ultrasonography is the most recommended helpful modality for detecting primary tumor as well as localizing cervical metastases in the central or lateral neck nodes, particularly those associated with multiple endocrine neoplasia (MEN) type 2A. Ultrasonography is superior to radionucleotide scanning for detecting

cancer foci within the thyroid or in the cervical lymph nodes. One can identify primary tumors as small as 3 mm by high-resolution ultrasonography. Lymph node metastases are common in patients with MEN 2A and familial medullary cancer. Pathologic examinations of the lymph nodes during primary staging revealed cervical lymph node involvement in 31% to 33% of the p'I'I cases,65.66 in 53% of the pT2 cases." and in 100% of the pT3 and pT4 patients. Ultrasonographic features include hypoechoic nodules with disseminated or focal echogenic calcifications that may cast an acoustic shadow and smooth or irregular delimited nodules with pseudopod-like projections (Fig. 16-8). These features are found both in primary tumors as well as in lymph node metastases. Since these ultrasonographic findings are nonspecific and may be present in adenomatous nodular goiters, one should interpret the ultrasonographic findings with the serum calcitonin levels.67,68 Serum calcitonin levels are highly specific for medullary thyroid cancer and are helpful for both preoperative planning and postoperative evaluation. Most patients with mild increases in calcitonin have metastatic tumors only in the cervical lymph nodes. Some of these metastatic nodes are too small to detect by palpation but may be detected by ultrasound scanning. Ultrasonography therefore is the first choice as a localization test. It is inexpensive and there is no radiation hazard. An experienced ultrasonographer, however, is essential for good results.

MmG Three years after the advent of 1321-metaiodobenzylguanidine (MIBG) as an imaging agent for pheochromocytomata.v? it was noted that some medullary thyroid cancers also could be identified by MIBG scanning. This is also true for metastases.?? From these observations it was expected that MIBG might be a helpful therapeutic agent." Unfortunately, due to the poor sensitivity of MIBG scintigraphy in medullary thyroid cancer, this agent is not suitable for initial diagnosis but can be used when internal radiation therapy with 1311-MIBG is planned. 1311-MIBG has been used for treatment of pheochromocytoma, paraganglioma, and medullary cancer when MIBG scanning is positive. Symptomatic control was achieved in all patients treated with 1311-MIBG alone, including hormonal improvement and tumor regression or stabilization in patients with

FIGURE 16-8. Calcification of medullary thyroid cancer (A) and of part of a multinodular goiter (B).

A

B

148 - -

Thyroid Gland

metastatic tumors with minimal adverse effects." Also, in many other articles, no important adverse effect is mentioned.Y" However, in one article, a patient with metastatic pheochromocytoma to the lung, liver, and paraaortic lymph node was treated with 3.7 GBq (100 mCi) of 1311_MIBG. The metastatic nodes in the lung and liver disappeared, and the secretion of catecholamine levels decreased to normal. Major but temporary untoward responses were hypertension and hyperglycemia."

Anti-CEA Monoclonal Antibody Medullary cancer contains and secretes CEA as well as calcitonin. 1311-labeled or 1llln-labeled CEA unfortunately detects only relatively large metastases (> 10 mrn'') as occurred in 5 of II patients with medullary thyroid cancer.s" Initially, radiolabeled CEA monoclonal antibodies were reported to be specific but not very sensitive. Subsequent investigation demonstrated nonspecific uptake of radiolabeled CEA in the spleen, kidneys, bone marrow, and liver, presumably due to the poor specificity of the antibody that was used." Hoefnagel," Zanin.t' and their associates suggested that 1311-labeled monoclonal antibody might be used therapeutically in patients with medullary thyroid cancer. In 1997, Juweid and colleagues'" reported that anti-CEA monoclonal antibodies were excellent agents for imaging recurrent, residual, or metastatic medullary thyroid cancer. The high lesion sensitivity in patients with known lesions, combined with the ability to detect disease, may make these agents ideal for staging patients, monitoring disease preoperatively or postoperatively, and especially for evaluating patients with recurrent or persistent elevated calcitonin or CEA levels after primary surgery." Sensitivity of anti-CEA radiolabeled antibody technique seems to be dependent on the quality of monoclonal antibody.P Combined therapy using 1311-labeled CEA with conventional chemotherapy of medullary thyroid cancer has been reported in animals.f" Behr and coworkers reported that 30 patients with smallvolume metastatic colorectal cancers have been treated with 13 'Llabeled anti-CEA as an adjuvant setting."

99mTc(V)-Dimercaptosuccinic Acid and Somatostatin Analog Ohta and associates first reported the use of DMSA for imaging medullary cancer of the thyroid in 1984. 88 Four patients with medullary cancer showed clear and specific tumor uptake in primary and/or metastatic foci. DMSA uptake was subsequently noted in the nasopharynx, axial skeleton, breast, liver, spleen, heart, kidney, urinary bladder, great vessels, and skeletal muscles." There was no DMSA uptake in the male breast. Positive uptake was seen in only one of three subjects younger than 15 years of age, in 16 of 23 patients (70%) between 15 and 50, and in 7 of 25 (28%) older than 50. 90 The overall sensitivity of DMSA ranged from 57% to 95%.91-96 The differences in sensitivity may depend on the method of preparing pentavalent DMSA since the pH of the mixture has to be high (7.5) for highest activity. When the pH is low, trivalent DMSA is synthesized, which makes DMSA sensitivity low.?? Unfortunately, most subsequent studies have not found DMSA to be sensitive

enough to recommend it for routine use in patients with medullary thyroid cancer. Kwekkeboom and colleagues'" have reported tumor localization in 11 of 17 patients (65%) with 1llln-octreotide with medullary thyroid cancer. They reported that neither serum calcitonin nor CEA levels differed significantly between patients whose tumor accumulated labeled octreotide in vivo and those tumors that did not. Numerous authors have subsequently presented their experience using octreotide scintigraphy for the localization of recurrent medullary cancer.99-107 When somatostatin scintigraphy was compared with MRI scanning in nine patients, the same 17 lesions were seen by both methods; however, 13 additional suspicious lesions were seen with somatostatin scintigraphy. Histologic confirmation was available from 19 metastases; MRI was positive in 13 (68%) and somatostatin receptor scintigraphy was positive in 18 (95%).99.100 Comparison of 1llln-octreotide and DMSA has also been done. Three papers concluded that octreotide is superior; however, the sensitivity of DMSA is relatively IOW. 91,1 02.108 Another investigation suggests that both 1111n and DMSA are relatively that insensitive. 103

Imaging of Metastases of Thyroid Cancer with Fluorine 18 Fluorodeoxyglucose FDG is a o-glucose analog, which is converted in cells to FDG-6-phosphate by hexokinase. FDG-6-phosphate is metabolically trapped and accumulates in tissue where glucose-6-phosphatase is lacking. Metabolic trapping is the key factor responsible for the biodistribution of 18F-2-deoxyglucose.109 Because other enzymes that act on glucose-6-phosphate have only a negligible affinity for FDG-6-phosphate and membrane permeability is low, the rate of accumulation of FDG-6-phosphate is proportional to the phosphorylation rate of exogenous glucose and o-glucose utilization of the tissue. 18F has a half-life of about 109 minutes, so that the patient is exposed to a tolerable amount of radiation. 110 FDG-PET is primarily used to localize recurrent differentiated and poorly differentiated thyroid cancers, especially in patients who are serum thyroglobulin positive and 131 1 WBS negative. Serum thyroglobulin determination and diagnostic 131 1 WBS provide the diagnosis of recurrent disease. Recurrent differentiated thyroid cancer mayor may not take up radioiodine. III A patient whose recurrent tumor is detected by radioiodine scanning has a significantly better prognosis than does a patient whose tumor does not take up 131I.ll2 FDG-PET can be positive in the same site as a WBS-positive site or WBS-negative site, or both can be present in the same patient. Grunwald and associates 113 reported that FDG-PET was particularly useful in WBSnegative patients, showing a high sensitivity of 85%. Patients with poorly differentiated thyroid cancers were more likely to be WBS negative and FDG-PET positive. Those patients also have a worse prognosis-FDG-PET helps stage the disease and guide treatment strategy. Possible therapeutic strategies include surgery, external-beam radiation, and redifferentiation therapy.Uv'!? Patients who

Localization Tests in Patients with Thyroid Cancer - - 149 are WBS positive and FDG-PET negative usually respond better to treatment with 1311. The result obtained from FDG-PET scanning may influence therapy; for example, the removal of mediastinum lymph node metastases usually should be omitted when additional distant metastases are detected by FDG-PET scan in 131 1 scan-negative patients. The benefit of further radioiodine therapy in thyroglobulin-positive 1311 scan-negative patients is controversial. Correlation between the grade of differentiation and the rate of detectability with FDG-PET and MIBI or WBS exists. Since glucose metabolism is increased particularly in poorly differentiated tumors, a higher sensitivity of FDGPET can be expected in these tumors, in association with a low sensitivity ofWBS.118-123 Metastases showing high FDG uptake but low 131 1 uptake often grow more rapidly and are generally more aggressive.l" A higher mortality rate in patients who have a negative WBS (with or without elevated thyroglobulin levels) in spite of proven metastases has also been reported.l" Grunwald and coworkersl-" reported a higher rate of positive FDG-PET scans in patients with highrisk patients by TNM staging. Thus, positive FDG-PET scans were observed in 2 of 14 patients (14%) with pTl/pT2 tumor stage versus 8 of 17 patients (47%) with pT3/pT4 tumors. Higher tumor stage correlates with a poorer prognosis. Positive FDG-PET scans also occur in patients with sarcoidosis.l" granulomas.I" parathyroid tumors.!" Hiirthle cell adenomas.F' follicular adenomas, and adenomatous goiters.F" FDG-PET scanning can detect metastases in lymph nodes less than 1 em in diameter. 123 Small pulmonary metastases «I em), with or without radioiodine uptake, were not detected by FDG-PET but were detected by spiral CT scanning.123.124

Conclusion Localization tests are helpful for documenting metastases in patients with thyroid cancer. Ultrasonography is recommended for cervical nodal metastases, spiral CT for pulmonary metastases, and FDG-PET scans for patients with poorly differentiated thyroid cancers and for thyroglobulin-positive, WBS-negative patients. Radioiodine scans are positive in about 75% of patients with metastases. Radioiodine scans require a previous total or near-total thyroidectomy. 131} can be used for ablative therapy. Sestamibi, thallium, DSMA, and octreotide scans are occasionally helpful but are not sensitive enough to be recommended for routine use in the follow-up of most patients.

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Localization Tests in Patients with Thyroid Cancer - - 151 80. Lumbroso J, Berche C, Mach JP, et al. [Use of tomographic scintigraphy with radiolabeled monoelonal antibodies for detecting human digestive cancers and medullary cancers of the thyroid]. Bull Cancer 1983;70:96. 81. O'Byrne KJ, Hamilton D, Robinson I, et al. Imaging of medullary carcinoma of the thyroid using 1IlIn-labelled anti-CEA monoelonal antibody fragments. Nuel Med Commun 1992;13: 142. 82. Hoefnagel CA, Delprat CC, Zanin D, van der Schoot JB. New radionuclide tracers for the diagnosis and therapy of medullary thyroid carcinoma. Clin Nuel Med 1988;13:159. 83. Zanin DE, van Dongen A, Hoefnagel CA, Bruning PE Radioimmunoscintigraphy using iodine-I 3 I-anti-CEA monoelonal antibodies and thallium-201 scintigraphy in medullary thyroid carcinoma: A case report. J Nuel Med 1990;31:1854. 84. Juweid M, Sharkey RM, Swayne LC, Goldenberg DM. Improved selection of patients for reoperation for medullary thyroid cancer by imaging with radiolabeled anticarcinoembryonic antigen antibodies. Surgery 1997;122:1156. 85. Juweid M, Sharkey RM, Behr T, et al. Improved detection of medullary thyroid cancer with radiolabeled antibodies to carcinoembryonic antigen. J Clin OncoI1996;14:1209. 86. Stein R, Chen S, Reed L, et al. Combining radioimmunotherapy and chemotherapy for treatment of medullary thyroid carcinoma: Effectiveness of dacarbazine. Cancer 2002;94:5 I. 87. Behr TM, Liersch T, Greiner-Bechert L, et al. Radioimmunotherapy of small-volume disease of metastatic colorectal cancer. Cancer 2002;94: 1373. 88. Ohta H, Yamamoto K, Endo K, et aJ. A new imaging agent for medullary carcinoma of the thyroid. J Nuel Med 1984;25:323. 89. Udelsman R, Ball D, Baylin SB, et al. Preoperative localization of occult medullary carcinoma of the thyroid gland with single-photon emission tomography dimercaptosuccinic acid. Surgery 1993;114:1083. 90. Nakamoto Y, Sakahara H, Kobayashi H, et aJ. Technetium-99m (V)-dimercaptosuccinic acid: Normal accumulation in the breasts. Eur J Nuel Med 1997;24: 1146. 91. Arslan N, Ilgan S, Yuksel D, et al. Comparison of In-Ill octreotide and Tc-99m(V)DMSA scintigraphy in the detection of medullary thyroid tumor foci in patients with elevated levels of tumor markers after surgery. Clin Nuel Med 2001 ;26:683. 92. Adams S, Baum RP, Hertel A, et aJ. Comparison of metabolic and receptor imaging in recurrent medullary thyroid carcinoma with histopathological findings. Eur J Nuel Med 1998;25:1277. 93. Kujat C, Neidl K, Muller-Leisse C. [Medullary carcinoma of the thyroid and 99mTc(V)-DMSAscintigraphy: Clinical results with a new radiopharmaceutical]. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1990;153:495. 94. Clarke SE, Lazarus C, Mistry R, Maisey MN, The role of technetium99m pentavalent DMSA in the management of patients with medullary carcinoma of the thyroid. Br J Radiol 1987;60: 1089. 95. Clarke S, Lazarus C, Maisey M. Experience in imaging medullary thyroid carcinoma using 99mTc(V)dimercaptosuccinic acid (DMSA). Henry Ford Hosp Med J 1989;37:167. 96. Guerra UP, Pizzocaro C, Terzi A, et al. New tracers for the imaging of the medullary thyroid carcinoma. Nuel Med Commun 1989;10:285. 97. Hirano T, Tomiyoshi K, Zhang YJ, et aJ. Preparation and elinical evaluation of technetium-99m dimercaptosuccinic acid for tumour scintigraphy. EurJ Nuel Med 1994;21:82. 98. Kwekkeboom DJ, Reubi JC, Lamberts SW, et al. In vivo somatostatin receptor imaging in medullary thyroid carcinoma. J Clin Endocrinol Metab 1993;76:1413. 99. Dorr U, Frank-Raue K, Raue F, et al. The potential value of somatostatin receptor scintigraphy in medullary thyroid carcinoma. Nuel Med Commun 1993;14:439. 100. Dorr U, Wurstlin S, Frank-Raue K, et al. Somatostatin receptor scintigraphy and magnetic resonance imaging in recurrent medullary thyroid carcinoma: A comparative study. Horm Metab Res SuppI1993;27:48. 101. Frank-Raue K, Bihl H, Dorr U, et al. Somatostatin receptor imaging in persistent medullary thyroid carcinoma. Clin Endocrinol (Oxf) 1995;42:31. 102. Eising EG, Farahati J, Bier D, et al. [Somatostatin receptor scintigraphy in medullary thyroid carcinomas, GEP and carcinoid tumors]. Nuklearmedizin 1995;34:1. 103. Bema L, Cabezas R, Mora J, et al. 11IIn-octreotide and 99mTc(V)_ dimercaptosuccinic acid studies in the imaging of recurrent medullary thyroid carcinoma. J Endocrinol 1995;144:339.

104. Baudin E, Lumbroso J, Schlumberger M, et al. Comparison of octreotide scintigraphy and conventional imaging in medullary thyroid carcinoma. J Nuel Med 1996;37:912. 105. O'Byrne KJ, O'Hare N, Sweeney E, et al. Somatostatin and somatostatin analogues in medullary thyroid carcinoma. Nuel Med Commun 1996;17:810. 106. Behr TM, Gratz S, Markus PM, et al. Anti-carcinoembryonic antigen antibodies versus somatostatin analogs in the detection of metastatic medullary thyroid carcinoma: Are carcinoembryonic antigen and somatostatin receptor expression prognostic factors? Cancer 1997;80:2436. 107. Tisell LE, Ahlman H, Wangberg B, et al. Somatostatin receptor scintigraphy in medullary thyroid carcinoma. Br J Surg 1997;84:543. 108. Celentano L, Sullo P, Klain M, et al. II I In-pentetreotide scintigraphy in the post-thyroidectomy follow-up of patients with medullary thyroid carcinoma. Q J Nuel Med 1995;39: 13 I. 109. Gallagher BM, Fowler JS, Gutterson NI, et al. Metabolic trapping as a principle of radiopharmaceutical design: Some factors responsible for the biodistribution of [1 8F]2-deoxy-2-fluoro-o-glucose. J Nuel Med 1978;19:1154. 110. Jones SC, Alavi A, Christman D, et al. The radiation dosimetry of 2 [F-18]fluoro-2-deoxy-o-glucose in man. J Nuel Med 1982;23:613. III. Schlumberger MJ, Incerti C, Pacini F, Reiners C. The role of recombinant thyroid-stimulating hormone (rhTSH) in the detection and management of well-differentiated thyroid carcinoma: A roundtable discussion. J Endocrinol Invest 1999;22:35. 112. Coburn M, Teates D, Wanebo HI. Recurrent thyroid cancer: Role of surgery versus radioactive iodine (' 311). Ann Surg 1994;219:587. 113. Grunwald F, Briele B, Biersack HJ. Non-P'Lscintigraphy in the treatment and follow-up of thyroid cancer: Single-photon-emitters or FDG-PET? Q J Nuel Med 1999;43:195. 114. Lerch H, Schober 0, Kuwert T, Saur HB. Survival of differentiated thyroid carcinoma studied in 500 patients. J Clin Oncol 1997;15:2067. 115. Farahati J, Reiners C, Stuschke M, et al. Differentiated thyroid cancer: Impact of adjuvant external radiotherapy in patients with perithyroidal tumor infiltration (stage pT4). Cancer 1996;77: 172. 116. Grunwald F, Menzel C, Bender H, et al. Redifferentiation therapyinduced radioiodine uptake in thyroid cancer. J Nuel Med 1998;39:1903. 117. Grunwald F, Pakos E, Bender H, et al. Redifferentiation therapy with retinoic acid in follicular thyroid cancer. J Nuel Med 1998;39: 1555. 118. Joensuu H, Ahonen A. Imaging of metastases of thyroid carcinoma with fluorine-18 fluorodeoxyglucose. J Nuel Med 1987;28:910. 119. Sisson JC, Ackermann RJ, Meyer MA, Wahl RL. Uptake of 18-fluoro-2-deoxy-o-glucose by thyroid cancer: Implications for diagnosis and therapy. J Clin Endocrinol Metab 1993;77:1090. 120. Fridrich L, Messa C, Landoni C, et al. Whole-body scintigraphy with 99Tcm-MIBI, 18F-FDG and 131 1 in patients with metastatic thyroid carcinoma. Nuel Med Commun 1997;18:3. 121. Feine U, Lietzenmayer R, Hanke JP, et al. [18FDG whole-body PET in differentiated thyroid carcinoma: Flipflop in uptake patterns of 18FDGand 131 1]. Nuklearmedizin 1995;34:127. 122. Gasparoni P, Rubello D, Ferlin G. Potential role of fluorine18-deoxyglucose (FDG) positron emission tomography (PET) in the staging of primitive and recurrent medullary thyroid carcinoma. J Endocrinol Invest 1997;20:527. 123. Dietlein M, Scheidhauer K, Voth E, et aJ. Fluorine-18 fluorodeoxyglucose positron-emission tomography and iodine-131 whole-body scintigraphy in the follow-up of differentiated thyroid cancer. Eur J Nucl Med 1997;24:1342. 124. Grunwald F, Schomburg A, Bender H, et al. Fluorine-18 fluorodeoxyglucose positron-emission tomography in the follow-up of differentiated thyroid cancer. Eur J Nuel Med 1996;23:312. 125. Platz D, Lubeck M, Beyer W. Einsatz der [18F]-deoxyglukose-PET in der Nachsorge von Patienten mit differenziertem und medullaren Schilddruesenkarzinom. Nuklearmedizin 1995;34: 152A. 126. Arslan N, Rydzewski B. Detection of a recurrent parathyroid carcinoma with FDG positron-emission tomography. Clin Nuel Med 2002;27:221. 127. Wiesner W, Engel H, von Schulthess GK, et al. FDG-PET-negative liver metastases of a malignant melanoma and FDG-PET-positive Hiirthle cell tumor of the thyroid. Eur Radiol 1999;9:975. 128. Adler LP, Bloom AD. Positron-emission tomography of thyroid masses. Thyroid 1993;3:195.

Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases Paolo Miccoli, MD • Furia Pacini, MD

Patients with distant metastases from differentiated thyroid carcinoma present an important therapeutic challenge. Among our nearly 3000 patients with thyroid cancer, 12.4% had distant metastases. J Similar percentages have been reported in other large series.>? Distant metastases, particularly in the bone, may be the presenting symptom of the disease, but about two thirds of distant metastases are found at the time of diagnosis or are identified by the postthyroidectomy iodine 131 scan. 1 Distant metastases may also develop as long as 15 years after initial treatment.t" Long-term follow-up of patients with differentiated thyroid cancer is certainly recommended.

Location of Distant Metastases The lungs are the most common site of distant metastases in differentiated thyroid cancer, followed by the skeleton. Both lung and bone metastases also occur in about one third of patients with distant metastases. Other less common sites of metastases are the brain, the liver, the skin, and, rarely, the omentum and adrenal glands." These rare sites of metastatic disease are found more frequently in patients with lung and bone metastases. The pattern of metastatic lung involvement may vary from one or more macronodular (> 1 em in diameter) nodules to a diffuse micronodular spread.l-v' The latter is usually not detected by chest x-ray films and sometimes not even by computed tomography (CT) scan but can be easily diagnosed by an 131 1 whole-body scan (WBS). Enlarged mediastinal lymph node metastases are relatively common in patients with papillary thyroid cancer.s'? Only 3.8% of our patients with differentiated thyroid cancer had bone metastases. They usually occur in patients with follicular cancer and in older patients. The vertebrae, pelvis, and ribs are the most frequently affected sites, but any bone may be involved. Single bone metastases are

152

present in one third of the patients. As shown in Table 17-1, most metastases are detectable by both WBS and x-ray film, but a significant proportion (25% in our series) were visible only by WBS.2,11 The latter group is more likely to respond to 131 1 therapy.

Diagnostic Procedures The identification of distant metastases from differentiated thyroid cancer requires a complete evaluation because many of the distant metastases are initially asymptomatic. Patients with pulmonary metastases are usually asymptomatic unless the metastases involve the pleura (21% in the series by Schlumberger and colleagues-). Bone metastases are more likely to cause pain or neurologic symptoms because of the tumor itself or because of the associated pathologic fractures. As mentioned, some patients with bone metastases are completely asymptomatic. After total thyroidectomy, postoperative 131 1 ablation of any thyroid remnant tissue, serum thyroglobulin (Tg) measurement, and 131 1WBS are valuable for detecting distant metastases.

Serum Thyroglobulin Measurement Most patients (about 95%) with distant metastases have an elevated serum Tg concentration when measured after withdrawal of thyroid-stimulating hormone (TSH) suppressive therapy. While patients are receiving i.-thyroxine (L-T4), their serum Tg concentrations are often relatively low, but these levels are usually higher than in patients with nodal metastases (Fig. 17_1).2,12 The best time to determine the serum Tg level is when the patient is hypothyroid in preparation for a radioscan. There is usually a good correlation between the serum Tg levels and 131 1WBS uptake.13,14 Detectable serum Tg levels are usually associated with a positive WBS, and undetectable

Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases - -

serum Tg levels are found in patients with a negative scan, indicating that the patient is in complete remission. However, serum Tg measurement results are more sensitive than WBS in predicting the presence of metastases. About 95% of patients with persistent thyroid cancer after total thyroidectomy have serum Tg levels above 3 mg/mL, whereas only about 75% of patients with metastatic thyroid cancer have uptake in the tumor. IS

Iodine 131 Whole-Body Scan Because most primary and metastatic well-differentiated thyroid cancers retain their ability to concentrate iodine, 131 1 is usually used to scan for and treat metastases.

105

NODES

METASTASES BONE "c,'}d LUNG

~

:J

a::

w

en

10

nd

ON

OFF

ON THERAPY

OFF

FIGURE 17-1. Behavior of serum thyroglobulin (Tg) levels in

patients with node metastases or distant metastases (bone and/or lung) studied with and without levothyroxine (L-T4 ) therapy. Note that when not receiving L-T4 , all patientshave elevatedserum Tg levels;when patientsare receivingL-T4, the serumTg levelsare still elevated, or at least detectable, in those with distant metastases (with one exception) and are suppressed to undetectable values in many of those with node metastases.

153

Radioiodine uptake by metastatic tumor increases as TSH stimulation increases. To increase serum TSH levels, total or near-total thyroidectomy is required before it is possible to detect or ablate local or distant metastases. It is important to withdraw thyroid hormone therapy for a long enough period of time to induce a state of hypothyroidism sufficient to elicit high endogenous serum levels of TSH.16.I7 The minimum level of serum TSH required for adequate incorporation of 131 1 in neoplastic tissues is about 30 ul.l/ml., a level that is usually achieved after 30 to 45 days without L-T4 and after 2 weeks without t-triiodothyronine (L-T 3). For effective 131 1 uptake, and thus treatment, the patient must also avoid any iodine intake, such as with intravenous contrast material during a CT scan. We also recommend a low-iodine diet for at least 2 weeks before scanning. The most frequent causes of a false-negative 131 1 WBS result are an insufficiently increased TSH and an increased iodine intake. Several centers, therefore, advocate checking the serum TSH concentration and urinary iodine concentration before performing 131 1 WBS and 131 1 therapy. WBS is performed 48 to 72 hours after the administration of 131 1, with the use of either a rectilinear scanner or a gamma camera. l3I1 doses of 2 to 5 mCi are usually used for scanning; higher doses are not indicated because of the possibility of producing a sublethal radiation effect in the metastatic cells, thus preventing uptake of the subsequent therapeutic dose of 1311. 18 When there is no abnormal 131 1 uptake despite elevation of serum Tg with the patient not receiving T 4, the search for metastases should include chest x-ray film, CT scan (without contrast), bone scintigraphy, and liver and neck echography. If no localization is found, a WBS performed 5 to 7 days after the administration of 100 mCi of 131 1 often allows the localization of small neoplastic foci not found by the conventional WBS and has a therapeutic effect in most patients. 19.20 The need to render the patient hypothyroid has been avoided by using exogenous TSH stimulation by the injection of recombinant human TSH (rhTSH, Thyrogen, Genzyme Therapeutics). Several large studies have shown that preparation of the patient by hypothyroidism or rhTSH is equally effective in eliciting sufficient uptake of radioiodine and Tg secretion by the tumor. 21· 24 Whenever a metastasis has been identified by WBS, a complete radiologic work-up should also be done. When a single bone metastasis is identified, we recommend surgical removal followed by 131 1 ablative treatment because such treatment is occasionally curative. 11.2S When pulmonary metastases are present, it is also extremely important to establish whether there is one or more macronodular lesions or multiple micronodules, not visible on the chest x-ray film but identified by the 131 1 scanning. Diffuse lung metastases, not detectable by x-ray film but identifiable by radioiodine scanning, such as those frequently encountered in children, are highly responsive to treatment with 13IJ.26.28 About two thirds of patients who are radioiodine scan positive and chest x-ray or CT scan negative can be rendered tumor free, whereas only about 8% of those with metastases seen on x-ray film or CT scan can be rendered tumor free. 16.26

154 - - Thyroid Gland

Therapeutic Procedures Surgery The decision to treat distant metastases surgically in patients with differentiated thyroid cancer depends on the overall health of the patient, the extent and number of distant metastases, the ability of the metastases to concentrate radioiodine, and the radiologic pattern. Pulmonary micrometastases are frequently completely ablated by radioiodine therapy. Surgical therapy is, therefore, useful in a minority of patients with a single or several macronodular metastases with or without mediastinal lymph node involvement, especially when these metastases do not take up radioiodine. The presence of mediastinal lymph node metastases supports a surgical approach.? These patients must be carefully selected because often more pulmonary metastases are present than expected. Operation generally consists of enucleation of the metastases or lobectomy; a pneumonectomy is rarely performed. Isolated metastases can often be removed thoracoscopically. Too few patients have been operated on for pulmonary metastases to know whether this treatment improves survival; however, in some of our patients, a long-term remission has been achieved, and in patients with isolated metastases, even definitive cure has been described." For patients with bone metastases, a surgical approach is gaining in popularity because of the relative insensitivity of these tumors to radioiodine therapy.9,11.25 The resection of bone metastases may be palliative or curative. Palliation is required in case of pathologic fractures or to ameliorate neurologic symptoms resulting from spinal cord compression by vertebral metastases. In these cases, the operation generally consists of laminectomy and sometimes must be performed emergently. Curative surgery is possible when the metastasis is single and localized, but this situation is uncommon. Large metastases are difficult to ablate with 131 1, and the pelvis is a more favorable site of bone metastases (Fig. 17-2). When the bones are large or are not totally resectable, surgery may help reduce the tumor mass, making subsequent treatment with radioiodine therapy more effective (Fig. 17-3). Among our patients with bone metastases, surgery was performed in 14 patients: 3 patients underwent laminectomy to ameliorate neurologic manifestations, 5 were operated on for palliation of pathologic fractures, and 6 patients, with a single bone metastasis, underwent radical resection; complete cure was achieved in 3 of these patients. Brain metastases are rare, ranging from 0.15% to 1.3% in different series. 30-33 When these metastases are present, the prognosis is poor. Although these metastases usually take up 131 1, the therapy of choice, whenever feasible, is surgical resection because of severe neurologic symptoms. External radiation is also sometimes required to treat pain and prevent fracture. It, unfortunately, is usually palliative rather than curative.

Radioiodine The role of and indications for 131 1 therapy in the management of distant metastases from differentiated thyroid

FIGURE 17-2. Surgical specimen of a single bone metastasis (rib) from follicular thyroid carcinoma treated with surgery. The patient had no recurrence in the subsequent follow-up.

carcinoma are well established. The results are reproducible in large series of patients and indicate complete responses in 35% and 45% of patients. 1,2,4,5,28 As mentioned, pulmonary metastases have a better response than bone metastases. In adult patients, the treatment dosage is usually 100 to 150 mCi, repeated every 8 to 12 months. Lower doses (empirically 1 mCi/kg body weight) should be used in children with lung metastases, particularly of the diffuse type, to avoid the risk of acute pulmonary insufficiency or more chronic radiation-induced pulmonary fibrosis. 25,34 In a review of 118 of our patients with distant metastases treated with 131 1, 43 patients (36.4%) were cured (defined as negative WBS and undetectable serum Tg in the absence of L-T 4), 28 (23.7%) died of their disease, and the others have persistent disease (Figs. 17-4 and 17-5).1 Of those who died, 10 had lung metastases, 8 had bone metastases, 9 had both, and 1 had skin metastases. Interestingly, patients with metastatic papillary cancers did better than patients with follicular tumors. The risk of dying was higher if lung metastases were macronodular and detectable by chest x-ray films, if bone metastases were multiple, and if both lung and bone metastases were present. The mean cumulative dosage of 131 1 used in cured patients was 233 mCi, delivered in 2.2 treatment courses during 3.4 years. Loss of radioiodine uptake was seen in four (5.2%) patients after a mean cumulative dose of 161 mCi 2.7 years from the beginning of treatment. Six patients with single bone metastases and one with

Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases - -

155

FIGURE 17-3. X-ray film and corresponding iodine 131 (1 311) whole-body scan (WBS) in a patient who had a partial response to

1311 therapy and a complete response after surgical resection of the iliac metastasis. Upper row, At the first diagnosis. Middle row, X-ray film and WBS after 700 mCi of 1311. It is possible to note the reduction of 1311 uptake in the left iliac bone and the disappearance of uptake in the middle area corresponding to L-3 (x-ray negative). Lower row, After resection of the left iliac lesion, no 1311 uptake was detected in this area; serum Tg at this stage was undetectable. (From Marcocci C, Pacini F, Elisei R, et al. Clinical and biologic behavior of bone metastases from differentiated thyroid carcinoma. Surgery 1989;106:960.)

156 - -

Thyroid Gland

80

[J papillary (n=77) .follicular(n=41)

70

71

l:iIaU (n=118)

60

FIGURE 17-4. Effect of radioiodine therapy in patients with distant metastases. Mean millicuries delivered, mean number of doses, and mean years over which iodine 131 was administered are shown at the bottom. (From Pacini F, Cetani F, Miccoli P, er al. Outcome of 309 patients with metastatic differentiated thyroid carcinoma treated with radioiodine. World J Surg 1994;18:600.)

50

40

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continued disease

161 1.5 2.7

a macronodular lung metastasis were treated surgically. In these patients, histology revealed that the metastatic tumor was less well differentiated than the corresponding primary tumor. Among patients with elevated serum Tg levels but no appreciable uptake, 13,14 the site of the metastatic deposits was usually the lung or mediastinal lymph nodes.13·14.19.26 About 20% of our patients with distant metastases were included in this group. The administration of high doses of 131 1 has a therapeutic effect on metastatic deposits in patients with low radioiodine uptake. Our data demonstrate that, within a few days after the administration of 131 1 therapy, there is a transient increase in serum Tg concentrations, which, in our opinion, can be explained only by the release of Tg into the circulation by radiation-damaged malignant cells. A progressive decrease of serum Tg levels and normalization of the abnormal chest CT scan in patients with radiographic evidence of micronodular lung metastases" have been observed in some patients. 19.26 Overall, about one third of these patients appeared to receive appreciable clinical benefits.f

A

536 4.7 4.3

Side Effects and Complications of Radioiodine Therapy Side effects after the administration oftherapeutic 131 1 doses are frequent but usually transient and mild. The symptoms usually include gastrointestinal symptoms, nausea, vomiting, and acute sialoadenitis. The last side effect, which is potentially serious if it becomes chronic (after several doses), may be reduced, in our experience, by hydration and by giving low doses of corticosteroids for 2 to 3 days after treatment. More serious complications are those involving blood and bone marrow. An increased risk of leukemia, on the order of five cases per 1000 treated patients, has been reported." The risk is increased by increasing cumulative doses, by reducing the intervals between treatments, and by giving total blood doses per treatment higher than 2 Gy.35 Pancytopenia has been reported in 4.4% of patients treated with mean 1311 doses of 536 mCi by Schober and colleagues." In the same study, anemia was found in about 25% of the patients and thrombocytopenia in 33%.

B

FIGURE 17-5. Representative example of negative diagnostic whole-body scan (WBS) with 5-mCi tracer dose (A) and of post-therapy (l00 mCi) WBS (B) showing diffuse uptake in the lung in the same patient.

Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases - -

Another complication of radioiodine therapy is radiationinduced pulmonary fibrosis, which may develop in patients treated repeatedly for lung metastases, particularly of the extensive diffuse type. Children seem to be particularly susceptible to this complication. We observed a 22-year-old woman who had been treated in another institution with high doses of 131 1 since she was 10 years old for lung metastases, who died, apparently free from disease, from pulmonary fibrosis.'? The occurrence of a second solid cancer after radioiodine treatment has also been reported. Three extra cases of bladder carcinoma and three extra cases of breast carcinoma among 258 patients treated for differentiated thyroid cancer have been documented." All these patients were treated with more than 900 mCi of 1311. The development of second malignancies is controversial, but there may be a very slight increased risk of developing other tumors. Whether radioiodine treatment can promote the transformation of a well-differentiated thyroid cancer to an anaplastic cancer is also controversial. Although a varying degree of "dedifferentiation" is observed in almost all series of thyroid cancer, the question is whether this is due to radioiodine or whether it is an independent biologic event. Studies of molecular biology38,39 have shown that anaplastic thyroid carcinoma is strictly associated with the loss of expression or function of the oncosuppressor gene p53, whereas p53 mutations are rare in differentiated thyroid tumors. It is possible, but not proved, that differentiated thyroid cancers, through a radiation-induced second mutation in the p53 gene or for other reasons, shift toward the poorly differentiated or undifferentiated histotype. Mutations of the p53 gene have not been detected in differentiated thyroid cancer of Belarussian children exposed to radiation after the Chernobyl accident.'" We have also reported the presence of reversible and nonreversible testicular damage, limited to the germinal epithelium, in men treated with high levels of administered activity of 131 1, particularly when they were treated for bone metastases close to the testis."

Prognostic Factors Successful treatment of patients with distant metastases depends largely on the size, location, and number of metastatic lesions and their ability to take up radioiodine. Patients with micronodular diffuse lung metastases and, to a lesser extent, small metastases in bone revealed by WBS in the absence of radiographic abnormalities have the greatest chance of cure. This is particularly true in children, who often have this pattern of metastatic pulmonary spread and yet do exceptionally well after treatment with radioiodine therapy.27,42 Patients with macronodules in the lung and large or multiple bone metastases have a poor prognosis, but long-term palliation and occasional cure can be accomplished by resection of these tumors in selected patients. Loss of radioiodine uptake by the metastatic tumor is also a prognostic indicator of a poor outcome. These findings emphasize the importance of early recognition and early treatment of distant metastases. This is best accomplished by total thyroidectomy or near-total thyroidectomy with

157

postoperative ablation of the remnant, and then serum Tg determination and radioiodine scanning to detect micrometastases that can be successfully ablated with 1311.

Importance of L- Thyroxine Suppressive Therapy Both the function and the growth of some metastatic thyroid tumors are under TSH control. It is a common observation that bone or lung metastases increase in size and take up radioiodine during periods of T, withdrawal, whereas a reduction in size and lack of uptake are observed during periods of T4 therapy. Serum Tg, a marker of cell function, increases dramatically during hypothyroidism (see Fig. 17-1), whereas Tg levels return to low values during treatment with T4 • In the classic article by Mazzaferri.P thyroid hormone therapy significantly influenced both recurrence rate and survival as an independent variable. In this regard, suppression of endogenous TSH to undetectable levels is to be regarded as a true antineoplastic therapy and should never be omitted in patients with active disease. The drug of choice is T4 , and the effective dosage is between 2.2 and 2.8 ug/kg body weight. Higher dosages are usually required in children. In any patient, attempts should be made to use the lowest dose necessary to suppress TSH secretion. The adequacy of the therapy is monitored by measurement of serum TSH, which should be undetectable with an ultrasensitive assay, and serum free T 3, which should be in the normal range to avoid iatrogenic thyrotoxicosis. When these guidelines are followed, T4 suppressive therapy is safe and is devoid of long-term side effects on the heart or bone."

Summary Distant metastases were present in 12.4% of nearly 1000 patients with differentiated thyroid cancer. Pulmonary metastases were most common, and bone metastases occurred in 3.8% of patients. Patients with distant metastases, in general, have a poor prognosis, but when these metastases are small and take up radioiodine, curative treatment or complete remission with 1311 ablative therapy is still possible in about 35% of patients. Children and young adults with pulmonary micrometastases identified by radiographic scanning, but not seen on chest x-ray film, have the best prognosis. These and other micrometastases are best detected when patients are treated by total thyroidectomy. Serum Tg levels and radioiodine scanning are the sensitive indicators of persistent disease. Our data and those in the literature support the use of total thyroidectomy and postoperative serum Tg and radioiodine scanning to detect and treat metastatic disease.

REFERENCES 1. Pacini F, Cetani F, Miccoli P, et al. Outcome of 309 patients with metastatic differentiated thyroid carcinoma treated with radioiodine. World J Surg 1994;18:600. 2. Sch1umberger M, Tubiana M, De Vathaire F, et al. Long-term results of treatment of 238 patients with lung and bone metastases from differentiated thyroid carcinoma. J C1inEndocrinol Metab 1986;63:960.

158 - - Thyroid Gland 3. Hoie J, Stenwig AE, Kullmann G, et aJ. Distant metastases in papillary thyroid cancer: A review of91 patients. Cancer 1988;61:1. 4. Brown AP, Greening WP, McCready VR, et aJ. Radioiodine treatment of metastatic thyroid carcinoma: The Royal Marsden Hospital experience. BrJ Radiol 1984;57:323. 5. Samaan NA, Schultz PN, Haynie TP, et aJ. Pulmonary metastasis of differentiated thyroid carcinoma: Treatment results in 10I patients. J Clin Endocrinol Metab 1985;60:376. 6. Massin JP, Savoie JC, Gamier H, et aJ. Pulmonary metastases in differentiated thyroid carcinoma: Study of 58 cases with implications for the primary tumor treatment. Cancer 1984;53:982. 7. Ruegemer JJ, Hay ID, Bergstralh EJ, et aJ. Distant metastases in differentiated thyroid carcinoma: A multivariate analysis of prognostic variables. J Clin Endocrinol Metab 1988;67:501. 8. Tubiana M, Haddad E, Schlumberger M, et aJ. External radiotherapy in thyroid cancers. Cancer 1985;55:2062. 9. Niederle B, Roka R, Schemper M, et aJ. Surgical treatment of distant metastases in differentiated thyroid cancer: Indication and results. Surgery 1986;100: 1088. 10. Beierwaltes WH, Nishiyama RH, Thompson NW, et aJ. Survival time and "cure" in papillary and follicular thyroid carcinoma with distant metastases: Statistics following University of Michigan therapy. J Nucl Med 1982;23:561. II. Marcocci C, Pacini F, Elisei R, et aJ. Clinical and biological behaviour of bone metastases from differentiated thyroid carcinoma. Surgery 1989;106:960. 12. Pacini F, Lari R, Mazzeo S, et aJ. Diagnostic value of a single serum thyroglobulin determination on and off thyroid suppressive therapy in the follow-up of patients with differentiated thyroid cancer. Clin Endocrinol 1985;23:405. 13. Pacini F, Pinchera A, Giani C, et aJ. Serum thyroglobulin concentrations and 1311 whole body scans in the diagnosis of metastases from differentiated thyroid carcinoma (after thyroidectomy). Clin Endocrinol 1980;13:107. 14. Ashcraft MW, Van Herle AJ. The comparative value of serum thyroglobulin measurements and iodine-131 total body scans in the follow-up study of patients with treated differentiated thyroid cancer. AmJMed 1981;71:806. 15. Pacini F, Ceccarelli C, Elisei R, et al, Serum thyroglobulin determination in thyroid cancer: A ten year experience. In: Nagataki S, Torizuka K (eds), The Thyroid. New York, Elsevier Science, 1988, p 685. 16. Schlumberger M, Charbord P, Fragu P, et aJ. Circulating thyroglobulin and thyroid hormones in patients with metastases of differentiated thyroid carcinoma: Relationship to serum thyrotropin levels. J Clin Endocrinol Metab 1980;51:513. 17. Schneider AB, Line BR, Goldman JM, et aJ. Sequential serum thyroglobulin determination 1311 scan and 1311 uptakes after triiodothyronine withdrawal in patients with thyroid cancer. J Clin Endocrinol Metab 1981;53:1199. 18. Jeevanram RK, Shah DH, Sharma SM, et aJ. Influence of initial large dose on subsequent uptake of therapeutic radioiodine in thyroid cancer patients. Nucl Med Bioi 1986;13:277. 19. Pacini F, Lippi F, Formica N, et aJ. Therapeutic doses of iodine-131 reveal undiagnosed metastases in thyroid cancer patients with detectable serum thyroglobulin levels. J Nucl Med 1987;28:1988. 20. Clark OH, Hoeltins T. Management of patients with differentiated thyroid cancer who have positive serum thyroglobulin levels and negative radioiodine scans. Thyroid 1994;4:501. 21. Haugen BR, Pacini F, Reiners C, et aJ. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999;84:3877. 22. Pacini F, Molinaro E, Lippi F, et aJ. Prediction of disease status by recombinant human TSH-stimulated serum Tg in the postsurgical

23.

24.

25. 26. 27. 28.

29. 30. 31. 32. 33. 34.

35. 36. 37. 38. 39.

40. 41. 42. 43.

follow-up of differentiated thyroid carcinoma. J Clin Endocrinol Metab 200 I ;86:5686. Robbins RJ, Tuttle RM, Sharaf RN, et aJ. Preparation by recombinant human thyrotropin or thyroid hormone withdrawal are comparable for the detection of residual differentiated thyroid carcinoma. J Clin Endocrinol Metab 2001;86:619. Pacini F, Molinaro E, Castagna MG, et aJ. Recombinant human thyrotropin-stimulated serum thyroglobulin combined with neck ultrasonography has the highest sensitivity in monitoring differentiated thyroid carcinoma. J Clin Endocrinol Metab 2003;88:3668. Roy-Camille R, Leger FA, Merland JJ, et aJ. Perspectives actuelles dans le traitement des metastases osseuses des cancers thyroidiens. Chirurgie 1980; I06:32. Schlumberger M, Arcangioli 0, Piekarski JD, et aJ. Detection and treatment of lung metastases of differentiated thyroid carcinoma in patients with normal chest x-ray. J Nucl Med 1988;29: 1790. Ceccareli C, Pacini F, Lippi F, et aJ. Thyroid cancer in children and adolescents. Surgery 1988; I04: 1143. Maxon HR, Smith HS. Radioiodine-I 3 I in the diagnosis and treatment of metastatic well-differentiated thyroid cancer. Endocrinol Metab Clin NorthAm 1990;19:685. Proye CAG, Dromer DHR, Carnaille BM, et aJ. Is it still worthwhile to treat bone metastases from differentiated thyroid carcinoma with radioactive iodine? World J Surg 1992;16:640. Mazzaferri EL. Papillary and follicular thyroid cancer: A selective approach to diagnosis and treatment. Annu Rev Med 1981;32:73. Parker LN, Wu SY, Kim DD, et aJ. Recurrence of papillary thyroid carcinoma presenting as a focal neurological deficit. Arch Intern Med 1986; 146: 1985. Hay ID. Brain metastases from papillary thyroid carcinoma. Arch Intern Med 1987;147:607. Venkatesh A, Leavens ME, Samaan NA. Brain metastases in patients with well-differentiated thyroid carcinoma: Study of II cases. Eur J Surg Oncol 1990; 16:448. Rail JE, Alpers JB, Lewallen CG, et aJ. Radiation pneumonitis and fibrosis: A complication of radioiodine treatment of pulmonary metastases from cancer of the thyroid. J Clin Endocrinol Metab 1957;17:1263. Leeper R. Controversies in the treatment of thyroid cancer: The New York Memorial Hospital approach. Thyroid Today 1982;5: 1. Schober 0, Gunter HH, Schwarzrock R, et aJ. Hamatologische Langzeitveranderungen bei der Schilddrusenkarzinoms. Strahlenther OnkoI1987;163:464. Edmonds CJ, Smith T. The long-term hazard of the treatment of thyroid cancer with radioiodine. Br J RadioI1986;59:45. Herrmann MA, Hay ID, Bartelt DH Jr, et aJ. Cytogenetic and molecular genetic studies of follicular and papillary thyroid cancers. J Clin Invest. 1991 Nov;88(5):1596-604. Pacini F, Pinchera A, Mancusi F, et aJ. Anaplastic thyroid carcinoma: A retrospective clinical and immunohistochemical study. Oncol Rep 1994; I :921. Fugazzola L, Pilotti S, Pinchera A, et aJ. Oncogenic rearrangements of the RET proto-oncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear accident. Cancer Res 1995;55:5617. Pacini F, Gasperi M, Fugazzola L, et aJ. Testicular function in patients with differentiated thyroid carcinoma treated with radioiodine. J Nucl Med 1994;35: 1418. Schlumberger M, De Vathaire F, Travagli JP, et aJ. Differentiated thyroid carcinoma in childhood: Long-term follow-up of 72 patients. J Clin Endocrinol Metab 1987;65: 1088. Marcocci C, Golia F, Bruno-Bossio G, et aJ. Carefully monitored levothyroxine suppressive therapy is not associated with bone loss in premenopausal women. J Clin Endocrinol Metab 1994;78:818.

Anaplastic Carcinoma of the Thyroid Gland Irving B. Rosen, MD • Sylvia L. Asa, MD, PhD • James D. Brierley, BSc, MB

It is ironic that the thyroid gland harbors two polar variants of cancer in regard to aggressiveness in behavior. At the one pole is the common, unaggressive, infrequently lethal, well-differentiated carcinoma, usually papillary, sometimes follicular, which makes up 80% of all thyroid cancers. At the other pole is anaplastic thyroid cancer (ATC), which is invariably lethal and has until recently constituted 4% to 18% of thyroid cancer. Currently, ATC is showing a marked decline throughout the world, but in the United States it still constitutes 1.6% of thyroid cancers and accounts for more than half of the deaths from thyroid cancer. The survival of ATC cases is usually measured in months. Although there is a paucity of cases, leading institutions throughout the world nevertheless have reported their results of treatment in up to 160 patients, usually after several decades of experience. Authors agree that ATC is an infrequent cancer that is highly lethal and is usually unresponsive to currently available treatment such as surgery, radiation, and chemotherapy. New treatments are therefore necessary and are being developed in the hope that they will lead to improved survival in ATC patients."!"

Clinical Presentation Anaplastic cancer, unlike its well-differentiated counterpart, presents a clinical picture that unarguably indicates the presence of an underlying cancer. Patients can be categorized into four different groups': (1) patients whose previous well-differentiated carcinoma had undergone treatment, has been stable over a long period of time, and then changes character; (2) patients who have been viewed and treated for presumptive benign goiter over a long period of time who then demonstrate a rapid growth and change in character of goiter; (3) patients who present de novo and acutely with an extensive thyroid mass; and (4) patients whose widespread

metastatic cancer may demonstrate evidence of anaplastic change. The process of transformation, poorly understood, should be appreciated. Two of our patients had undergone incisional biopsies for adenoma elsewhere as a basis for conservative nonsurgical management with the eventual emergence of fatal anaplastic cancer years to a decade later. Such patients demonstrate not only anaplastic transformation but also the fallibility of incisional biopsy results in long-term prognostication. In consideration of anaplastic transformation.P'P one should recognize that there is a high incidence of p53 mutations in ATC,15 which is not the case for differentiated cancer, even when the two are coexistent. Inactivating mutations of the tumor suppressor gene p53 are of importance in the progression of differentiated to undifferentiated or anaplastic cancer." The N-ras oncogene shows an inverse correlation with thyroglobulin expression that is absent in ATe. No N-ras mutations were seen in well-differentiated thyroid cancer in some reports, whereas gene mutations were present in ATC that usually did not secrete thyroglobulin." Other oncogenes have been identified in some ATC cases, including c-myc and NM23,1O as well as other alterations in tumor suppressor genes. 15 RET/PTC rearrangements are common in papillary thyroid cancer but uncommon in poorly differentiated malignancy so that progression from a well-differentiated to poorly differentiated malignancy is questioned. 16 Mutations in ~-catenin. a widely expressed cytoplasmic protein that has a crucial role both in E-cadherinmediated cell-cell adhesion and as a downstream signal molecule, are common in ATC.I? ~-Catenins activate transcription factors, supporting the idea that they act as an oncogene that contributes to the highly aggressive behavior of ATe. Investigations have shown that both adenomas and follicular carcinomas have N-ras mutations but that p53 mutation is unique in occurring in poorly and undifferentiated thyroid cancer, supporting a multistep transformation

159

160 - -

Thyroid Gland

in such tumors." Studies have further demonstrated that ATC frequently involves a loss of l6P as documented by comparative genomic hybridization studies and associated with transformation from well-differentiated thyroid cancer to anaplastic tumor.'? ATC also often overexpresses the protooncogene HGF (hepatocyte growth factor) and its receptor HGF-R.

Clinical Features Anaplastic cancer affects women and men in a ratio of 1.0:1.5.2 The peak incidence of this disease occurs in the seventh decade of life (mean, 64 yearsj.l-' It is unusual for patients younger than 40 years to be affected by this disease, and when it occurs one should question the reliability of the diagnosis. Radiation exposure has been documented but does not seem to have a critical role in pathogenesis. Patients usually present with a rapidly enlarging, bulky, thyroid mass1,2·5 that is firm to hard and frequently fixed. There may be a variation in the extent of anaplasia because some thyroid tumors may show small areas of dedifferentiation, which would still qualify them in the consideration of anaplastic cancer. However, such cases usually do not pose the same problem or have the dire outlook of the diffusely involved gland. Anaplastic cancer may compress the trachea and infiltrate the skin, causing overlying necrosis. Lymph node enlargement is frequent (84%) and early.l-' The tumor extends to and becomes fixed to the larynx, esophagus, and carotid vessels. Vocal cord paralysis can occur because of tumor infiltration of the recurrent laryngeal nerve or vocal cord, and glottic obstruction is of concern. Obstruction of the superior vena cava can be seen in more extensive cancer, particularly when there is a retrosternal component. Symptoms such as dysphagia, dysphonia, and dyspnea are common.P> Systemic metastases occur in 75% of patients and usually involve lung (more than 80%) as well as bone and brain (15%), adrenal glands (33%), and intra-abdominal nodes (17%).1,2 Investigation can vary and depends on the circumstances of the individual patient. Thyroid function tests are usually normal, but with a rapidly growing tumor, evidence of at least incipient compensated hypothyroidism can be seen by virtue of an elevated thyroid-stimulating hormone serum level by sensitive assay. Scintiscan of the thyroid gland shows a classic cold area at the site of the tumor. Chest x-ray film and computed tomography scan can demonstrate extrathyroidal extension and invasion. Diagnosis can be established by fine-needle aspiration biopsy (FNAB).4.7 Scandinavian authors adamantly prefer FNAB for tissue diagnosis because they view incisional biopsy as associated with poor healing, delay of treatment, and acceleration of tumor growth.t? The diagnosis of anaplastic cancer must be differentiated from that of lymphoma and poorly differentiated medullary carcinoma, and appropriate immunophenotyping and other marker examinations may be required. DNA cytometry of anaplastic cancer usually shows an aneuploid picture indicative of a poor outlook. Other thyroid investigational imaging procedures such as ultrasonography,

computed tomography scan, and magnetic resonance imaging document the limits of the imaging of a mass and sometimes extensive invasion but cannot establish the tumor histology. Somatostatin scans are occasionally positive in ATC and in other thyroid cancers. Positron emission tomography scans are unreliable in ATCs but appear to be positive in patients with poorly differentiated thyroid cancer that does not take up radioiodine."

Pathology Microscopically, three general patterns can be recognized. The most common type is the giant cell variant, which is composed mainly of large cells with marked cytologic pleomorphism.P The plump tumor cells harbor bizarre, often multiple hyperchromatic nuclei (Fig. 18-1) with abundant amphophilic or eosinophilic granular cytoplasm and densely acidophilic, intracytoplasmic, hyaline globules. These tumors grow in solid sheets; artifactual tissue fragmentation may create the appearance of an alveolar pattern. The squamoid variant is composed of nests of large, moderately pleomorphic epithelial cells resembling squamous carcinoma, which may form keratin pearls. Spindle cell anaplastic carcinomas resemble sarcomas (Fig. 18-2); the fascicular architecture and dense stromal collagen may resemble fibrosarcoma, markedly atypical cells and inflammatory infiltrates may suggest malignant fibrous histiocytoma, and prominent vascularization may mimic hemangioendotheliorna.P>' In all three variants, mitotic figures, including atypical forms, are frequent. Vascularization is prominent, and extensive areas of necrosis surrounded by inflammation may occur so that the only viable tumor is seen around blood vessels. Reactive osteoclast-like giant cells of monocytic-histiocytic lineage may be seen. 25,26 Malignant cells usually grow between residual thyroid follicles, invading skeletal muscle, adipose tissue, and other peri thyroidal structures. Blood vessel invasion and thrombosis with or without tumor cell involvement are frequent.

FIGURE 18-1. A giant cell anaplastic thyroid carcinoma is composed of large pleomorphic cells with abundant cytoplasm and hyperchromatic, often multiple, nuclei. Mitoses are conspicuous (arrows).

Anaplastic Carcinoma of the Thyroid Gland - -

FIGURE 18-2. A spindle cell anaplastic thyroid carcinoma h~s

fascicular architecture resembling that of a sarcoma. (Hematoxylin and eosin stain.)

Anaplastic carcinomas do not usually show reactivity for thyroglobulin, and the few that are positive show a weak or focal reaction 26-3o that may be due to trapped nontumorous follicles or isolated follicular cells and the known phenomenon of thyroglobulin diffusion into tumor cel.ls.23 T~e epithelial nature of the malignant cells ca~ be ven~ed w~th stains for low-molecular-weight cytokeratms and vimentm, and in squamoid areas there may be reactivity for highmolecular-weight cytokeratins and epithelial membrane antigen as well. 26-28 Carcinoembryonic antigen (CEA) may be localized in the center of squamoid nests. 26-28 Occasional tumors have been reported to exhibit reactivity for calcitonin, but this finding should alter the diagnosis to that of anaplastic medullary carcinoma.v-" It has been shown that . anap Iast'IC carcmom . as 24-28., p53 mutations are frequent m mutated forms of this putative tumor suppressor gene have prolonged half-lives, permitting immunolocalization.P and the application of this technique has yielded positive results in ATCs (Fig. 18-3).34

161

By electron microscopy,25.27,29,35.36 ther~ may ?e evidence of epithelial differentiation with the formation of mtercellular junctions of the zona adherens type an~ the presence ~f microvilli. The cells may form basal lammae focally. Their large nuclei have clumped chromatin and prominent nucleoli; the abundant cytoplasm usually contains poorly developed endoplasmic reticulum, numerous free ribosomes, lipid droplets, lysosomes, and mitochondria. Scattere~, dense bodies may be seen, but the cells do not contam secretory granules. Occasional intermediate filaments probably represent keratin or vimentin; these may form filamentous whorls that correspond to the acidophilic hyaline globules seen by light microscopy. . Small cell carcinomas and lymphomas constItute a source of diagnostic error, often being misclassified as anaplastic carcinornas.P:" The former are now well r~cognized as neuroendocrine carcinomas, usually poorly differentiated medullary carcinomas that can mimic giant cell or spindle cell anaplastic carcinomas. They can be recogni~ed by immunohistochemical positivity for neuron-specific enolase, chromogranin, calcitonin, calcitonin gene-related peptide, and CEA and by the ultrastructural detection of membrane-bound secretory granules. Lymphoma is usually composed of relatively uniform, small, round cells that do not exhibit the marked pleomorphism of anaplastic carcinoma but do stain for leukocyte common antigen and other immunohistochemical markers of lymphoid cells, and have features of lymphocytes by electron microscopy. Rarely, primary intrathyroidal thymoma may be mistaken for anaplastic carcinoma." Even in tumors without immunohistochemical or ultrastructural markers of epithelial differentiation, the diagnosis of anaplastic carcinoma should be favored for any thyroid pleomorphic lesion occurring in an older patient. Poorly differentiated or insular carcinoma is a tumor of follicular cell differentiation with morphologic and biologic attributes between those of differentiated and anaplastic carcinomas of the thyroid 38.39 and is composed of large, well-defined clusters or nests of neoplastic cells reminiscent of neuroendocrine tumors (Fig. 18-4). The neoplastic cells are moderate to small and uniform in size and shape, with

FIGURE 18-3. Many tumor cells in an anaplastic thyroid carci-

noma show nuclear reactivity for p53, indicating accumulation of protein as a result of mutation. (Streptavidin-biotin peroxidase method with hematoxylin counterstain.)

FIGURE 18-4. An insular thyroid carcinoma is composed of solid

nests of small, polygonal, follicular epithelial cells with individual cell necrosis (arrows). (Hematoxylin and eosin stain.)

162 - -

Thyroid Gland

FIGURE 18-5. A focus of anaplastic thyroid carcinoma characterized by giant epithelial cells (arrow) is seen in a tumor that is predominantly well-differentiated papillary carcinoma (top left) but also exhibits insular architecture (bottom right). (Hematoxylin and eosin stain.)

little pleomorphism and no bizarre, giant, or multinucleated cells. There is a variable degree of mitotic activity, and single-cell necrosis is prominent. Tumor cells stain for lowmolecular-weight cytokeratins and are focally positive for thyroglobulin. Insular carcinoma appears to be intermediate in the spectrum from well-differentiated to anaplastic carcinoma and may represent a transition of the former into the latter 39 .40 (Fig. 18-5) because of factors still to be defined. Accumulation of genetic mutations underlying oncogene activation or the loss of tumor suppressor gene activity correlates with the stepwise progression from adenoma to carcinoma in tissues," and a similar pattern of molecular events has been suggested for thyroid." The expression of various ras mutations in benign thyroid tumors and welldifferentiated carcinomas suggests that activation of this oncogene is an early event.t'" The expression of p53 in anaplastic carcinomas is consistent with a late event that may account for the aggressive behavior of such tumors.

Treatment The standard form of treatment of thyroid cancer has been surgical ablation, but in anaplastic cancer this maneuver is usually not feasible. In our experience, in only 2 of 20 patients labeled initially as having anaplastic cancer could total thyroidectomy be carried out; subsequently, it was demonstrated that these cases represented respectively lymphoma and secondary thyroid cancer from a pancreatic primary tumor. Nonetheless, there appears to be well-documented, ongoing experiences with thyroidectomy. Venkatesh and colleagues I reported that 47% of 100 patients underwent total thyroidectomy, 8% underwent subtotal thyroidectomy, and 30% had lobectomy. Only 25% underwent biopsy only. Tann and colleagues also reported that 7 of 21 (33%) patients had undergone a thyroidectomy.- Famebo and coworkers" also viewed thyroid resection as a possibility after induction chemotherapy.

Postoperative external radiation has been historically used. Of 91 patients, in 30 of whom curative surgery had been attempted, 86 underwent postoperative external beam radiation, 18 with chemotherapy.f Overall survival reported by Junor and associates" was 11% at 3 years (median survival, 21 months). Local recurrence occurred in 50 patients, distant only in 20, demonstrating the inability of external beam radiation to guarantee local control, which is highly desirable to avoid an unpleasant death of the patient. Attempting to improve on the historic radiation approach, Simpson" gave hyperfractionated radiation to 32 patients with unresectable disease (age range, 31 to 87 years). This was done with a single 5-Gy fraction followed by hyperfractionated radiation, 1 Gy four times daily, with an interfraction period of 3 hours, for a total dose of 35 to 45 Gy. Fourteen patients received doxorubicin every 3 weeks. This gave a local control rate of 22% with a median survival of 6 months and 3-year survival of 18%. There were three treatment deaths resulting from radiation-myelopathy (two) and neutropenic sepsis (one)-and this protocol was discontinued (Fig. 18-6). Multimodality therapy was further pursued. Kim and Leiper" reported a complete remission rate of 84% and local control of 68% in 19 patients treated with hyperfractionated radiation and weekly doxorubicin (median survival, 6 months; 3-year survival, 20%). Schlumberger and coworkers," using low-dose hyperfractionated radiation with doxorubicin, cisplatin, or mitomycin C, reported a complete response rate in 5 of 20 patients, although only 3 patients survived more than 20 months. Tennvall and colleagues" gave combined radiation and chemotherapy preoperatively and postoperatively by hyperfractionation using doxorubicin as a single agent replacing

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0.0 +-----,--,-------,----,---r-----\ 12 o 24 36 Months FIGURE 18-6. Survival graph of 32 patients wirh anaplastic thyroid cancer treated by hyperfractionated radiotherapy (Princess Margaret Hospital experience'"),

Anaplastic Carcinoma of the Thyroid Gland - -

bleomycin, 5-fluorouracil (5-FU), and cyclophosphamide because of reduced toxicity. In 33 such patients, debulking surgery was possible in 23 (70%), achieving local control in 48% with death from local disease in 8 of 33 patients. Only four patients lived for more than 2 years. Chemotherapeutic agents such as doxorubicin, cisplatin, and 5-FU have radiation-sensitizing activity and have been given beyond termination of radiation in an attempt to improve survival. Hoskin and Harmer f studied the use of single and combination agents and found only partial responses in three patients, or 17% of the series. Williams and coworkers'? reported on a phase II study from the Southeastern Cancer Study Group using combined doxorubicin and cisplatin in seven patients, with only one partial response and considerable toxicity. Shimaoka and colleagues," in a randomized, controlled study through the Eastern Cooperative Oncology Group, compared doxorubicin with doxorubicin and cisplatin in 39 patients with anaplastic cancer. There was a 5% partial response rate to doxorubicin but an 18% response to the combined regimen, suggesting that combined drug therapy was superior to single-agent therapy but bore the cost of increased toxicity. Schlumberger and associates," who gave doxorubicin every 4 weeks for up to nine courses in addition to radiation, achieved 15% survival at 20 months. Radioiodine and external thyroid feeding appeared to have no inhibiting influence on anaplastic thyroid carcinoma. The role of chemotherapy alone in anaplastic cancer is limited. At one of the University of Toronto's radiation centersthe Princess Margaret Hospital-hyperfractionated radiotherapy'" without chemotherapy (60 Gy in 40 fractions, 1.5-Gy fractions twice a day over 4 weeks) was prescribed for the rare patient who had had a resection and for other patients who had no evidence of metastatic disease and had good performance status. Otherwise, palliative radiation was given at 20 Gy in five 4-Gy fractions over 1 week. This was repeated 4 weeks later if a good response had been achieved. An expectant policy was pursued in elderly patients with poor performance status or patients with distant metastatic disease and relatively little in the way of local symptoms (Fig. 18-7). Although anaplastic cancer is a rare tumor, an increasing number of patients have been reported in series in the literature. The role of surgery in management has been significantly supported with l-year survival rates of 73%, 60%, and 21%, respectively, for patients with incidental and ordinary ATC who underwent surgery and those with ordinary ATC who underwent no surgery.P These figures seem inordinately high and appear to be based on selection bias. They document, however, that thyroidectomy, when feasible, should be performed. The Mayo Clinic reported the results of treatment in 134 patients. In 30%, complete resection was possible with 9.7% I-year survival. Thirty patients were treated with multimodal treatment consisting of debulking procedures, postoperative radiation, and chemotherapy, and only 23% survived more than 1 year. Overall survival did not vary among these groups. They concluded that "ATC is a lethal malignancy" that has "seen no improvement in outcome during 50 years." The Thyroid Center at Padua General Hospital reported on 39 consecutive ATC patients and noted that a combination

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FIGURE 18-7. A 75-year-old patient with anaplastic thyroid

cancer 10 years after incisional biopsy of "benign adenoma" who died within 2 months of diagnosis.

of therapy with radiation, total thyroidectomy, and chemotherapy provided apparent benefits and that preoperative chemotherapy and radiotherapy may enhance surgical resectability.P The Institute of Oncology in Ljubljana, Slovenia, reported on 79 patients; their best results were obtained in those who had the tumor surgically removed and had primary chemotherapy and radiotherapy. 14 The Swedish group has had a long-standing repeated program for the management of patients with ATC that they have reported. Their experience indicates that multimodality treatment consisting of radiation, chemotherapy, and then surgery and further radiation and chemotherapy provides the best results.t-"!' Their current standardized strategy includes radiation of 46 Gy in 29 fractions, namely 1.6 Gy twice a day, with simultaneous doxorubicin at 20 mg intravenously once weekly for 4 weeks and surgery between the fourth and fifth weeks, consisting of total thyroidectomy when possible as well as nodal resection. Currently, no patient has failed to complete the protocol because of toxicity, and in only 25% of cases was death attributed to local failure. Five patients or 9% of the group survived more than 2 years. 11 There have been ongoing attempts at accelerating radiation treatment aiming to improve local response. One such program treated patients twice daily 5 days a week to a total dose of 60.8 Gy in 32 fractions over 20 to 24 days. Although the response rate was encouraging, the program was modified because toxicity was unacceptable.>' Chemotherapy has also received attention. In a phase 2 trial, the collaborativeAnaplastic Thyroid Health InterventionTrials Group assessed paclitaxel." This agent failed to improve survival in patients with ATC, suggesting other new agents or combined agents are necessary. 55 Adding manumycin to paclitaxel resulted in an enhanced cytotoxic effect and increased apoptotic cell death in ATC cells in vitro and in vivo.56 Activity of this combination was also deemed effective, without significant toxicity. The combination of gemcitabine and cisplatin in anaplastic thyroid cell lines appeared to show promising cytostatic activity in an in vitro study.57

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Survival Figures Survival figures vary and are based on a small number of cases. They have been reported at 2 years as near 0%,5 14%,2 and 17%1; at more than 3 years as 12%7; and at 5 years as 10%.2 Assiduous attempts have been made to define prognostic factors. I Factors favoring prolonged survival included younger age «45 years), disease confined to the neck, treatment characterized by total or subtotal thyroidectomy, and treatment by radiotherapy or chemotherapy or both. There appeared to be no significant survival advantage in the transformed group over the de novo anaplastic group. Analysis of long-term survivors (>24 months) indicated that they were significantly younger at diagnosis, had less disease, and received more extensive surgery, although this had not reached statistical significance. Ten of 12 long-term surviving patients received combined radiotherapy and chemotherapy postoperatively.' In the Roswell Park Memorial series," patients who were female, who had tumors smaller than 6 em and who had undergone complete resection survived significantly longer. One study from Latin America reported significantly longer survival in (l) patients with differentiated carcinoma with areas of anaplastic lesions limited to one lobe, (2) patients receiving a complete chemotherapy regimen, (3) patients with tumors smaller than 10 em, and (4) those with a symptom duration of less than 4 months-" A Japanese study reported a I-year survival rate in 44 patients with ATC to be 16%. The presence of acute symptoms, large tumors (>5 em), distant metastasis, and leukocytosis correlated with a poor outcome. A prognostic index (PI) based on these four factors was devised; patients with a PI less than or equal to 1 had 62% survival at 6 months, whereas no patients with a PI greater than 3 survived longer than 6 months.59

Investigation The dismal outcome of patients after treatment in ATC has stimulated research investigation to improve outcome results. Exogenous interleukin 6 has been used but unfortunately was ineffective/" After gene transfection with wild-type p53,

three ATC cell lines became more sensitive to doxorubicin (Adriamycin), suggesting that combining wild-type p53 and chemotherapy might improve the results of therapy?' The transfection of a human thyroperoxidase gene to restore iodine trapping in non-iodide-concentrating tumor cells seen in anaplastic cancer was not effective.f Bone morphogenetic protein (BMP-7) resulted in growth inhibition in ATC cells by inhibiting cyclin-dependent kinase activity, shifting the Rb protein to the hypophosphorylated state. 63 The compound 1,25-dihydroxyvitamin D 3 and several of its non-calciomimetic analogs show dose-dependent inhibition of cell growth in ATC cells in vitro'" and in vivo. 65 Growth inhibition of anaplastic cancer cells was also demonstrated by histone deacetylase inhibitors as a result of increased apoptosis, with activation of the caspase cascade and the induction of a cell cycle arrest through reduction of cyclindependent kinase activity/" Bovine seminal ribonuclease has been reported to have beneficial effects for treatment of aggressive thyroid cancer/" An ElB 55-kDa gene-defective adenovirus (ONYX-015) worked synergistically with two antineoplastic drugs (doxorubicin and paclitaxel) to increase cell death in ATC.68 Apigenin, a flavonoid, showed promise by inhibiting the signal transduction pathways regulating growth and survival in human ATC cells.s? It has also been documented that levels of (k)alpha 1 tubulin relative to thyroglobulin were greatly increased in anaplastic cancer so that chemotherapy targeted at microtubulin might prove to be useful for ATC treatment."? Restoration of p53 expression in ATC inhibited proliferation and restored differentiation in human ATC cells as well as responsiveness to physiologic stimuli." It has also been reported that CA4P, a tubulin-binding agent derived from the African bush willow, may have antitumor effects in ATC, thought to be due to a combination of primary antineoplastic effects and impairment of tumor vascularity." Although investigation into the biologic character of ATC continues, therapeutic innovations are still relatively scanty. Even as prospective trials continue to be limited, it has been noted that ATC arising from papillary or follicular thyroid malignancies have different genetic backgrounds and retain some of the cytogenetic characteristics of the parent problem.F BRAF mutations have been demonstrated to be

Anaplastic Carcinoma of the Thyroid Gland - -

restricted to papillary cancer and poorly differentiated and anaplastic cancer arrising from papillary malignancy, with distinct properties that enable them to develop poorly differentiated and anaplastic cancer." Also, a panel of tumor suppressor genes has been studied that is associated with thyroid neoplasia. The results demonstrate a pattern of alloleic loss, so that the majority of cases showed mutations in two distinct areas and substantial increases in mutation rates in the anaplastic components of the transformed ATC from preexisting well-differentiated malignancy?" PlO7 is thought to play a constitutive role in the progression of papillary cancer to anaplasia, showing a marked decrease in the anaplastic component." Efforts have also been made to investigate the expression of cytokeratin 20 (ck20) in differentiated and anaplastic cancer, and the resultant investigation has demonstrated that ck20-positive tumors have a poor prognosis, reinforcing the need for adjuvant treatment in such a selected group." Cytogenetic work has also shown that different gene dosage copy sequence and balances are important to pathways of transformation of follicular into anaplastic cancers." The transcriptional factor E2Fl controls the RB-E2F signaling pathway, and there is enough regulation of E2Fl in papillary cancer as compared with ATC that may demonstrate a role in carcinogenesis." Gene therapy of ATC has been investigated using the interleukin-l Z gene in BALB/C (nulnu) mice, and initial results suggest a clinical application may be considered." Other investigation has demonstrated that the radiosensitivity of transformed thyroid cells is due in part to the elevated basal activity in the induction of the active form of nuclear transcription factor kappa B, prompting investigators to theorize that inhibition of NF-kappa B could enhance radiation therapy of ATC.8o Workers have also looked at imatineb mesylate monotherapy in treatment of ATC only to find that future clinical studies are futile and not to be encouraged." It has also been demonstrated that experimental in vitro incorporation of gemcitabine into liposomes enhances the drug's cytotoxic effect, indicating a more effective drug intake inside the cell, which may permit lower dosage of this drug in the treatment of ATC.82 Etiology and more complex treatment programs may be investigated, but surgical investigators are still left with the rather simplistic feeling that, although there is no successful treatment for ATC, patients who have undergone liberal surgery for thyroid neoplasia or early surgery with complete resection of ATC have the best chance of response and survival. 83

Conclusion ATC is rare and lethal; fortunately, it appears to be decreasing in frequency" but is nevertheless still a persistent occurrence. The decrease in frequency appears to be associated with improvement in socioeconomic status, more accurate diagnosis, histologic definition and exclusion of medullary cancer and lymphoma, and the elimination of iodine deficiency. It is apparent that the traditional approaches of surgery and postoperative radiation are inadequate in ATC treatment if one is to expect a curative outcome. Currently, the most effective treatment, at least for the control of local disease, is a multimodality treatment consisting of a combination of

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initial simultaneous radiotherapy and chemotherapy, followed by surgical resection of as much tumor as safely possible, followed by combined chemoradiotherapy, u Obviously, more research is required and deserves support so that a new therapeutic regimen may evolve to produce improved and more successful results. 55-83

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25. Gaffey M, Lack E, Christ M, Weiss I. Anaplastic thyroid carcinoma with osteoclast-like giant cells. Am J Surg Pathol 1991;15:160. 26. Ordonez N, El-Naggar A, Hickey R, Samaan N. Anaplastic thyroid carcinoma. Am J Clin PathoI1991;96:15. 27. Carcangiu M, Steeper T, Zampi G, Rosai J. Anaplastic thyroid carcinoma. Am J Clin Pathol. 1985;83:135. 28. Hurlimann J, Gardiol D, Scazziga B. Immunohistology of anaplastic thyroid carcinoma. Histopathology 1987;11:567. 29. LiVolsi VA, Brooks J, Arendash-Durand B. Anaplastic thyroid tumors. J Clin Pathol 1987;87:434. 30. Pilotti S, Collini P, DelBo R, et al. A novel panel of antibodies that segregates immunocytochemically poorly differentiated carcinoma from undifferentiated carcinoma of the thyroid gland. Am J Surg Pathol 1994;18: 1054. 31. Fagin J. Genetic basis of endocrine disease. J Clin Endocrinol Metab 1992;75:1398. 32. Ito T, Seyama T, Mizuno T, et al. Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland. Cancer Res 1992;52:1369. 33. Levine A. The p53 tumor-suppressor gene. N Engl J Med 1992; 326:1350. 34. Nigro J, Baker S, Preisinger A, et al. Mutations in the p53 gene occur in diverse human tumor types. Nature 1989;3412:705. 35. Gaal J, Horvath E, Kovacs K. Ultrastructure of two cases of anaplastic giant cell tumor of the human thyroid gland. Cancer 1975;35:1273. 36. Jao W, Gould V. Ultrastructure of anaplastic (spindle and giant cell) carcinoma of the thyroid. Cancer 1975;35: 1280. 37. Asa SL, Dardick I, VanNostrand A, et al. Primary thyroid thymoma: A distinct clinicopathologic entity. Hum Pathol 1988;19:1463. 38. Carcangiu ML, Zampi G, Rosai J. Poorly differentiated ("insular") thyroid carcinoma: A reinterpretation of Langhans' "wuchernde Struma." Am J Surg Pathol 1984;8:655. 39. Sakamoto A, Kasai N, Sugano H. Poorly differentiated carcinoma of the thyroid: A clinicopathologic entity for a high-risk group of papillary and follicular carcinomas. Cancer 1983;52: 1849. 40. van der Laan F, Freeman JL, Tsang RW, Asa SL. The association of well-differentiated thyroid carcinoma with insular or anaplastic thyroid carcinoma: Evidence for dedifferentiation in tumor progression. Endocr Pathol 1993;4:215. 4 I. Vogelstein B, Fearon E, Hamilton S, et al. Genetic alterations during colorectal tumor development. N Engl J Med 1988;319:525. 42. Suarez H, duViIlard J, Severino M, et al. Presence of mutations in all three ras genes in human thyroid tumors. Oncogene 1990;5:565. 43. Namba H, Rubin S, Fagin F. Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol EndocrinoI1990;4: 1474. 44. Junor E, Paul J, Reed N. Anaplastic thyroid carcinoma. Eur J Surg Oncol 1992; I8:83. 45. Simpson WI. Anaplastic thyroid carcinoma: A new approach. Can J Surg 1980;23:1,25. 46. Kim J, Leiper R. Treatment of locally advanced thyroid carcinoma with combination doxorubicin and radiation therapy. Cancer 1987; 60:2372. 47. Schlumberger M, Parmentier C, Delisle M, et al. Combination therapy for anaplastic giant cell thyroid carcinoma. Cancer 1991;67:564. 48. Tennvall G, Lundell G, Hallquist A, et al. Combined doxorubicin, hyperfractionated radiotherapy and surgery in anaplastic thyroid carcinoma. Cancer 1994;74: 1348. 49. Hoskin P, Harmer C. Chemotherapy for thyroid cancer. Radiother OncoI1987;10:187. SO. Williams S, Birch R, Einhorn L. Phase II evaluation of doxorubicin plus cis platinum in advanced thyroid cancer: Southeastern Cancer Study Group Trial. Cancer Treat Rep 1986;70:405. 51. Shimaoka K, Schoenfeld D, DeWys W, et al. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 1985;56:2155. 52. Wong C, Van Dyk J, Simpson WJ. Myelopathy following hyperfractionated accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol 1991 ;20:3. 53. Sugino K, Ito K, Mimura T, et al. The important role of operations in the management of anaplastic thyroid carcinoma. Surgery 2002; 131:245. 54. Mitchell G, Huddart R, Hanner C. Phase 2 evaluation of high dose accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother OncoI1999;50:33.

55. Ain K, Egorin MJ, DeSimone PA. Treatment of anaplastic thyroid carcinoma with paclitaxel: Phase 2 trial using ninety-six-hour infusion. Thyroid 2000;10:587. 56. Yeung SC, Xu G, Pan J, et al. Manumycin enhances the cytotoxic effect of paclitaxel on anaplastic thyroid carcinoma cells. Cancer Res 2000;60:650. 57. Voigt W, Bulankin A, Muller T, et al. Schedule dependent antagonism of gerncitabine and cisplatin in human anaplastic thyroid cancer cell lines. Clin Cancer Res 2000;6:2087. 58. Pacheco-Ojeda LA, Martinez AL, Alvarez M. Anaplastic thyroid carcinoma in Ecuador: Analysis of prognostic factors. Int Surg 2001;86:117. 59. Sugitani I, Nobukatsu K, Fujimoto Y, Akio Y. Prognostic factors and therapeutic strategy for anaplastic carcinoma of the thyroid. World J Surg 2001;25:617. 60. Fiore L, Pollina L, Fontanini G, et al. Cytokine production by new undifferentiated human thyroid carcinoma cell line FB-I. J Clin Endocrinol Metab 1997;82:4094. 61. B1agosklonny MV, Giannakakou P, Wojtowicz M, et al. Effects of P53-expressing adenovirus on the chemosensitivity and differentiation of anaplastic thyroid cancer cells. J Clin Endocrinol Metab 1998; 83:2516. 62. Haberkorn U, Altmann A, Jiang S. Iodine uptake in human anaplastic thyroid carcinoma cells after transfer of human thyroid peroxidase gene. Eur J Nucl Med 2001;28:633. 63. Franzen A, Heldin NE. BMP-7-induced cell cycle arrest of anaplastic thyroid carcinoma cells via p21 (CIP\) and p27 (KIP\). Biochem Biophys Res Commun 2001 ;285:773. 64. Liu W, Asa SL, Fantus IG, et al. Vitamin D arrests thyroid carcinoma cell growth and induces p27 dephosphorylation and accumulation through PTEN/akt-dependent and -independent pathways. Am J Pathol 2002;160:511. 65. Dackiw AP, Ezzat S, Haung P, et al. Vitamin D3 administration induces nuclear p27 accumulation, restores differentiation, and reduces tumor burden in a mouse model of metastatic follicular thyroid cancer. Endocrinology 2004; 145:5840. 66. Krainberg VL, Williams JM, Cogswell JP, et al. Histone deacetylase inhibitors promote apoptosis in differential cell cycle arrest in anaplastic thyroid cells. Thyroid 2001; II: 315. 67. Kotchetkov R, Cinatl J, Krivtchik AA, et al. Selective activity of BS-RNase against anaplastic thyroid cancer. Anticancer Res 200 I; 21:1035. 68. Portell a G, Scala S, Vitagliano D, et al. Onyx-015. an EIB gene-defective adenovirus, induces cell death in human anaplastic thyroid carcinoma cell lines. J Clin Endocrinol Metab 2002;87:2525. 69. Yin F, Giuliano AE, VanHerle AJ. Signal pathways involved in apigenin inhibition of growth in induction of apoptosis of human anaplastic thyroid cancer cells (ARO). Anticancer Res 1999; 19:4297. 70. Takano T, Hasegawa Y, Miyauchi A, et al. Overexpression of kalpha I tubulin mRNA in thyroid anaplastic carcinoma. Cancer Lett 200 I; 168:51. 71. Dziba J, Marcinek R, Venkataraman G. et al. Combretastatin A4 phosphate has primary antineoplastic activity against human anaplastic thyroid carcinoma cell lines and xenograft tumors. Thyroid 2002; 12:1063. 72. Miura D, Wada N, Chin K, et al. Anaplastic thyroid cancer. Thyroid 2003; 13:283. 73. Nikiforova M, Kimura E, Gandhi M, et al. BRAF mutation in thyroid tumors. J Clin Endocrinol Metab 2003:88:5399. 74. Hunt J, Tometsko N, Livolsi V, et al. Molecular evidence of anaplastic transformation in coexisting well-differentiated and anaplastic carcinomas of the thyroid. Am J Surg Pathol 2003: 12: 1559. 75. Ito Y, Yoshida H, Tomoda C, et al. Decreased expression of pl07 as correlated with anaplastic transformation in papillary carcinoma of the thyroid. Anticancer Res 2003:23:3819. 76. Schmidt-Winnenthal F. Weckauf H, Haufe S, et al. Detection and prognosis relevance of cytokeratin 20 in differentiated and anaplastic thyroid carcinoma by RT-PCR. Surgery 2003;134:964. 77. Rodrigues R, Roque L, Rosa-Santos J, et al. Chromosomal imbalances associated with anaplastic transformation of follicular thyroid carcinoma. Br J Cancer 2004;90:492. 78. Onda M, Nagai H, Yoshida H. Up-regulation of transcriptional factor B2FI in papillary and anaplastic thyroid cancer, J Hum Genet 2004; 49:312.

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ineffective in suppressing human anaplastic thyroid carcinoma cell growth in vitro. J Clin Endocrinol Metab 2004;89:2127. 82. Ciano M, Calvagno M, Bulotta S, et al. Cytotoxic effects of gemcitabine loaded liposomes in human anaplastic thyroid carcinoma cells. BMC Cancer 2004;4:63. 83. Kihara M, Miyauchi A, Yamauchi A, Yokomise A. Prognostic factors of anaplastic thyroid carcinoma. Surg Today 2004:34:394.

Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid Janice L. Pasieka, MD, FRCSC, FACS • Lloyd A. Mack, MD, FRCSC

Unusual Thyroid Cancers Unusual thyroid cancers, including the intermediately differentiated carcinomas, account for only 10% to 15% of all primary thyroid neoplasms (Table 19-1). This unique group of neoplasms behaves differently than the more common type-the well-differentiated thyroid cancers (WDTCs). They therefore present a challenge to both the surgeon and the endocrinologist-oncologist. Most of these cancers behave in an aggressive fashion and, at times, present as a medical emergency. Multimodality therapy is the mainstay of treatment for these tumors. As a result, it is important for the endocrine surgeon to have a clear understanding of the nature of these tumors and recognize when surgery is indicated.

Plasmacytoma Primary extramedullary plasmacytomas are rare forms of plasma cell tumors. Solitary extramedullary plasmacytomas may develop in any organ, but they occur predominantly in the upper respiratory tract. 1·4 The thyroid gland is one of the rarer sites; approximately 50 cases of solitary lesions have been reported in the literature.l It is not uncommon, however, for multiple myeloma to involve the thyroid gland.r" The diagnosis of solitary extramedullary plasmacytoma can be made only after the exclusion of skeletal multiple myeloma on long-term follow-up.v'? Clinical Features. Extramedullary plasmacytoma of the thyroid usually presents with a painless diffuse or nodular goiter. In several cases, it was a rapidly enlarged goiter that brought the patient to seek medical advice.5.8.9.11 Typically, the patient is euthyroid and presents in the sixth decade of life. Extramedullary plasmacytoma predominantly affects females. II On physical examination, the thyroid is a firm, nontender, mobile, multilobulated goiter. There is usually no associated

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cervical lymphadenopathy. Biochemically, antithyroid antibodies may be elevated. Some authors have suggested an association with autoimmune thyroiditis." However, the thyroiditis may represent a nonspecific inflammatory reaction to the presence of the tumor and may not be linked to the cause of the tumor. Pathology. Grossly, the lesions have a fleshy, red-brown neoplastic appearance. Histologically, the tumor demonstrates a dense infiltration of mature plasma cell arranged in sheets or clusters replacing the normal thyroid architecture. Cellular atypia may be seen and mitotic figures can be numerous (Fig. 19-1). 8 Immunohistochemical staining can demonstrate monoclonal plasma cells for both kappa or lambda immunoglobulin chains." Diagnosis and Treatment. The diagnosis of a solitary extramedullary plasmacytoma of the thyroid is suspected on the clinical presentation and the pathologic appearance of the tumor. Fine-needle aspiration (FNA) cytology results may be misinterpreted as medullary thyroid carcinoma.'? Because of the rarity of these tumors, there are no reported cases of the diagnosis being made on the basis of FNA. As stated earlier, it is important to rule out disseminated multiple myeloma by performing a bone marrow aspiration. Up to 25% of patients with solitary plasmacytoma have elevated levels of M proteins in their blood or urine. 13 The optimal treatment for this tumor consists of a total thyroidectomy plus high-dose external-beam radiation to the neck. Surgery or low-dose radiation therapy alone has been associated with a high local recurrence rate. 13 Some institutions have treated these rare tumors with only high-dose radiation (5000 to 6000 rad) and have had relative success.t'" Local recurrence does not appear to alter survival, and most reported cases have been controlled with further radiation therapy. I I The overall 5-year survival using combined treatment is 85%.9 However, long-term follow-up of these patients is necessary because progression to multiple myeloma has been reported.t

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Paraganglioma Paragangliomas are rare tumors derived from the extra-adrenal paraganglia cells of the autonomic nervous system. Most paragangliomas occur in the retroperitoneum or the head and neck region (carotid body tumor). Over the last few decades, several authors have reported unique thyroid lesions that have been categorized as paraganglioma of the thyroid.'>" The presence of a primary paraganglioma in the thyroid is difficult to explain embryologically. Some authors have suggested that these lesions may be a form of medullary thyroid cancer. However, amyloid has not been identified in these lesions, and none of the lesions have stained for calcitonin.l'v" Several authors have described lesions that appear to have a histologic appearance similar to paragangliomas on light microscopy but demonstrated positive thyroglobulin immunoreactivity and negative immunoreactivity for calcitonin and neurofilament.t-P These investigators concluded that true paraganglioma of the thyroid has not been proven to exist and that these lesions represent a variant of follicular adenomas, describing these lesions as "hyalinizing trabecular adenoma"23.24 or "paraganglioma-like adenoma.r'P

FIGURE 19-1. Plasmacytoma of the thyroid: two thyroid follicles entrapped in a sea of plasma cells (hematoxylin-eosin stain).

Clinical Features. The patients usually present with a solitary, nontender thyroid nodule. Patients' ages range from 27 to 67 years (mean age, 46 years). Paragangliomas occur predominantly in women.P:'? Some of these lesions are "hot" on thyroid scintigraphy. Pathology. The cytologic features on FNA can resemble those of medullary thyroid cancer. Negative staining for calcitonin of these cells can aid in the differential diagnosis preoperatively (Fig. 19-2A). Grossly, the lesions are solid and well encapsulated. They are described as tan to pink-gray in appearance and granular in texture. Histologically, the tumors are composed of oval, elongated spindle cells arranged in a trabecular fashion. The cytoplasm is eosinophilic and finely granular (Fig. 19-2B). Immunohistochemically, the lesions stain positive for thyroglobulin, neuron-specific enolase, and S-IOO but negative for calcitonin and neurofilament.20-23 LaGuette and associates" suggest that an immunohistochemical panel is essential for making the correct diagnosis of this rare tumor. Diagnosis and Treatment. Whether these lesions represent a variant of follicular adenomas or are truly paragangliomas of the thyroid is debatable. However, these rare lesions exhibit several microscopic characteristics that are similar to those of medullary thyroid cancer and can be potentially misinterpreted if not initially recognized as such. Most patients reported to date have been successfully treated with surgical excision alone. 22.23 External-beam radiation was used unsuccessfully in one report.'? The literature suggests that most of these lesions can be treated in a similar fashion to a follicular adenoma, that of an unilateral thyroid lobectomy, and these patients have the same excellent prognosis. It is unclear whether lesions demonstrating local invasion are arising from the thyroid or are extrathyroidal in origin, invading into the thyroid.l'v'? Therefore, when local invasion is found, complete en bloc excision of the paraganglioma is necessary.

Sarcoma Throughout the medical literature there are many case reports of sarcoma arising in the thyroid gland. This is to be distinguished from anaplastic thyroid carcinoma that has been shown to demonstrate a variety of growth patterns, including those resembling sarcomas.P:" In the case reports of primary thyroid sarcoma presented in the literature, patients usually present with large, ill-defined masses of the thyroid associated with rapid growth.P?' Gender predilection appears to be equal. The question as to whether primary mesenchymal thyroid neoplasms exist continues to be debated in the literature. There are, however, reports of hemangioendotheliomas of the thyroid that have confirmed the endothelial nature of the tumor with electron microscopy, immunohistochemical staining, and lack of thyroglobulin messenger RNA expression. 29,31-3S Liposarcomas, carcinosarcomas, dendritic cell sarcomas, and leiomyosarcomas of the thyroid gland have also been reported. 26.30,36-39 Immunoreactivity of these tumors for actin, desmin, and vimentin with negativity for thyroglobulin, cytokeratin, and S-IOO protein supports the distinct identity of these rare tumors. 30.38 All subgroups of these tumors generally have a poor prognosis despite treatment attempts with surgery, external-beam radiation, and/or chemotherapy.29,31,34,3S,38,39

170 - - Thyroid Gland squamous cell carcinoma of the thyroid is rare, having been estimated to make up only 0.2% to 0.3% of all thyroid cancers.v A unique group of spindle cell squamous carcinomas associated with tall cell papillary thyroid cancer (PTC) has also been described.">? The patients tend to be women in their seventh decade of life.53.55.56.58 Most patients have advanced disease at presentation, with invasion into adjacent structures and distant metastases being common. Few patients survive more than 12 months. 53.55.57.58 Diagnosis is usually made after pathologic examination of the surgical specimen, although Mai and colleagues described diagnosis based on FNA,59 Total excision of gross disease, when possible, may be curative when followed by external-beam radiation. 53,6o The clinical usefulness of chemotherapy is uncertain, with no proven responses.w'" Useful palliation may be achieved with combined surgical debulking and radiation in selected patients. 53,6o

Intermediately Differentiated Carcinomas

B FIGURE 19-2. A, Cytology of a thyroid paraganglioma. B, Paraganglioma of the thyroid. Shown are oval, elongated spindle cells arranged in a trabecular fashion (hematoxylin-eosin stain).

Teratoma Teratomas are believed to arise from totipotential cells and, therefore, commonly arise in the reproductive organs. The exact site of origin in the thyroid is unclear. Teratomas of the thyroid can be either benign or malignant.f? The benign teratomas are usually cystic and occur in children. 41,42 Teratomas that develop in adults are more common in women, present with progressively enlarging thyroid masses, and are usually malignant.Pr'? In the adult, thyroid teratomas are characteristically large tumors with areas of hemorrhage and necrosis. Microscopically, the tumors demonstrate an admixture of immature tissues with features of the three germ cell layers. These tumors are highly aggressive. To date, treatment consists of total thyroidectomy and neck dissection for diagnosis and potential locoregional control. External-beam radiation has been used; however, in general, these tumors tend to be resistant to chemotherapy and radiation therapy.43,47,49 There have been a few long-term survivors with aggressive combination chemotherapy.s'-"

Squamous Cell Carcinoma Primary squamous cell carcinoma of the thyroid has been extensively described in the literature.v" The frequency of

A recent classification of thyroid cancer based on tumor prognosis has been suggested by Fadda and LiVolsi. 61 This classification includes a group of intermediate variants of thyroid cancer, including insular, columnar, mucoepidermoid, and diffuse sclerosing PTC; tall cell carcinoma; and the solid/trabecular variant of PTC.61.63 These tumors have a biologic aggressiveness that is intermediate between that seen in WDTC and that of lethal anaplastic thyroid cancer. Although the intermediate variants make up only 10% to 15% of all thyroid cancers, they are important variants for the endocrine surgeon to be aware of because in many cases they require a multimodality therapy that differs from that of WDTC. INSULAR CARCINOMA

Insular carcinoma of the thyroid was first described by Langhans in 1907,64 and several decades later, Carcangiu and coworkers established diagnostic criteria for this tumor.s' There are now more than 200 cases reported in the literature, accounting for 2% to 6% of all thyroid cancers. 66,67 Clinical Features. Insular carcinoma is a highly aggressive form of thyroid cancer.f Most of the tumors are relatively large, with a mean size of 5.5 em (ranging from 5 to 10 cm).68 There is a 2: 1 female predominance; age of onset ranges from 37 to 76 years, with the mean age of presentation being 56 years. Most patients are euthyroid and present with a cold thyroid nodule. There is usually no history of low-dose radiation to the head and neck region in these patients." Most patients have cervical and mediastinallymphadenopathy on presentation. Locoregional and/or distant metastases have been reported in up to 70% of patients." Pathology. Macroscopically, insular carcinoma is a solid pale or gray color, often with areas of necrosis or hemorrhage. Microscopically, the tumor is characterized by the formation of a large, well-defined nest of monotonous round and oval tumor cells with occasional small follicles. These nest of tumor cells resembles the pattern seen with carcinoid tumors-hence, the name insular. 65 ,69 The tumor cells are uniform and lack prominent nucleoli. Many of the nuclei are optically clear, resembling the ground-glass nuclei of PTC. Mitotic figures are present in all tumors (Fig. 19-3).65

Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - -

FIGURE 19-3. Insular carcinoma: well-defined nests (insulae) of

round oval cells.

There is increasing evidence to support the concept that insular carcinoma represents an intermediate step in the dedifferentiation of WDTC to anaplastic thyroid cancer. First, the presence of WDTC in combination with insular cancer is seen in up to 59% of reported cases.F" Second, similar to WDTC, insular carcinomas stain positive for thyroglobulin and negative for calcitonin, chromogranin, and carcinoembryonic antigen. 65. 72 Finally, up to 38% of insular cancers stain positive for p53 mutations, which is a higher rate than reported in WDTC and significantly lower than that seen in anaplastic carcinoma." Diagnosis and Treatment. The rarity of these tumors has not allowed for a uniform approach to treatment. In the series of 25 patients by Carcangiu and associates, most of the patients with insular carcinoma underwent total or neartotal thyroidectomy. Some patients had neck dissections, and others received external-beam radiation. The extent of surgical excision did not seem to influence the local or distant recurrence rates. More than 85% of patients developed local, regional, or distant metastases in the 8-year follow-up. The mortality rate during this same period of follow-up was 56%.65 In a recent review of the literature, the mean rate of local and/or distant metastasis for insular carcinoma was calculated to be 64%.68 In one series, 75% of metastatic insular tumors concentrated radioiodine." Therefore, the current treatment for insular thyroid cancer remains aggressive surgical intervention, with or without lymph node dissection, adjuvant radioiodine treatment (although not prospectively evaluated), plus the possibility of external-beam radiation for incompletely excised tumors.

171

an aggressive behavior and an unfavorable prognosis. However, in two small series, when the tumor was circumscribed and encapsulated, the prognosis was similar to that of WDTC,79.82 Mean age at presentation is 44 years. 79.8l The tumors tend to be large, with a mean tumor size of 5.3 cm. 68 Patients typically present with a cold thyroid nodule and may have regional lymph node metastases. The overall rate of distant metastases is 32%, although no cases of distant metastases have been reported when the tumor was encapsulated. Distant metastases when present are found predominantly in lung, bone, and regional lymph nodes.68.79.81 Pathology. FNA cytology has been described for these lesions." The cytologic features can be confused with PTC, medullary carcinoma of the thyroid, and metastatic adenocarcinoma. Grossly, the thyroid tumor tends to be an irregular, multinodular, tanned mass (Fig. 19-4A). Histologically, the tumors may be encapsulated or diffusely invasive. 79,82 In contrast to well-differentiated PTC, the epithelium consists of tall, columnar tumor cells displaying a pronounced nuclear stratification. Columnar cell carcinoma has scant cytoplasm with no oxyphilic changes. Most tumors display a papillary growth pattern with mitotic figures and immunohistochemically stain positive for thyroglobulin (Fig. 19-4B).

COLUMNAR CELL CARCINOMA

Evans 74 in 1986 described two cases of thyroid cancer with a distinct histologic pattern that he termed columnar cell carcinoma. Others have since reported similar cases, all displaying aggressive clinical behavior and a universally poor prognosis.25.75.78 Columnar cell carcinoma is rare, accounting for only 0.15% of all PTCS.79.81 Clinical Features. Earlier reports suggested a higher incidence in males; however, in a recent review of the reported cases in the literature, there was a female predominance.f Most of these columnar cell tumors are associated with

B FIGURE 19-4. A, Columnar cell carcinoma of the thyroid: Gross picture of a resected liver metastasis. The multilobulated, tanned color of this tumor is characteristic of these tumors. B, Columnar cell carcinoma of the thyroid. The tall columnar tumor cells display pronounced nuclear stratification (hematoxylin-eosin stain).

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Columnar cell carcinoma differs histologically from the tall cell variant of PTC51,52,83 in that the degree of nuclear stratification and height of the columnar cell are much more excessive in columnar cell tumors.r'-" The exact proportion of columnar cells displaying nuclear stratification required to make the diagnosis of columnar cell variant has not been defined. In the largest reported series, the diagnosis of columnar cell variant required more than 70% of the tumor demonstrating nuclear stratification." Diagnosis and Treatment. Most patients have been treated with total or near-total thyroidectomy, with or without lymph node dissection. Until recently the prog~osis of columnar cell carcinoma was thought to be universally poor.74.76 Encapsulated or minimally infiltrative lesions h~ve a relatively good prognosis, with all reported cases remaming disease free at 5 years. In contrast, tumors with extrathyroidal spread have a high incidence of distant metastases, and 67% of the patients have died of the disease, with a mean mortality of only 40 months. 68,79,81,82 Radioactive iodine has been used in about 60% of cases without evidence of demonstrated improvement.Y" External-beam radiation should be considered when residual disease is present or for palliation. MUCOEPIDERMOID CARCINOMA

In 1977, Rhatigan and colleagues's first described primary mucoepidermoid carcinoma of the thyroid. Fourteen years later, Chan and coworkers described sclerosing mucoepidermoid thyroid carcinoma arising from a metaplastic follicle in Hashimoto's thyroiditis.f" There have been several case reports of this rare tumor, with significant debate in the literature regarding its histogenesis.t"?' It is believed that mucoepidermoid tumors of the thyroid arise from either metaplasia of the follicular epithelium89,92,93 or as vestiges of the ultimobranchial body.94-98 Clinical Features. Although these tumors were original described as indolent or low-grade tumors,63,84 many case series suggest a more aggressive behavior, with a high incidence of local invasion,85,86.9I,93 ability to metastasize distantly,87.88 and mortality.P?' The tumor presents as a painless neck mass that is "cold" on thyroid scintigraphy. There is a female predominance occurring most commonly in the fifth to eighth decades of life.84,85,89

Pathology. Microscopically, neoplastic proliferation is composed of squamous or epidermoid areas with intermingling mucous cells. The epidermoid cells have round or oval nuclei, prominent nucleoli, and eosinophilic cytoplasm. Mucocytes with abundant clear to foamy-appearing cytoplasm and peripheral hyperchromatic nuclei are present. Sclerosing mucoepidermoid carcinoma with the eosinophilia variant often has a background of thyroiditis and prominent sclerohyaline stroma infiltrated with eosinophils.Pv" Immunohistochemistry on these tumor is positive for mucin '.c . 63 '85 ,89 . stains . but negative and cytokeratin lor ca lei citorun. Diagnosis and Treatment. FNA cytology has diagnosed these tumors; however, more commonly the diagnosis is only made after surgical excision."? An en bloc thyroidectomy is the treatment of choice with potential for cure even in locally invasive disease.84,91,100 External-beam radiation and chemotherapy have been used with minimal success at controlling locoregional disease.87,88,92,93 Information regarding this tumor's usual clinical course is lacking because of its rare occurrence.

DIFFUSE SCLEROSING VARIANT OF PAPILLARY THYROID CANCER

The simultaneous occurrence of thyroiditis and PTC was first described in 1985 by Vickery and associates. 101 This variant, termed diffuse sclerosing variant of PTe, was later incorporated into the World Health Organization (WHO) classification of thyroid tumors and today accounts for 2% to 6% of all thyroid tumors. 102-105 To date, there have been 72 cases of diffuse sclerosing PTC reported in the adult literature.P Diffuse sclerosing PTC has also been described in the children affected by the Chernobyl disaster. 106,107 Clinical Features. Diffuse sclerosing PTC occurs predominantly in females, with the age of presentation being in the third decade of life. Patients present with either localized or diffuse thyroid enlargement that may be painfu1.68,108 Fifty to 70% of patients have measurable titers of antimicrosomal and antithyroglobulin antibodies, leading to the mistaken diagnosis at presentation of subacute or chronic thyroiditis in 28% to 40% of patients. 102,108 Cervical lymph node metastases are found in 70% of patients, and distant metastases can be found in up to 60%.68,102-104 Pathology. The FNA cytology of diffuse sclerosing PTC demonstrates the usual nuclear features of PTC: nuclear grooves, pseudoinclusions, and overlapping nuclei. !he presence of relative nuclear enlargement and pleomorphism may help distinguish this variant from the usual PTC.109 These tumors usually demonstrate a diffuse involvement of the thyroid lobe, with a pale, fibrous appearance macroscopically. Histologically, diffuse sclerosing PTC is made up of numerous papillae with squamous metaplasia. The tumors tend to have interstitial fibrosis, psammoma bodies in a background of lymphocytic inflammatory infiltrate (Fig. 19-5). Extrathyroidal extension is seen in 40% of patients. I 10 Diagnosis and Treatment. Diffuse sclerosing PTC tends to have a higher propensity for locoregional metatatic compared with that found in WDTC. Local recurrence rates are reported to be as high as 50%, and distant metastatic rates of 60% have been described. 102,103,108,110 In a recent review of 65 reported adult cases of diffuse sclerosing PTC,

FIGURE 19-5. Diffuse sclerosing papillary thyroid cancer, This

low-power view demonstrates interstitial fibrosis, psammoma bodies, and lymphocytic infiltrate.

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173

the mean weighted local recurrence rate was only 13%, and the mean weighted distant metastatic rate was calculated to be only 19%.68 Tumor-related mortality for this variant is excellent, with only one reported death in the literature. 103 The treatment of diffuse sclerosing PTC begins with the awareness of this tumor's ability to mimic subacute thyroiditis at the time of presentation. The treatment of this tumor should involve an en bloc excision of the thyroid gland and any of the infiltrated structures within the neck. Given the high rate of lymph node metastases, a modified neck dissection should also be included. Following surgery, adjuvant radioactive iodine therapy should be used. TALL CELL VARIANT OF PAPILLARY THYROID CANCER

The tall cell variant of thyroid cancer accounts for 3% to 12% of all PTCs of the thyroid, although this is believed to be an underestimate of the disease because of the difficulty the pathologist may have at making the diagnosis.!" Tall cell cancer of the thyroid was first described by Hawk and Hazard in 1976. 52 These tumors are characterized by having a significant proportion of the tumor composed of cells in which the cell height is at least twice its width. There is variation in the literature regarding the percentage of tall cells within the tumor required to make the diagnosis. Most series have used a minimum of 30% of the tumor composed of tall cells to classify the tumor as a tall cell variant, whereas others have used percentages as high as 50% to 70%.111-114

Clinical Features. There have been more than 200 reported cases in the English literature of tall cell variant thyroid cancer." Although some authors have described a male predominance, 115. 11664% of the patients reported in the literature were women, with the average age of presentation being 51 years (range, 43% to 65%).68 The tumor tends to be larger than WDTC, averaging a diameter greater than 3 cm. 117 Extrathyroid extension is common and is found on average in 67% of the patients, in contrast with WDTC that demonstrates extrathyroid invasion in less than 20% of patients. Regional lymph node metastases occur on average in 57% of the patients (range, 40% to 83%). Distant metastases typically appear in the lung and bone and are found on average in 22% of the patients.v" Pathology. The cytologic features of tall cell cancer are similar to those seen in PTC, including nuclear pseudoinclusions, nuclear enlargement, and nuclear grooves. ll8,119 Feature that help the cytopathologist to differentiate this variant from PTC include larger cell size, eccentric nucleus, and increased nuclear pleomorphism. Macroscopically, these tumors appear as pale, firm neoplasms. Multifocality is commonly seen in 36% to 58%.116 The characteristic tall cells have a height that is at least twice their width, with abundant cytoplasm and basal positioning of the nucleus (Fig. 19-6). These features are distinct from the columnar cell variant of PTC, which has stratification of its nuclei and less cellular cytoplasm (see Fig. 19-4B). Most tall cell tumors stain positive for thyroglobulin, vimentin, and kertin.'!" Tall cell tumors have been shown to have a significantly higher incidence of p53 mutations compared to welldifferentiated PTC (61% vs. 11%); however, p53 mutations

FIGURE 19-6. Tall cell variant of papillary thyroid cancer. The height of the cells is greater than twice their width.

have not been demonstrated to be a predictor of worse outcome. I12 Diagnosis and Treatment. Regardless of the patient's age or the tumor size, the histologic diagnosis of tall cell carcinoma has been demonstrated to be an independently poor prognostic factor. 113,120 With the exception of Ozaki and coworkers.!" who found no recurrence or mortality in 13 patients with tall cell cancer, most authors have reported tumor-related mortality rates up to as high as 74%.lI1,I15.117 Locoregional recurrence rates are greater than those seen in PTC, with the risk of recurrence being greater in patients older than 50 years of age and in tumors larger than 4 cm. 11 I,117 In the study of 18 patients by Taylor and associates, the use of radioiodine therapy in 131I-avid tumors was shown to reduce the progression of the tumor signiflcantly.V' However, in another study, Ain found that only 13% of tall cell tumors were 131I-avid, and half of these patients eventually lost radioiodine uptake in the metastases over time.P" The aggressive nature of this tumor warrants aggressive surgical intervention. Total thyroidectomy combined with lymphadenectomy of cervical nodes and an en bloc resection of adjacent tissues should be done when there is evidence of local invasion. Since radioiodine therapy has been shown to be of benefit in some patients, it should be used in all P'f-avid tumors. External-beam radiation should be considered in all cases of tall cell carcinoma that have demonstrated extrathyroidal extension, incomplete resection, or positive lymph node involvement. SOLIDITRABECULAR VARIANT OF PAPILLARY THYROID CANCER

The presence of focal areas of solid or trabecular growth patterns in WDTC is common. When the tumor demonstrates exclusively or predominantly a solid or trabecular pattern, the diagnosis of a solid/trabecular variant of PTC is made. Between 12% and 16% of PTCs are the solid/trabecular variants. 123.124 More recently, this variant has been identified in 37% of the radiation-induced thyroid cancers seen in children exposed to the Chernobyl nuclear disaster.l'" This is a

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significantly higher rate of occurrence than that seen in agematched nonradiation-induced PTC, in which the solid/ trabecular variant made up only 4% of the tumors. 125 Clinical Features. The solid/trabecular variant is seen in both the adult and pediatric population. In adults, the mean age of presentation is in the fifth decade of life, with a strong female predominance.P' In contrast, the radiationinduced tumors in the pediatric population exposed in the Chernobyl disaster affected both males and females equally.I'" Most of these children presented with a thyroid nodule averaging 2 em in size, with clinical lymphadenopathy found in 85%. In adults, cervical nodal disease occurs in between 57% and 83% of cases, and distant metastases are found in up to 21% of patients at presentation. 123,124 Pathology. Macroscopically, these tumors appear as nonencapsulated, firm, whitish nodules with evidence of local invasion present in 84% of the patients. 106 Microscopically, these tumors are made up of solid nests or a cordiike trabecular arrangement of epithelial cells, as shown in Figure 19-7. The solid variant has typical nuclear features of PTC, including nuclear inclusions and nuclear grooves. Most tumors stain positive for thyroglobulin, and a high prevalence of ret/PTC3 rearrangement has been demonstrated. 125 Diagnosis and Treatment. It is unclear in the literature as to whether the solid/trabecular variant has a worse prognosis than that of WDTC. Mizukarni and colleagues reported a lO-year survival rate of the only 72% in a series of 30 patients.!" In contrast, Carcangui and coworkers reported no tumor mortality in their series of 28 patients followed longer than 6 years.123 The follow-up of solid/trabecular variant tumors from the Chernobyl disaster is too brief to draw any conclusions on the long-term prognosis of these children. Total thyroidectomy and cervical lymph node dissection should be the treatment of choice because of the high propensity of the solid/trabecular variant to extend beyond the thyroid and to metastasize to lymph nodes. The use of radioactive iodine in these tumors has not been studied. Given that the histologic features of these tumors resemble those of PTC, it seems reasonable to use radioiodine therapy following surgical intervention.

Lymphoma of the Thyroid Primary lymphomas of the thyroid are rare, accounting for only 1% to 2% of thyroid malignancies and less than 2% of extranodal Iymphomas.P'P''!" Most thyroid lymphomas are non-Hodgkin's lymphomas of B-cell origin, although Hodgkin's disease of the thyroid has been described. 126.129 I~ a large proportion of cases, thyroid lymphomas are associated with Hashimoto's thyroiditis and histologically may be difficult to distinguish from this chronic lymphocytic disease.25,130 Follow-up studies have estimated the relative risk of thyroid lymphoma in patients with chronic lymphocytic thyroiditis to be 70 to 80 times higher than in controls. 131 The actual relationship between Hashimoto's thyroiditis and thyroid lymphomas remains obscure. Whether the presence of lymphocytes in the thyroid provides the tissue in which the lymphoma can develop or whether the chronic stimulation of the lymphocytes predisposes the cells to develop malignant clones has not been defined. Clinically, primary lymphoma poses a diagnostic and therapeutic challenge because it can present in a fashion similar to that of small cell anaplastic carcinoma of the thyroid. 132-135 As a result, it is essential to be able to distinguish these two diseases, because there are different therapeutic and prognostic implications for each.

Clinical Features Most patients present with a several-week history of a rapidly enlarging goiter. 134,135 Thyroid lymphomas tend to present in women in their seventh decade of life who may have had a long-standing history of Hashimoto's thyroiditis. It is usually painless and often associated with hoarseness and dysphagia. 26,130.135 Less frequently, the patients may present with tracheal compression, dyspnea, and respiratory obstruction.!" Most patients are euthyroid. On palpation, the thyroid is firm, with either unilateral or bilateral involvement. The gland may be fixed to adjacent structures, and enlarged regional lymph nodes are not unusual. Computed tomography usually demonstrates a diffusely enlarged thyroid gland with evidence of invasion into adjacent structures and lymphadenopathy (Fig. 19-8A). PATHOLOGY

FIGURE 19-7. Solid/trabecular variant of papillary thyroid cancer. This high-power view demonstrates a cordlike trabecular arrangement of the cells.

Thyroid lymphomas grossly appear as pale gray or light tan fleshy tumors (Fig. 19-8B). Most thyroid lymphomas are the non-Hodgkin's type. 134,135 Aozasa and colleagues!" reported that most thyroid lymphomas appear to be exclusively B-cell-derived tumors. Histologically, primary thyroid lymphomas can be of several subtypes, classified by the Revised European-American Lymphoma study group (REAL) and the WHO classifications.Pv'F Deringer and coworkers'> described four main subtypes in their large series: 38% diffuse large B-celilymphoma without marginal zone lymphoma, 33% diffuse large B-cell lymphoma with marginal zone B-celilymphoma, 28% marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), and fewer than I % follicle-center lymphoma. The percentage of MALT lymphoma varies in the literature from 23% to 77%.134.135,138.140 Many authors suggest that large cell

Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - -

c

175

D

FIGURE 19-8. A, CT scan of a thyroid lymphoma, showing diffuse enlargement with tracheal compression. B, Thyroid lymphoma: left resected lobe of the thyroid, with fleshy appearance on the cut surface. C, Thyroid lymphoma demonstrating diffuse replacement of the thyroid parenchyma by lymphoma. D, Thyroid lymphoma extending beyond the thyroid capsule to invade surrounding strap muscles (C and D, hematoxylin-eosin stain).

lymphomas may also evolve from low-grade lymphomas of MALT.140-143 In general, the tumor cells are noncohesive and have a lymphoid monomorphoric appearance.i" Thyroid lymphoma may form nodules or may present with a diffuse infiltrative pattern. Mitotic figures can be numerous (Fig. 19-8C). Extrathyroid extension of the neoplastic cells helps the pathologist distinguish this as a neoplastic process versus chronic inflammation. DNA flow cytology and immunohistochemical staining for CD 19 and CD20 are helpful for demonstrating the B-cell nature of the lymphocytes, and the restricted expression of immunoglobulin light chains allows for the distinction from chronic lymphocytic thyroiditis.25.128.134.144

Diagnosis and Treatment Thyroid lymphoma can be confused clinically with an anaplastic thyroid carcinoma. FNA has helped distinguish these two conditions preoperatively and has decreased the need for open biopsy.126.130.145 Up to 88% of thyroid

lymphomas in some series are diagnosed on FNA alone without further invasive testing.145.146 The use of flow cytometry, immunohistochemistry, and polymerase chain reaction has improved diagnostic results. 138.147.148 However, FNA is experience dependent, and there are difficulties in distinguishing thyroid lymphoma from Hashimoto's thyroiditis. This difficulty can lead to the need for open surgical biopsy to make the diagnosis. 149.150 Once the diagnosis has been established or is suspected, the patient's disease must be staged, as follows: • Stage IE involves localized disease within the thyroid. • Stage lIE is disease confined to the thyroid and regional lymph nodes. • Stage IIIE involves disease on both sides of the diaphragm. • Stage IVE is disseminated disease. The treatment of thyroid lymphoma remains controversial. Initially, surgery was used extensively for the treatment of this disease. More recently, however, surgical removal has been shown to have a limited benefit. 150.151 Not all investigators

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Thyroid Gland

have agreed with this; some have suggested that the addition of surgical debulking is necessary because the amount of residual disease in the neck correlated to the relapse rate for stages IE and lIE disease. Rosen and associates'V demonstrated a longer overall and relapse-free survival with complete or near-complete resection. However, most of the literature reports have failed to demonstrate the benefit of aggressive surgical intervention compared with combined radiation and chemotherapy. The Mayo Clinic achieved a complete response with predominantly radiation therapy in stages IE and lIE lymphomas in 88% of its patients. 151 Since most patients present with disease beyond the thyroid, the surgical role in advanced tumors is limited to open biopsy when needed.135.150.15I Thyroid lymphomas have been shown to be both radiosensitive and chemosensitive; therefore, most current recommendations are to treat these tumors with a combinedmodality therapy.127.150.153 Doria and colleagues, in their large 1994 review, demonstrated that nearly 30% of patients with localized stage IE or lIE disease have systemic relapse when treated with local radiation alone or in combination with surgical debulking.F' They suggested that combined radiation and chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone with or without the addition of methotrexate, doxorubicin, or both may decrease the chance of distant relapse. Radiation alone, however, has been successfully used in localized thyroid lymphoma of the MALT variety. Similar to MALT lymphomas of other sites, radiation alone has resulted in a 96% complete response, with only a 30% relapse rate. I39,154 Many centers treat all thyroid lymphomas (localized or disseminated) with multimodality therapy, including radiation and chemotherapy. 134,150 Advanced stage of the tumor, a size greater than 10 em, mediastinal involvement, and the presence of dysphagia have been shown to be poor prognostic factors in primary thyroid lymphoma.P'T" Most recurrences develop within the first 4 years. The overall survival of patients with thyroid lymphoma ranges from 50% to 70%.150,151 The 5-year survival is 80% for stage IE, 50% for stage lIE, and less than 36% for stages IIIE and IVE. 151

renal cancer patients, 10% of lung cancer patients, and 10% of patients with primary head and neck tumors.P" Case reports and studies of metastases to the thyroid gland from less common primary tumor sites have been published, including colon, soft tissue, neuroendocrine, stomach, bladder, and gynecologic tumors.160-165 The incidence of clinically apparent metastases appears to be lower than the incidence found in autopsy material. According to Shimaoka and colleagues.P" the thyroid metastases were clinically apparent in only 5% to 10% of patients in their study. Renal cell carcinoma is the most common secondary to the thyroid when defined by clinical detection. ' 64,166-168 Usually, there is a latency period lasting years between the diagnosis of the primary cancer and the appearance of a thyroid mass. 159,166-171 This finding is especially true for breast and renal primary tumors. Less commonly, patients may present with metastatic disease in the thyroid before a primary diagnosis of cancer. l7u n

Diagnosis and Treatment The presentation of a cold thyroid nodule years after the treatment of a primary cancer often poses a diagnostic dilemma. FNA has allowed for the preoperative diagnosis of a secondary tumor, thus changing the preoperative work-up of such a patient (Fig. 19_9).168,172.173 Once the diagnosis of metastatic disease has been confirmed on FNA, the patient should undergo a metastatic work-up to rule out other distant metastases. Several authors have demonstrated that for isolated thyroid metastasis, thyroidectomy has prolonged survival. l 64,166.167,169-171 This is especially true for tumors that

Metastases to the Thyroid The true incidence of metastases to the thyroid gland has not been clearly established. Autopsy studies have reported an incidence ranging from 2% to 25%.156-159 In the study by Mortensen and colleagues, 4% of patients with metastatic neoplasms had secondary tumors of the thyroid gland.P? Silverberg and Vidone-? found the incidence to be much higher. In their study, they meticulously examined the thyroid and found the incidence of metastatic disease to the thyroid to be 24% in patients dying from metastatic cancer. This study suggested that the incidence of microscopic disease in the thyroid is greater the more diligently it is looked for. Shimaoka and coworkersl'" studied the occurrence of thyroid metastases for a given primary neoplasm. In their autopsy study of patients who died of metastatic cancer, they found that metastases to the thyroid occurred in 39% of melanoma patients, 21% of breast cancer patients, 12% of

FIGURE 19-9. Algorithm outlining the approach to a thyroid nodule in the face of a history of primary cancer. FNA = fine-needle aspiration.

Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - - 177

present years after the treatment of the primary cancer and for breast and renal carcinomas. 164.166.167.170.171

Summary Unusual thyroid neoplasms, intermediate variants, primary lymphomas, and metastases to the thyroid gland make up a rare group of tumors. Although they are uncommon, it is important for the endocrine surgeon and endocrine oncologist to be able to recognize and differentiate them from the more common thyroid neoplasms. These tumors, on the whole, tend to behave more aggressively and, in most cases, the use of multimodality therapy is recommended.

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Recurrent Thyroid Cancer Erol Diiren, MD • Mete Diiren, MD

The clinical course of patients with thyroid cancer is unpredictable. Numerous studies, however,have documented that patients can be classified into groups at low or high risk for recurrence or death on the basis of age, gender, tumor size, histology, and extent of local invasion as well as the presence or absence of distant metastases. 1 Resectability and extent of resection, with the adjuvant use of iodine 131 and thyroid-stimulating hormone (TSH) suppression therapy, also influence outcome. The various scoring systems such as AGES (age, grade, extent, and size), AMES (ages, metastases, extent, and size), and TNM (tumor, node, metastasis) attempt to identify prognostic factors of tumor behavior for recurrence and survival.I Goiter, or thyroid nodules, occur in 4% to 6% of women and in 2% of men in North America; clinical thyroid cancer, however, occurs only in about 40 persons per million.' A selective approach, therefore, must be used to determine who will benefit from thyroidectomy and who can be safely observed or treated with thyroid hormone. If this selection process is not judicious, there will be delays in diagnosis and an adverse outcome. Earlier diagnosis of thyroid cancer, in the much larger number of patients with goiter, has a considerable impact on both the recurrence and the survival rate of patients with thyroid cancer. Recurrent thyroid cancer after treatment may be local, regional, or distant. Local recurrence is related both to the invasiveness of the cancer at presentation and to the surgical procedure used for the eradication of the malignant tissue. Extracapsular invasion and multicentricity of the tumor are determinant factors that also need to be considered. Unfortunately, these factors usually cannot be ascertained preoperatively to determine the extent of the resection. In high-risk patients, recurrence is common (-30%), and treatment of recurrence is less successful.v' Because one cannot precisely predict tumor behavior, we favor total thyroidectomy for most patients with thyroid cancer when this operation can be safely performed. Just as the expression "no acid, no ulcer" is generally accepted in patients with peptic ulcer disease, the notion that "no tissue left, no local recurrence" may also be valid. In patients with clinical thyroid cancer, local recurrence may occur in the residual thyroid tissue, in the thyroid bed, or in the immediately adjacent area, excluding lymph nodes. An insufficient thyroidectomy, failure to remove all the thyroid, and the cancer may be

responsible for some recurrences; microscopic extension into the adjacent tissue accounts for the remainder. The results of thyroidectomy are well documented in the study of 963 papillary thyroid cancer patients at the Mayo Clinic by Grant and associates.' The risk of cancer death with a local recurrence located outside the thyroid remnant was much greater than with a remnant recurrence alone. Practically, however, the exact type of this kind of recurrence, whether in residual tissue or in thyroid bed and adjacent tissues, is often difficult to determine when the recurrent tumor has reached appreciable size. Of concern also is that even patients judged to be at low risk have about a 15% recurrence rate, and at least 33% of these patients die from their thyroid cancer. 1,3

Efforts to Prevent Recurrence Preoperative Recognition of the Malignancy Efforts to prevent local recurrence should start with the preoperative, or at least perioperative, recognition of the malignancy. Once it is revealed, a total or near-total thyroidectomy is the procedure of choice. It is common practice for our surgical group to perform a meticulous, complete lobectomy on the tumor side, and, while preparing the other lobe, confirm the diagnosis histologically by frozen section examination, if it is not already known to be a cancer by fine-needle aspiration (FNA) biopsy cytology. The contralateral lobe is then removed unless there is concern about the viability of the parathyroid glands. In the latter patients, a small amount ('"1 em) of thyroid tissue may be left to protect the contralateral upper parathyroid gland or recurrent laryngeal nerve at the level of the cricoid cartilage at the posteromedial limit of the thyroid. For patients who have thyroid cancer diagnosed by FNA, we remove the entire thyroid gland as one piece because we do not wish to violate the thyroid capsule. Extra care must be taken when performing a total thyroidectomy, because permanent hypoparathyroidism and recurrent laryngeal nerve injuries are serious complications. 3,6 Thyroid cancers should also not be fractured during the thyroidectomy because of possible implantation in the thyroid bed.

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182 - - Thyroid Gland Total thyroidectomy is usually not necessary for patients with occult papillary thyroid cancer or minimally invasive follicular thyroid cancer (capsular invasion only). Reoperation for minimally invasive follicular cancer or occult papillary carcinomas is also usually unnecessary.' The prognosis in such patients is usually excellent. The outcome of such patients, when compared with similar patients with papillary thyroid cancer who underwent total thyroidectomy during the same period, was similar, suggesting that reoperation is usually not necessary for patients with occult or minimally invasive tumors who have undergone lobectomy. This compromise is mainly due to the increasing morbidity of reintervention and because the prognosis is good without reoperation. Reoperative thyroidectomy is often associated with increased complications, including recurrent laryngeal nerve injury and hypoparathyroidism. Bearhs" reported that vocal cord paralysis occurred in 12.1% and hypoparathyroidism in 11.2% of the patients having thyroid reoperations for malignant disease. A low incidence of vocal cord paralysis (2%) and permanent hypoparathyroidism (4%) at reoperation has been reported by Reeve," Levin,'? Attie, 1I and their colleagues. Reeve and coworkers' experience with 408 secondary thyroidectomies during a 20-year period appears to be associated with an improved outcome." Levin and associates'? reported that there should be no higher complication rate if patients were initially treated by a thyroid lobectomy, because the remaining parathyroid glands and recurrent nerve are in unviolated territory. Nevertheless, preoperative or intraoperative recognition of the malignancy is important in limiting the number of patients requiring reoperation, and the easiest time to perform a total thyroidectomy is at the initial operation.

Total Thyroidectomy Despite possible increased risks of complications, we recommend a completion total thyroidectomy in most patients with thyroid cancer when a significant amount of normal or neoplastic thyroid tissue remains. Most papillary thyroid cancers are multifocal. Even though multifocality has only a minor detrimental effect on outcome, the likelihood of malignancy in the contralateral thyroid lobe is great." Clark reviewed his personal experience with 82 consecutive patients who underwent total thyroidectomy.P Evaluation of the resected thyroid showed that if less than a total, or "near-total," thyroidectomy were performed, 31 (61%) of the 51 patients with thyroid cancer would have had malignancy remaining in the contralateral thyroid lobe.'? Despite this observation, in most patients residual microscopic thyroid cancer in the remaining thyroid lobe does not recur. Tollefsen and colleagues 13 examined the thyroid glands of the patients who had been treated by total thyroidectomy despite clinical involvement of one lobe and found that 5 of the 17 patients (29%) had occult thyroid carcinoma in the other lobe. Despite this observation, only 4.6% of the patients who initially underwent one-sided total lobectomy proceeded to develop clinical recurrence in the opposite lobe within 15 years. This striking difference between the local recurrence rate in the opposite lobe in the group of patients undergoing lobectomy (4.6%) and the six times higher frequency of minute cancer found in the contralateral lobe

of total thyroidectomized patients has been reported by other groups.I? Obviously, most occult thyroid cancers do not grow, but no one as yet has been able to predict the course of a particular patient with residual disease. Similar observations have also been made in patients with metastatic cervical lymph nodes. Ozaki and coworkers!" studied the extent of regional lymph node involvement in 586 patients. Among the 78 patients judged as stage NO during the operation, histologic examination of the prophylactically removed lymphatic tissue revealed micrometastases in 34 cases (43.6%). Noguchi and associates'S reported that more than 80% of patients with papillary thyroid cancer who underwent prophylactic neck dissections had occult nodal metastases. Despite this observation, clinically evident nodal metastases develop in only about 8% of similar patients who do not have prophylactic neck dissections.' It also appears that papillary thyroid cancer in lymph nodes rarely metastasize to distant sites. Follicular thyroid cancers account for about 10% of thyroid cancers, are somewhat more aggressive than papillary thyroid cancers, and usually metastasize by the hematogenous route rather than the lymphogenous route." Simpson and colleagues'? analyzed 1074 patients with papillary cancer and 504 with follicular cancer treated in Canada. They demonstrated that, from a recurrence point of view, prognostic factors of papillary and follicular cancers differed. They recommended total thyroidectomy for patients with follicular thyroid cancer to facilitate postoperative uptake of radioactive iodine by possible subclinical metastases. It is also important to emphasize, however that microscopic distant pulmonary metastases in patients with papillary thyroid cancer can also be ablated with radioiodine." For this reason, we recommend total thyroidectomy and postoperative l3 l I scanning and ablative therapy for patients with papillary thyroid cancers larger than 1.5 em in diameter or extending through the thyroid capsule and in high-risk patients with thyroid cancer of follicular cell origin. Tisell and coworkers'? reported that, in 32 patients with medullary thyroid carcinoma (MTC) who had elevated stimulated plasma calcitonin (CT) levels after thyroidectomy, completion total thyroidectomy and meticulous nodal dissection resulted in normalization of CT levels in 28% of these patients and a decrease in CT levels by 40% or more in another 42%. For patients whose primary MTC invaded beyond the thyroid gland or into lymph nodes and for patients with markedly elevated CT levels, repeat operations are unlikely to be curative and CT levels usually remain elevated.P Van Heerden and associates'? reported satisfactory long-term results with a "wait-and-see" policy in the management of patients with persistently elevated CT levels but no patients were cured. These authors recommended reintervention only in those patients with radiologically or clinically demonstrable disease. We would agree that a wait-and-see policy is indicated when patients have had definitive surgery-that is, total thyroidectomy, bilateral central, and lateral neck dissections.

Thyroid-Stimulating Hormone Suppression Ozaki and colleagues" identified 19 patients with thyroid cancer among 743 patients with Graves' disease. These patients had markedly invasive tumors with lymph node

Recurrent Thyroid Cancer - - 183 metastases, even though the primary tumor was small. The clinical course in these patients suggested that thyroidstimulating antibodies playa part in the progression of these neoplasms and that these antibodies may promote thyroid cancer growth and invasion in a manner similar to TSH. Pellegriti-' and Belfiore-' and their coworkers made similar observations, but many other groups have not drawn this conclusion." Considerable clinical and biologic data suggest that welldifferentiated thyroid cancer cells of follicular cell origin often respond to TSH stimulation; TSH suppression with oral thyroxine (T4) has been a standard practice in the management of patients with thyroid cancer. To benefit, patients should receive enough thyroid hormone to suppress TSH secretion. Clark stated that dosage of thyroid hormone is critical to obtain adequate reduction of TSH.2.25 Mazzaferri and Young" studied the impact of medical (TSH suppression), surgical, and radioiodine treatment in 576 patients with papillary thyroid carcinoma. They documented a significantly lower recurrence rate in patients who received enough thyroid hormone to suppress TSH secretion. There was recurrence in 40% of patients who did not receive thyroid hormone but in only 13.1% of patients who received thyroid hormone. Unfortunately, some patients eventually escape from the suppressive effects of this treatment." Pujol et aF7 more recently reported a longer tumor-free period and improved survival among 141 patients whose TSH levels were suppressed less than 0.1 IlU/mL. Cady and colleagues" studied 761 patients who had operable, well-differentiated thyroid cancer. Contrary to these and most other reports, they did not find statistically significant improvement in survival among patients receiving thyroid hormone.i" These authors volunteered, however, that they did not know whether their patients were compliant in taking their thyroid medication and that their observation should not alter current recommendations for postoperative treatment with thyroid hormone to suppress serum TSH levels. Overall, it appears from clinical observations and laboratory studies that TSH suppression has a positive impact, at least on prolongation of the disease-free interval between surgery and recurrence, if not on survival rate, as mentioned earlier.3.27,29.}0 Therefore, all patients with differentiated thyroid cancer of follicular cell origin should be treated postoperatively with suppressive doses of thyroid hormone whether or not endogenous thyroid gland secretion is sufficient to prevent hypothyroidism. Patients with MTC and anaplastic thyroid cancer should receive enough thyroid hormone to keep them euthyroid, but suppressive doses are unnecessary because these tumors do not have TSH receptors.

Adjuvant Use of Iodine 131 A long follow-up period is required to determine the effectiveness of any treatment modality in patients with welldifferentiated thyroid cancer. Many, but certainly not all, clinicians reserve the adjuvant use of 131 1 after total or neartotal thyroidectomy for moderate- to high-risk patients with well-differentiated thyroid cancer (i.e., for those with invasive disease and less well-differentiated cancer, for tumors> 1.5 em, and for patients> 45 years of age)." Mazzaferri and Young" noted that the recurrence rate in patients who

were judged to be free of disease after surgical treatment was lower when the patients were treated with radioiodine and TSH suppression when compared with patients receiving only thyroid hormone (6.4% vs. 13.1%, respectively). In the subgroup of these patients with small primary tumors «1 em), the results of treatment with thyroid hormone only were similar to those after treatment with both 131 1 and TSH suppression. A few well-differentiated thyroid carcinomas have been documented to concentrate radioiodine in the presence of functional normal thyroid tissue. However, in most patients, removal or ablation of all normal thyroid tissue is necessary before 131 1 is effective in ablating metastatic disease. Normal thyroid tissue generally has a 100-fold greater avidity for radioactive iodine than does differentiated thyroid cancer.' Before scanning, TSH values should be greater than 30 mU/mL. This degree of hypothyroidism is usually reached 6 weeks after discontinuing T4 , 2 weeks after discontinuing triiodothyronine (T3) , or after treatment with two doses of recombinant TSH. We recommend waiting at least 6 weeks after thyroidectomy and treatment with T 3 to avoid the unpleasant symptoms of hypothyroidism and to allow the operative wound to recover from the operative edema and tissue ischemia that may influence the uptake of 131 1 by the tumor. T 3 treatment is then discontinued for 2 weeks, during which time the patient is given a low-iodine diet before scanning to increase the endogenous serum TSH level. A scanning dose of 131 1 or a treatment dose of 131 1 is then given. Several days prior to scanning and treatment, a blood test is obtained for thyroglobulin (Tg) and TSH and a pregnancy test for patients who could become pregnant. Since TSH is the best provocative test for increasing the Tg level in patients with residual thyroid cancer of follicular cell origin, documenting the Tg level is most important. A longer period of hypothyroidism prior to radioiodine treatment may influence the amount of radioactive iodine taken up by the tumor, but patients are uncomfortable." Recombinant human TSH is an alternative method used for scanning and avoids hypothyroidism.Y'" It is used for patients with brain metastases when hypothyroidism might stimulate tumor growth.

External Radiation Therapy External irradiation offers effective treatment for some patients with locally invasive, inoperable, or recurrent differentiated or poorly differentiated thyroid cancers, as well as for patients with undifferentiated thyroid cancer. External irradiation is used when there is no appreciable uptake of radioiodine in patients with known microscopic or macroscopic unresectable cancer after thyroidectomy. Such treatment is thus used in patients when other treatments have failed. These patients obviously have the least favorable prognosis. Tubiana" reported that in 15 patients with MTC who received postoperative prophylactic radiation therapy, the elevated CT levels decreased slowly. In many patients with MTC, serum CT levels remain elevated for years despite the absence of clinically recurrent tumor. Virtually all these patients have micrometastases, usually in the liver. Currently, most studies do not support the use of external radiation for occult disease.P One must be sure that patients with MTC

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Thyroid Gland

Measurement of Serum Thyroglobulin

FIGURE 20-1. MRl of a 65-year-old woman with anaplastic thyroid cancer that invades the surrounding tissues.

have received definitive treatment, which includes total thyroidectomy and bilateral central neck and ipsilateral (unilateral disease) or bilateral modified neck dissection. Several studies document that meticulous surgery can return serum CT levels to normal and presumably cure patients, especially when the CT values are slightly elevated.'? Anaplastic carcinomas of the thyroid are locally invasive and often metastatic (Fig. 20-1). Although some tumors can be completely resected, most cannot. Treatment therefore usually includes radiation and chemotherapy. Thyroidectomy is recommended as the initial treatment when complete resection is possible, whereas radiation and chemotherapy are recommended when it is not. Unfortunately, the long-term outlook is dismal, even in patients with respectable tumors. When resection is done first, the neck and mediastinum should be subsequently irradiated as soon as wound healing permits. Unfortunately, in patients with undifferentiated thyroid cancer, recurrence occurs commonly, even after surgery and radiation therapy. Some clinicians recommend the combined use of chemotherapy and radiation therapy first for 4 weeks, followed 2 weeks later with removal of as much as is safely possible, and then after 2 weeks completion of the course of radiation and chemotherapy." This is the mode of treatment we generally recommend.

Diagnosis of Recurrence After thyroid resection in patients with thyroid cancer some patients develop (l) local recurrence in the thyroid bed, (2) recurrence in the regional lymph nodes, usually ipsilateral, or (3) distant metastases. Tumor markers, Tg for papillary, follicular, and their Hurthle cell variations and calcitonin for MTC, are sensitive methods for detecting tumor persistence and recurrence.

Because normal and abnormal thyroid tissue are the only sources of Tg in the peripheral blood, patients who have undergone total thyroidectomy should have no circulating Tg except that produced by residual normal thyroid tissue or local or metastatic thyroid cancer. Measuring serum Tg levels is most useful and sensitive after total ablation of the thyroid gland, either surgically or after thyroidectomy and 1311 ablation. Tg is normally present in serum in low concentrations «60 ng/mL). Most (",95%) thyroid cancers of follicular cell origin are sufficiently differentiated to produce Tg. Even poorly differentiated thyroid cancers usually retain the ability to make Tg, even though the ability for these cancers to take up iodine has been lost. LoGerfo and associates'? reported that Tg levels in 46 members of a healthy control group ranged from 0 to 60 ng/mL, whereas all 10 patients with recurrent thyroid cancer had increased Tg levels of more than 90 ng/mL. Seven of 10 patients with known active metastatic disease had Tg levels higher than 450 ng/ml., whereas the other 3 patients with known residual but clinically inactive disease had moderately raised levels of 100 to 260 ng/mL. Duren." Schlurnberger.'? and their colleagues suggested that Tg levels higher than 40 to 50 ng/mL after total thyroidectomy suggest distant metastases. Tg levels are currently the most sensitive indicator of persistent or recurrent disease after total thyroidectomy, but Tg levels can also be helpful for following patients after treatment with less extensive procedures such as lobectomy, especially when preoperative Tg values are available.'? Measurement of Tg levels in patients receiving suppressive doses of T4 provides useful information about the presence of thyroid cancer but is not as sensitive as Tg levels after recombinant TSH or after thyroid hormone withdrawal, resulting in hypothyroidism." Tg levels in patients with residual thyroid cancer usually increase when serum TSH levels increase (e.g., when the patient is not receiving thyroid hormone in preparation for a radioiodine scan). Elevated antithyroglobulin antibody levels can produce inaccurate Tg levels in 8% to 22% of patients.f However, measuring messenger RNA transcripts of Tg in peripheral blood may solve this problem.f Tumor-associated glycoprotein antigen CA 50 has also been used as a marker for patients with persistent thyroid cancer." For patients with MTC, determining serum CT and carcinoembryonic antigen levels helps determine tumor persistence or recurrence.

Radioactive Iodine Scintigraphy Radioiodine can be given as soon as 6 weeks after total or near-total thyroidectomy. The delay following total or near-total thyroidectomy allows endogenous blood thyroid hormone levels to decrease and subsequently blood TSH levels to increase. Patients can receive T3 during the first 4 weeks to avoid hypothyroidism. T 3 is used rather than T4 because it has a much shorter half-life than T 4 (T 3 half-life '" 1 day vs. T4 haf-life '" 7 days). As previously mentioned, all thyroid hormone is then discontinued for 2 weeks and a lowiodine diet is given before scanning and or ablation. Also, as previously mentioned, thyroid cancer rarely concentrates enough 1311 to be seen in the presence of remaining normal

Recurrent Thyroid Cancer - -

thyroid tissue. Therefore, when the thyroid operation is less than near- total thyroidectomy, postoperative scanning with 131 1 identifies only the remnant normal thyroid tissue. This tissue can be ablated with about 30 mCi of 1311, but completion thyroidectomy is generally recommended. A repeat scan can be done again after at least 6 months to document possible metastatic disease. Such treatment wastes 1311, which might subsequently be necessary to ablate residual cancer. 1311 whole-body scanning is more sensitive than radiography or computed tomography scanning for detecting pulmonary or osseous metastases. However, some poorly differentiated thyroid cancers may produce Tg but not take up 1311. This is especially true in patients with poorly differentiated tumors. In such patients, Tg levels may be high (>60 ng/mL), but there is no uptake of 1311. 45 Serum Tg determination and radioiodine scanning should be considered to be complementary.tv" Kodama and coworkers" used immunohistochemical staining for T 4, T 3, and Tg. Tumors that were positive for T 4, T 3, and Tg were most likely to "take up" radioiodine. In the absence of T4 and T 3 staining, however, no prediction could be made. We recommend scanning after total thyroidectomy in hypothyroid patients and a follow-up scan 1 year after 1311 ablation in patients who had evidence of radioiodine uptake outside the thyroid bed. Subsequent scanning is probably unnecessary in low-risk patients, unless they experience clinical abnormalities or an increase in serum Tg level or, as mentioned, unless the previous radioiodine scan was positive. Ablative therapy with 1311 should rarely be used more frequently than at 6-month intervals, and for most patients at I-year intervals, because leukemia is reported to be more likely with shorter periods. Thallium 201 scintigraphy, computed tomography, magnetic resonance imaging (MRI), and positron emission tomography (PET) are also used for the detection of recurrent or metastatic thyroid carcinoma." Ohnishi and associates'? compared MRI with thallium 201 scintigraphy in the followup of 39 patients who had undergone thyroidectomy and modified radical neck dissection for differentiated thyroid carcinoma. Among 51 tumor sites, 39 sites of recurrence were detected by MRI and 24 were detected by thallium 201 scintigraphy. According to the results obtained, MRI was more sensitive than thallium 201 scintigraphy for the detection of recurrent tumors (especially for small metastatic nodes). In Japan, most surgeons treat patients with papillary thyroid cancer with lobectomy and ipsilateral neck dissection so that postoperative radioiodine scanning is usually not useful. We recommend computed tomography (without contrast material) or MRI scanning, and sometimes sestamibi or thallium scanning, for patients who are at high risk for recurrence and have residual thyroid tissue or who have no uptake on radioiodine scanning and for patients who have elevated serum Tg levels and negative radioiodine scans.

Incidence of Various Kinds of Recurrence and Management Despite the satisfying results of treatment modalities and favorable clinical course of most patients with differentiated

185

thyroid carcinomas, approximately one third of the patients who develop recurrent thyroid cancer, including low-risk patients, eventually die from the disease.v'? Among 74 patients with recurrent differentiated thyroid cancer studied retrospectively by Coburn and colleagues.l" 53% of recurrences were regional, 28% were local, 13% were in the form of distant metastases, and 6% were combined locoregional metastases. This anatomic distribution is consistent with other investigations.v-? The site of recurrence appears to influence the prognosis. Thus, Rossi and coworkers" reported that treatment was successful in 73% of patients with nodal recurrence but in only 53% of patients with local recurrence and 25% of patients with distant metastases. Coburn and associates'? reported similar findings. All of their patients with recurrent disease and distant metastases died, regardless of treatment. Kukkonen and colleagues-' reported that 11 of 20 patients (55%) with recurrent papillary thyroid cancer in the neck died and 8 of 11 patients (73%) with distant metastases died. However, other studies reported long-term survival in patients with recurrent metastatic well-differentiated thyroid cancer, especially when the metastatic foci concentrated 1311. 6,54 Different survival rates have also been reported in patients whose recurrence was detected scintigraphically versus those diagnosed clinically. The mortality or persistence of the recurrence after treatment was significantly higher in clinically diagnosed cases in contrast with scintigraphically detected cases." Obviously, when larger tumors are present, they are more difficult to remove and probably are more likely to have metastasized. Also, tumors that take up radioiodine are better differentiated and, therefore, are more likely to be less aggressive; most of these patients can be successfully treated with radioiodine. The site and predisposition for recurrence vary in different types of thyroid cancer. For example, of 168 of our patients with differentiated thyroid cancer, 8 patients with papillary cancer and 3 with follicular thyroid cancer experienced recurrent cancer in the neck. In contrast, only 2 patients with papillary cancer and 5 patients with follicular cancer experienced distant metastases." Wu and coworkers'" also reported that patients with papillary thyroid cancer are more likely to die of recurrent central neck disease and those with follicular cancer from distant metastases. Patients who develop recurrent cancer in lateral cervical lymph nodes are easier to treat successfully than those who develop recurrent cancer in the central neck, because the operative field is in unviolated tissues. Reoperative central dissections are often tedious and place the parathyroid glands and recurrent laryngeal nerve at risk." Lung metastases from differentiated thyroid cancers have been shown to accumulate more radioactive iodine than bone metastases, so that patients with lung metastases respond better to radioiodine therapy than those with bone metastases. This is especially true for micrometastases in the lung. For patients with isolated (Fig. 20-2) or only several bone metastases, surgical resection followed by radioiodine treatment is recommended. If no uptake of 1311 occurs, external radiation therapy usually relieves pain, decreases the risk of fracture, and is occasionally curative.V-? Schlumberger and associates.V as mentioned, also documented that 1311 is more effective for treatment of pulmonary micrometastases than for palliation of macronodules.

186 - - Thyroid Gland micrometastases can frequently be ablated after total thyroidectomy with postoperative 1311 therapy, especially in young patients. Resection of recurrent disease is most successful for nodal metastases, but cure and long-term palliation can also be obtained by resection of central neck recurrence as well as isolated distant metastases followed by 1311 ablation. Palliative resection is also indicated to avoid progression of central neck and mediastinal disease. In patients who have no 1311uptake in their tumors and who are Tg negative, a redifferentiation trial with retinoids has been proposed as a treatment option by Simon and colleagues, but overall the effects have unfortunately not proven to be very helpful.60

Summary

FIGURE 20-2. Radiograph of the right femur of a 60-year-old woman with follicular cancer metastasis.

This finding supports the concept of detecting and treating recurrent or persistent thyroid cancers before they become clinicallyevident. Such tumors can only be detected in patients who have been treated by total thyroidectomy and receive radioiodine scans. Recurrent cancer in regional lymph nodes is best detected by ultrasound examination and treated by modified radical neck dissection. Local recurrence in the central neck should be treated surgically and with postoperative 1311 ablation and TSH suppression therapy. External radiation treatment is helpful when tumors cannot be completely removed. As mentioned, however, local recurrence carries a poorer prognosis compared with regional lymph node metastases. Reoperations in the form of total thyroidectomy for patients who have already had bilateral procedures or debulking of the tumor masses are also associated with a higher morbidity rate and subsequent recurrent disease. For this reason, it is essential to perform a meticulous, complete hemithyroidectomy for all unilateral nodules that might be cancerous, with removal of any possible involved nodes in the central neck. Close follow-up for recurrent disease is also indicated because it is easier to cure patients and resect small rather than large metastases. Thus, initial treatment with total or near-total thyroidectomy, radioiodine scanning, and postoperative ablation with 131 1 and TSH suppressive treatment appear to decrease the incidence of recurrent thyroid cancer. 18,54 Distant

Despite the favorable clinical course of most patients with differentiated thyroid carcinoma, nearly one third of the patients who experience recurrent thyroid cancer eventually die from this disease. Therefore, every effort should be made to prevent recurrence, including (1) early diagnosis and treatment of the disease; (2) complete removal of the tumor at the initial operation; (3) total thyroidectomy, ipsilateral central neck dissection, and ipsilateral therapeutic modified radical neck dissection when indicated and when this can be done safely; (4) adjuvant use of 1311 therapy, particularly in high-risk patients postoperatively; (5) TSH suppression therapy; and (6) selective use of external radiation therapy in patients with unresectable cancer. For patients with MTC, bilateral central and lateral neck dissection are necessary. Blood Tg and calcitonin level determinations are sensitive techniques for detecting recurrent or persistent subclinical disease in patients with tumors of follicular and parafollicular cell origin, respectively. 1311 scintigraphy, ultrasonography, computed tomography, MRI, and PET are helpful, as are regular and long-term follow-up physical examinations. Early diagnosis and treatment of recurrent or persistent disease appear to improve survival; recurrence with definitive surgery or other surgery improves survival.

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bilateral lobar resection in papillary thyroid carcinoma: A retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 1987;102:1088. Clark OH. Thyroid nodules and thyroid cancer. In: Clark, OH (ed), Endocrine Surgery of the Thyroid and Parathyroid Glands. St. Louis, CV Mosby, 1985, P 56. Cady B. Surgery of thyroid cancer. World J Surg 1981;5:3. Harness JK, McLeod MK, Thompson NW. et aJ. Deaths due to differentiated thyroid cancer: A 46-year perspective. World J Surg 1988;12:623. Grant CS, Hay !D, Gough IR, et aJ. Local recurrence in papillary thyroid carcinoma: Is extent of surgical resection important? Surgery 1988;104:954. Rossi RL, Cady B. Silverman ML, et aJ. Current results of conservative surgery for differentiated thyroid carcinoma. World J Surg 1986; 10:612. Sugino K, Ita K, Mimura T, et aJ. The enucleation of thyroid tumors indeterminate before surgery as a papillary thyroid carcinoma: Should immediate reoperation be performed? Jpn J Surg 1994;24:305. Beahrs OH. Surgical treatment for thyroid cancer. Br J Surg 1984; 71:976.

Recurrent Thyroid Cancer - - 187 9. Reeve TS, Delbridge L, Brady P, et al. Secondary thyroidectomy: A twenty-year experience. World J Surg 1988;12:449. 10. Levin KE, Clark AH, Duh QY, et al. Reoperative thyroid surgery. Surgery 1992;III :604. II. Attie IN, Moskowitz GW, Margouleff D, et al. Feasibility of total thyroidectomy in the treatment of thyroid cancer. Am J Surg 1979;38:555. 12. Clark OH. Total thyroidectomy: The treatment of choice for patients with differentiated thyroid cancer. Ann Surg 1982;196:361. 13. Tollefsen HR, Shah JP, Huvos AG. Papillary carcinoma of the thyroid: Recurrence in the thyroid gland after initial surgical treatment. Am J Surg 1972;124:468. 14. Ozaki 0, Ito K, Kobayashi K, et al. Modified neck dissection for patients with nonadvanced, differentiated carcinoma of the thyroid. World J Surg 1988;12:825. 15. Noguchi S, Noguchi A, Murakami N. Papillary carcinoma of the thyroid: Developing pattern of metastases. Cancer 1970;26: 1053. 16. Donohue JH, Goldfein SD, Miller TR, et al. Do the prognoses of papillary and follicular thyroid carcinomas differ? Am J Surg 1984;148:168. 17. Simpson WJ, McKinney SE, Carruthers JS, et al. Papillary and follicular thyroid cancer: Prognostic factors in 1578 patients. Am J Med 1987;83:479. 18. Mazzaferri EL, Young RL. Papillary thyroid carcinoma: A IO-year follow-up report of the impact of therapy in 576 patients. Am J Med 1981;70:511. 19. Tisell LE, Moley JF, Wells SA, et al. Reoperation for recurrent or persistent medullary thyroid cancer. Surgery 1993;114:1090. 20. Van Heerden JA, Grant CS, Gharib H, et al. Long-term course of patients with persistent hypercaicitoninemia after apparent curative primary surgery for medullary thyroid cancer. Ann Surg 1990;212:395. 21. Ozaki 0, Ito K, Kobayashi K, et al. Thyroid carcinoma in Graves' disease. World J Surg 1990;14:437. 22. Pellegriti G, Belfiore A, Giuffrida D, et al. Outcome of differentiated thyroid cancer in Graves' patients. J Clin Endocrinol Metab 1998; 83:2805. 23. Belfiore A, Russo D, Vigneri R, et al. Graves' disease, thyroid nodules and thyroid cancer. Clin Endocrinol (Oxf) 2001;55:711. 24. Burman KD, Baker JR Jr. Immune mechanisms in Graves' disease. Endocr Rev 1985;6:183. 25. Clark OH. TSH suppression in the management of thyroid nodules and thyroid cancer. World J Surg 1981;5:39. 26. Block MA. Management of the carcinoma of the thyroid. Ann Surg 1977;185:133. 27. Pujol P, Daures JP, Nskala N, et al. Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer. J Clin Endocrinol Metab 1996;81:4318. 28. Cady B, Cohn K, Rossi RL, et al. The effect of thyroid hormone administration upon survival in patients with differentiated thyroid carcinoma. Surgery 1983;94:978. 29. Crile G Jr. Changing end results in patients with papillary carcinoma of the thyroid. Surg Gynecol Obstet 1971;132:460. 30. DeGroot MJ, Stanbury lB. The Thyroid and Its Diseases, 4th ed. New York, John Wiley, 1975, p 666. 31. Hamburger Jl, Serum TSH levels in therapy of thyroid carcinoma. J Nucl Med 1980;21:492. 32. Haber RS. Recombinant human TSH testing for recurrent thyroid cancer: A re-appraisal. Thyroid 2002; 12:599. 33. Ladenson PW. Recombinant thyrotropin for detection of recurrent thyroid cancer. Trans Am Clin Climatol Assoc 2002;113:21. 34. Tubiana M. External radiotherapy and radioiodine in the treatment of thyroid cancer. World J Surg 1981;5:75. 35. Sizemore GW, van Heerden JA, Carney JA. Medullary carcinoma of the thyroid gland and the multiple endocrine neoplasia type 2 syndrome. In: Kaplan EL (ed), Surgery of the Thyroid and Parathyroid Glands. Edinburgh, Churchill Livingstone, 1983, p 75. 36. Kim JH, Leeper RD. Treatment of locally advanced thyroid carcinoma with combination doxorubicin and radiation therapy. Cancer 1987;60:2372. 37. LoGerfo P, Stillman T, Colacchio D, et al. Serum thyroglobulin and recurrent thyroid cancer. Lancet 1977;23:881.

38. Duren M, Siperstein A, Shen W, et al. Value of stimulated thyroglobulin levels for detecting persistent or recurrent differentiated thyroid cancer in high- and low-risk patients. Surgery 1999;126:13. 39. Schlumberger M, Charbord P, Fragu P, et al. Circulating thyroglobulin and thyroid hormones in patient with metastases of differentiated thyroid carcinoma: Relationship to serum thyrotropin levels. J Clin Endocrinol Metab 1980;51:513. 40. Harvey RD, Matheson NA, Grabowski PS, et al. Measurement of serum thyroglobulin is of value in detecting tumor recurrence following treatment of differentiated carcinoma by lobectomy. Br J Surg 1990;77:324. 41. Black EG, Gimlette TMD, Maisey MN, et al. Serum thyroglobulin in thyroid cancer. Lancet 1981;2:443. 42. Sisson Je. Thyroid. In: Early PJ, Sodee DB (eds), Principles and Practice of Nuclear Medicine, 2nd ed. St. Louis, Mosby-Year Book, 1995, p 617. 43. Biscolla RP, Cerutti JM, Maciel RM. Detection of recurrent thyroid cancer by sensitive nested reverse transcription-polymerase chain reaction of thyroglobulin and sodium/iodide symporter messenger ribonucleic acid transcripts in peripheral blood. J Clin Endocrinol Metab. 2000;85:3623. 44. Skrzypek J, Jarzab B, Podwinski A. Tumor-associated glycoprotein antigens in thyroid cancer. Br J Surg 1994;81(Suppl):46. 45. Clark OH, Hoelting T. Management of patients with differentiated thyroid cancer who have positive serum thyroglobulin levels and negative radioiodine scans. Thyroid 1994;4:50 I. 46. Robbins J. Thyroid cancer. In: van Middleswort L (ed), The Thyroid Gland. Chicago, Year Book, 1986, p 405. 47. Kodama T, Fujimoto Y, Obara T, et al. Histochemical demonstration of thyroxine, triiodothyronine, and thyroglobulin in the primary lesion of thyroid carcinoma, and its predictability for radioiodine uptake by metastatic lesions. World J Surg 1988;12:439. 48. Lips P, Comans EF, Hoekstra OS, et al. Positron emission tomography for the detection of metastases of differentiated thyroid carcinoma. Neth J Med 2000;57: 150. 49. Ohnishi T, Noguchi S, Murakami N, et al. Detection of recurrent thyroid cancer: MR versus thallium-201 scintigraphy. Am J Neuroradiol 1993; 14:1051. 50. Coburn M, Teates D, Wanebo HJ. Recurrent thyroid cancer: Role of surgery versus radioactive iodine (1-131). Ann Surg 1994;219:587. 51. Davies C. Surgery of thyroid cancer. In: Lynn J, Bloom SR (eds), Surgical Endocrinology. Oxford, England, Butterworth/Heinemann, 1993, p 254. 52. Young RL, Mazzaferri EL, Rahe AJ, et al. Pure follicular thyroid carcinoma: Impact of therapy in 214 patients. J Nucl Med 1980;21:733. 53. Kukkonen ST, Reijo KH, Kaarle OF, et al. Papillary thyroid carcinoma: The new, age-related TNM classification system in a retrospective analysis of 199 patients. World J Surg 1990;14:837. 54. Grant MD, Hay MB, Gough IR, et al. Local recurrence in papillary thyroid carcinoma: Is extent of surgical resection important? Surgery 1988;104:954. 55. Diiren M, Ertem M, Biikey Y, et al. [Thyroid carcinoma: An analysis of a personal series.] Ulusal Cerrahi Dergisi 1996;12:43. 56. Wu HS, Young MT, Ituarte PH, et al. Death from thyroid cancer of follicular cell origin. J Am Coli Surg 2000; 191:600. 57. Hamming JF, van de Velde CJH, Fleuren GJ, et al. Differentiated thyroid cancer: A stage-adapted approach to the treatment of regional lymph node metastases. In: Hamming JF (ed), Differentiated Thyroid Cancer: Current Considerations on Diagnosis and Surgical Treatment. Leiden, Netherlands, Drukkerij Groen BV, 1988, P 65. 58. Schlumberger M, Tubiana M, de Vathaire F, et al. Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab 1986;63:960. 59. Marocci C, Pacini F, Elisei R, et al. Clinical and biological behaviour of bone metastases from differentiated thyroid carcinoma. Surgery 1989;106:960. 60. Simon D, Koehrle J, Reiners C, et al. Redifferentiation therapy with retinoids: Therapeutic option for advanced follicular and papillary thyroid carcinoma. World J Surg 1998;22:569.

Thyroidectomy Sten Lennquist, MD, PhD

The Accurately Performed Thyroidectomy: A Challenge with a Bad Response Thyroid surgery has been and always will be the most common endocrine surgical operation. Some subspecialists in endocrine surgery are performing only thyroid and parathyroid operations. Even in specialized centers in which the rarer endocrine tumors (adrenal and gastrointestinal) constitute an appreciable part of the workload, thyroid gland operations are still the most common procedures. An accurately performed operation on the thyroid gland requires both experience and technical ability. In my experience, including more than 20 years of highly specialized endocrine surgery in a large university hospital, a good thyroid operation presents a greater challenge and requires more technical precision and skill than an adrenalectomy or removal of any gastrointestinal endocrine tumor. Many other experienced endocrine surgeons are of the same opinion. The thyroid operation is considered by many to be at the zenith of endocrine surgery; the surgeon who can perform a good thyroidectomy can, with little additional training, handle most of the other operations within this field, because the technique required is much the same. With this background it is astonishing that relatively little effort is put into teaching the art of thyroid surgery. The main reason for this may be that it is more glamorous to teach and talk about rare endocrine tumors (that most general surgeons will never see) than to teach "everyday routine work." Teaching about proper surgical technique is essential if we, as surgeons, are to avoid complications. When thyroid operations are performed without sufficient interest, training, or experience, the incidence of preventable complications increases. In many reported series, the incidence of complications is high: figures such as 5% for persistent recurrent laryngeal nerve injuries after operations for benign thyroid lesions have been reported, I whereas it has been documented repeatedly that the incidence of such complications can be close to 0% or at least less than 1%.2-5 Figures for

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persistent hypoparathyroidism of 20% or more after bilateral operations have been reported," whereas it has also been shown that with careful technique this figure should be less than 1%.2-5,7 Of concern is that the figures in unreported series are even higher," Both hypoparathyroidism and recurrent laryngeal nerve injury cause disability and suffering for patients. One of the greatest responsibilities for endocrine surgeons today is to make these poor results a thing of the past by designing appropriate training programs that establish uniform protocols for accurate reporting of results and uniform guidelines and standards for performing these operations.

General Principles The following principles apply to all thyroid operations: 1. Good exposure of the thyroid gland is essential for good results. 2. No operation should be performed on the thyroid gland without proper identification of the anatomic structures. 3. Bleeding can and should be kept to a minimum. 4. Diathermy (even bipolar) should be avoided in the area around the laryngeal nerves.

Optimal Access As in all operations, optimal access to the entire operative field is one of the keys to success. It is a misconception, however, that good exposure means a long incision. Good exposure can be achieved by a number of simple procedures, which are described later. Time and effort spent learning these techniques are repaid many times during the operation.

Identification of the Anatomic Structures Another misconception is that operations in this area could or even should be done without proper identification of the anatomic structures. It is hoped that this way of operating

Thyroidectomy - - 189 has been abandoned today. As late as 1976, however, published recommendations could be found that advocated that "the dissection at no time should be directed at identification and uncovering of the recurrent laryngeal nerve," I and identification of the parathyroid glands was described as "an erroneous guesswork implying a risk of inducing hypoparathyroidism."} It is still possible to find surgeons who continue to follow these principles; this is difficult to understand because the general principle in surgery is that it is "always better to see what you are doing." It is generally considered to be impossible to perform a safe, complete lobectomy without identification of the anatomic structures. The argument that time is saved by not identifying the anatomic structures is also based on a false premise: a surgeon who can see what he or she is doing operates not only more safely but also faster than a surgeon who does not know precisely where the parathyroid glands or recurrent nerves are positioned."

Minimal Bleeding My recommendation is that suction should not be used routinely during thyroid surgery. First, the surgeon who does not use suction dissects gently and precisely, with meticulous ligation of vessels. Second, frequent suctioning may injure the parathyroid glands and the nerves.

Restricted Use of Diathermy The true state of the art of thyroid surgery can best be judged by the way in which the recurrent laryngeal nerves are handled. This is where the truly skilled thyroid surgeon can be separated from the others. The process of meticulous dissection and ligation of the vessels in Berry's ligament requires absolute precision. It is a good technical exercise for the whole field of endocrine surgery and should be done properly. This is the only safe way to avoid injuries to the recurrent laryngeal nerve.

description of the additional maneuvers needed for a resection or total thyroidectomy.

Access to the Gland Dressing of the operation field, lines of incision, and the technique of freeing and mobilizing the thyroid gland are shown in Figures 21-1, 21-2, and 21-3. After these first steps, it is a matter of personal preference whether to start the free dissection of the lobe by the lateral (starting at the recurrent laryngeal nerve and inferior thyroid artery) or the cranial (starting with the superior thyroid artery) approach. Both are used by experienced thyroid surgeons, but I prefer to start with the lateral approach, which I also use when teaching. This approach provides good mobilization of the thyroid lobe at an early stage of the operation and, therefore, facilitates dissection of the superior pole vessels. It also provides better exposure of the external branch of the superior laryngeal nerve. When the goiter or tumor is large, however, it can be difficult to identify the inferior thyroid artery and recurrent laryngeal nerve without first mobilizing and dividing the superior pole vessels, so in these cases I start superiorly.

The Recurrent Laryngeal Nerve and the Inferior Thyroid Artery The best way to identify the recurrent laryngeal nerve is to stand on the opposite side of the patient, with the patient rotated toward you, and apply firm traction to the thyroid lobe, pulling it upward and toward the midline, putting the tissues lateral to the thyroid under tension. This traction is best applied with a gauze sponge held in the surgeon's hand. Passing grasping instruments or sutures through the thyroid

Resection or Complete Lobectomy? A complete thyroid lobectomy and isthmectomy should be performed for all unilateral nodules, for several reasons. First, if additional surgery is required, the field of a previous operation should be avoided because it makes reoperation more difficult and considerably increases the risk of complications. This can easily happen because neither fine-needle aspiration cytology nor frozen section will always give the correct histopathologic diagnosis. Second, if one accepts the concept that operations on the thyroid gland should be performed only with proper identification of the anatomic structures, complete hemithyroidectomy is no more difficult than resection and may be even simpler and more straightforward." In fact, it can be accomplished with less bleeding and more precision. In most training programs in endocrine surgery, the first step should be to learn how to perform a complete lobectomy followed at a later stage by a resection. The technique of hemithyroidectomy is described in the following text in detail, step by step, followed by a short

FIGURE 21-1. The incision is made two fingerbreadths above the clavicles and 3 to 3.5 cm on each side of the midline, which is

sufficient for full access to the thyroidgland. If there are metastatic lymph nodes in the lateral compartment of the neck, the line of incision should be somewhat extended, but vertical incisions should be avoided. (From LennquistS. Surgical strategyin thyroid carcinoma. Acta Chir Scand 1986; 152:321.)

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A

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c

B

FIGURE 21-2. A, The subcutaneous fat and platysma muscle are divided in the line of incision and dissected free from the underlying investing fascia of the neck and the anterior jugular veins. To facilitate the later dissection in the midline, it is important that the free dissection of the platysma is extended in a cephalad direction to well above the thyroid cartilage (B) and in a caudal direction to the substernal notch (C). (From Lennquist S. Surgical strategy in thyroid carcinoma. Acta Chir Scand 1986;152:321.)

gland is less effective and may cause bleeding from the thyroid capsule or possible spreading of malignant cells. During this traction, the fascia between the thyroid gland and the common carotid artery can be opened by a combination of sharp and gentle blunt dissection with a hemostatic forceps, starting laterally. The dissection should always be parallel, rather than perpendicular, to the anticipated course of the nerve. The neurovascular intersection (where the inferior thyroid artery crosses the recurrent laryngeal nerve) should be identified (Fig. 21-4), and a loop placed around the trunk of the inferior thyroid artery. Slight tension applied to this loop facilitates further gentle dissection around the recurrent laryngeal nerve. This loop should be removed when the dissection has been completed. The inferior thyroid artery should be ligated not truncally but peripherally on the

A

capsule of the thyroid gland to preserve the vascular supply to the parathyroid glands (see Fig. 21-4).

The Superior Laryngeal Nerve and the Superior Thyroid Artery As mentioned, the dissection around the superior thyroid artery is made considerably easier by the procedure just described: incision of the fascia in the midline as far as the sternal border and previous lateral mobilization of the thyroid lobe. After these procedures are completed, one can place a finger behind the superior pole and rotate it upward. Transverse division of the muscles is rarely necessary. The most critical structure to keep in mind when dividing the vessels of the superior pole is the external branch of the

B

FIGURE 21-3. A, After division of the investing fascia in the midline, the fascia covering the thyroid gland is carefully incised so that the surface of the gland is clearly seen. It is most important to obtain the correct plane of cleavage. The thyroid lobe in most cases can easily be mobilized and rotated medially and upward with a sweeping finger movement. B, During this mobilization, care must be taken not to tear the medial thyroid vein, which is ligated and divided. (From Lennquist S. Surgical strategy in thyroid carcinoma. Acta Chir Scand 1986;152:321.)

Thyroidectomy - -

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FIGURE 21-4. The first step after mobilization of the thyroid lobe is to identify the recurrent laryngeal nerve (1) and the inferior thyroid artery. As soon as the nerve is identified, a thread is pulled around the trunk of the inferior thyroid artery (2). Slight tension on this thread facilitates further dissection to free the nerve. After free dissection of the nerve, this thread should be removed and the artery ligated, not truncally but peripherally. Otherwise, the vascular supply of the parathyroid glands (3) will be compromised. (From Lennquist S. The thyroid nodule: Diagnosis and surgical treatment. Surg Clin NorthAm 1987;67:221.)

superior laryngeal nerve. This nerve branch has been referred to as the "neglected" nerve in thyroid surgery. Injuries to it may easily be overlooked because they are difficult to diagnose at laryngoscopy and because the initial symptoms are often minimal and regarded as "natural postoperative voice disturbance without injury to the recurrent laryngeal nerve." Jansson and Tisell lo performed electromyographic studies in an unselected series of patients after thyroid surgery and reported that more than 20% had persistent symptoms (e.g., voice exhaustion and impaired ability to sing) that were confirmed by electromyography as being caused by injury to the external branch of the superior laryngeal nerve. These symptoms can be especially troublesome to singers and professional speakers. Preservation of this nerve deserves proper attention. In anatomic and clinical studies of the superior laryngeal nerve, with special reference to its anatomic relations to the pharyngeal constrictor muscle, we found that in 20% of cases the distal part of the nerve was entirely covered by fibers of that muscle. I I In these cases, the nerve could not be identified without intramuscular dissection, which probably does more harm than good. On the other hand, 20% of the nerves that passed lateral to the pharyngeal constrictor muscle took a perilous course, partly lateral to the superior thyroid artery and its branches. I recommend that the tracheothyroid space always be carefully dissected and that the superior thyroid artery and its branches be skeletonized before division. When the superior laryngeal nerve is not identified during this procedure, identification by dissection into the pharyngeal constrictor muscle is not recommended. Our technique is shown in Figure 21-5. This does not take long, and it lessens the risk of injuring the external branch of the superior laryngeal nerve. In this way, many patients can be spared the unnecessary

C

FIGURE 21-5. Technique for preservation of the external branch of the superior laryngeal nerve. A, A hemostatic forceps is placed on the thyroid part of the superior thyroid artery (4). B, During traction on this forceps caudally and laterally, the cricothyroid space is opened up with another forceps so that the external branch of the superior laryngeal nerve (5) can be identified and dissected free. C, The superior pole vessels can now be ligated easily without risk of injury to the nerve. (From Lennquist S. The thyroid nodule: Diagnosis and surgical treatment. Surg Clin North Am 1987;67:222.)

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inconvenience and discomfort of vocal disturbance and loss of singing ability. When the vessels of the superior pole have been ligated and divided, the pole is mobilized, and the lobe can be retracted medially and downward and inspected in its entirety from the lateral side.

The Parathyroid Glands Even though hypoparathyroidism does not occur after unilateral thyroid operations, one should treat every parathyroid as if it were the last, because one never knows whether the patient may require a thyroid operation on the other side. This means that one should always attempt to identify both parathyroid glands on both sides. Some parathyroid glands are present in ectopic locations so that all parathyroid glands will not be identified in all patients (see Chap. 38). The lower gland, for example, is frequently situated in the thymus. Routine exploration of the thymus to find such a gland is not recommended because it might devascularize the parathyroid glands. When neither parathyroid gland can be identified during thyroid lobectomy, the thyroid capsule must be scrupulously examined to ensure that the missing gland is not removed accidentally. It has long been thought that the vascular supply of the parathyroids comes only from the inferior or superior thyroid artery, or both. This is not true. We used laser Doppler flowmetry to study the parathyroid circulation during thyroid surgery" and found that an appreciable part of the vascular supply to the parathyroid glands comes from the small vessels in the thyroid capsule, without apparent communication with the superior or inferior thyroid arteries. Using meticulous technique, most of these vessels can be preserved by dissecting them downward, even during complete removal of the thyroid gland. Truncal ligation of the inferior thyroid artery should be avoided and should be done only when technical problems arise; otherwise, it should be divided peripherally to the neucovascular intersection on the thyroid capsule (see Fig. 21-7 A). The procedure for preservation of the parathyroid glands is shown in Figure 21-6. In some patients, it is impossible to dissect the parathyroid gland free from the thyroid capsule with an adequate vascular supply. Such glands should be removed, cut into small pieces with a microsurgical knife, confirmed histologically, implanted into an adjacent muscle, and marked by a nonabsorbable suture. In the case of an aggressive tumor with the potential for recurrence, the parathyroid gland should be autotransplanted outside the operation field.

Final Dissection of the Recurrent Laryngeal Nerve As the thyroid lobe is rotated further medially, the recurrent laryngeal nerve should be systematically and carefully dissected free from the thyroid gland (Fig. 21-7A to C). There are many variations in the anatomic relationship among the recurrent laryngeal nerve, the inferior thyroid artery and its branches, and the thyroid gland. The nerve may run in front of or behind the inferior thyroid artery and its branches, and more than 30 variations have been described, sometimes differing on the two sides. In 40% to 80% of cases, the nerve

A

B FIGURE 21-6. Technique for preservation of the parathyroid gland. A, The upper parathyroid gland (3) is gently loosened from

the thyroid capsule and dissected downward, with preservation of its vascularsupply. B, The figurealso illustrates the rather common branching of the recurrent laryngeal nerve (I) immediately after the neurovascular intersection where the nerve passes the inferior thyroid artery (2). (From Lennquist S. Surgical strategy in thyroid carcinoma. Acta Chir Scand 1986;152:321.)

may branch into two or more parts before it enters the larynx (see Fig. 21-6). This branching may be below the level of the thyroid, which further increases the number of possible variations. In about 1% of patients, the recurrent laryngeal nerve on the right side is nonrecurrent and runs directly from the cervical vagus to the larynx. It may also be transposed among branches of the inferior thyroid artery, resulting in its transposition to a level anterior to the wall of the trachea. Consequently, there is no "safe" level at which the surgeon can maneuver without first identifying the recurrent nerve. It is clear that the recurrent laryngeal nerve must be identified and dissected precisely (see Figs. 21-6 and Fig. 21-7). After the thyroid lobe has been separated from the tracheal wall, the isthmus is divided at the point where it enters the opposite lobe, and the remaining thyroid tissue is continuously sutured.

Thyroidectomy - - 193 Using intraoperative scintigraphy, we have shown that one of the most common areas in which there is residual uptake of iodine is the site of the pyramidal lobe. 13 This indicates that this structure is difficult to identify and remove completely. Good access to the pyramidal lobe by extension of the midline incision between the strap muscles is, therefore, important. The pretracheal fascia (anterior superior suspensory ligament) and all thyroid tissue associated with it should be excised, together with the thyroid gland.' Care should be taken to stay medial when mobilizing the pyramidal lobe and to stay caudal to the cricothyroid muscle when dividing the anterior superior suspensory ligament to avoid injury to the external branch of the superior laryngeal nerve.

A

B

Closing the Wound Using drains after thyroidectomy cannot replace good hemostasis and are of little or no use if severe postoperative bleeding occurs. To reduce or remove a small hematoma, however, a drain can sometimes be useful. If a drain is used, it should be a small silicone drain with a closed, passive evacuation system. Active suction fails to increase the evacuation capacity and may injure the recurrent laryngeal nerve. The strap muscles are reapproximated, as is the platysma, with interrupted or continuous absorbable sutures. The skin may be closed by subcuticular suture, or with the use of special broad clips removed after the first or second day, and Steri-Strips placed. Whichever technique is used, it should be done carefully; scars in this area can and should be almost invisible.

Resection of the Opposite Side The only difference between thyroid lobectomy and thyroid resection, if or when this is indicated, should be that the final separation of the thyroid lobe from the wall of the trachea is not done. Identification of the anatomic structures and the thorough mobilization of the thyroid lobe are the same.' Mobilization of the thyroid lobe by the technique just mentioned enables adjustment of the remnant to the optimal size and makes a safe resection possible, with minimal risk or complications.!':'"

C FIGURE 21-7. Technique for final free dissection of the inferior laryngeal nerve (I). A, The branches of the inferior thyroid artery (2) are individually ligated with absorbable sutures and divided;

in this way, the lobe can be successively separatedfrom the nerve. Before entering the laryngeal cartilage, the superior laryngeal nerve temporarily diverges in a ventral direction and then turns back toward its entrance. This "knee" of the nerve is one of the most critical points of the dissection. In the final separation of the thyroid lobe from the tracheal wall,the fine paratracheal vessels (6) in the ligament of Berry have to be ligated before division. At this closerangeto the nerve, diathermy shouldnotbe used. C, Afterdivision of the ligament of Berry, the thyroid gland can be separated from the tracheal wall with a sharp knife. The thyroidcapsulenow can be removed intact, and no residual tissue is left on the tracheal wall (8) or at the nerve entrance (7). 9 = carotid artery; 10 = vagal nerve; II = internal jugularvein. (FromLennquist S. Surgical strategy in thyroid carcinoma. ActaChir Scand 1986;152:321.) B,

Total Thyroidectomy Total thyroidectomy in reality is two hernithyroidectomies.P'" Because every surgeon who deals with the thyroid gland should be able to perform a safe, complete lobectomy, he or she should also be able to perform a safe complete bilateral hemithyroidectomy or total thyroidectomy.' When performing a total thyroidectomy, I recommend an en bloc procedure, which means that the hemithyroidectomy is continued on the opposite side without dividing the isthmus, and the whole thyroid is removed as one piece (together with the lymph nodes in the central compartment of the neck if there are any lymph node metastases). This technique has been described in detail elsewhere.t->!? Dissection of the lymph nodes in the lateral compartment of the neck and the management of invasive tumors are described in Chapter 22.

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Goiters or Thyroid Tumors in the Mediastinum It is possible to remove most intrathoracic goiters and thyroid tumors through a cervical incision. If it is difficult to mobilize the thyroid lobe from the mediastinum, several procedures, discussed next, may help. TRANSVERSE DMSION OF THE STRAP MUSCLES

When it is necessary to divide the sternohyoid or sternothyroid muscles, or both, this should be done in the top of the wound to avoid scar fixation and to denervate less muscle, because the ansa hypoglossal nerve innervates these muscles inferiorly. DMSION OF THE SUPERIOR THYROID ARTERY

One should divide the superior thyroid artery and veins because this makes it easier to pull the lobe upward. DMSION OF THE ISTHMUS

Division of the isthmus further facilitates the pulling of the goiter upward from the mediastinum. T INCISION

Although making an inferior T in the Kocher transverse collar incision is rarely necessary, in some patients it avoids a mediastinotomy and also increases the preparedness for a sternal split if excessive bleeding were to occur when mobilizing the substernal mass. If these procedures, done by an experienced surgeon, are insufficient to mobilize the thyroid from the mediastinum, I do not recommend dividing or morselizing the tissue to get it up, as has been advocated by others. This is not good surgery, and in these patients a median sternotomy should be done. The risks and discomforts of median sternotomy have been exaggerated. The procedure is performed daily in thousands of patients worldwide for cardiac operations and can be done with minimal morbidity. 18 Some patients have pain after sternotomy because it is not done properly. Some surgeons believe that performing a partial split is less dangerous and causes less pain. This is wrong. Partial sternotomy means breaking the sternocostal cartilage when opening the chest. This causes considerable postoperative pain. The technique for mediastinal exploration is described elsewhere."

Summary Thyroid surgery requires experience and recogrution of the anatomy, especially the parathyroid glands and recurrent, and external laryngeal nerves. The risk of complications

during thyroid operations should not exceed 1% to 2%. Complication rates higher than 5% suggest that the surgeon does not have sufficient training or interest in thyroid surgery and should improve his or her training or refer the patients elsewhere.

REFERENCES I. Perzik SL. The place of total thyroidectomy in the management of patients with thyroid disease. Am J Surg 1976;132:480. 2. Clark OH. Total thyroidectomy: The treatment of choice for patients with differential thyroid cancer. Ann Surg 1982;196:361. 3. Smeds S, Madsen M, Lennquist S, et al. Evaluation of preoperative diagnosis and surgical management of thyroid tumors Acta Chir Scand 1984;150:513. 4. Total thyroidectomy in the treatment of thyroid carcinoma. In: Thompson NW, Vinik AU (eds), Endocrine Surgery Update. New York, Grone & Stratton, 1983. 5. Thompson NW. The resection therapy of carcinoma of the thyroid. Surg Rounds 1984;100. 6. Crile G Jr. Changing trends and results in patients with papillary carcinoma of the thyroid. Surg Gynecol Obstet 1971;131:460. 7. Andaker L, Johansson K, Lennquist S, Smeds S. Surgery for hyperthyroidism: Hemithytoidectomy plus contralateral resection or bilatera resection? A prospective randomized study with regard to postoperative complications and long-term results. World J Surg 1992;16:765. 8. Scandinavian Surgical Society. Multicenter study on thyroid carcinoma. Proceedings of the Scandinavian Surgical Society, Division of Endocrine Surgery, Stockholm, 1991. 9. Lennquist S. Total Thyroidectomy with Safe Preservation of the Laryngeal Nerves and Parathyroid Glands. Chicago, American College of Surgeons Film Library, 1991. 10. Jansson S, Tisell LE. Partial superior laryngeal nerve (SLN) lesions before and after thyroid surgery. World J Surg 1988;12:526. II. Lennquist S, Cahlin C, Smeds S. The superior laryngeal nerve in thyroid surgery. Surgery 1987;102:999. 12. Ander S, Johansson K, Lennquist S, Smeds S. Human parathyroid blood supply determined by laser Doppler flowmetry. World J Surg 1994;18:417. 13. Lennquist S, Persliden J, Smeds S. The value of intraoperative scintigraphy as a routine procedure in thyroid carcinoma. World J Surg 1988;12:586. 14. Lennquist S, Smeds S. The hypermetabolic syndrome hyperthyroidism. Surg EndocrinoI1991;9:127. 15. Lennquist S. Surgical strategy in thyroid carcinoma: A clinical review. Acta Chir Scand 1986;152:321. 16. Lennquist S. The thyroid nodule: Diagnosis and surgical treatment. Surg Clin North Am 1987;67:213. 17. Lennquist S. The laryngeal nerves in thyroid surgery. In: van Heerden J (ed), Common Problems in Endocrine Surgery. Chicago, Year Book, 1988, p 123. 18. Lennquist S, Andaker L, Lindvall B, Smeds S. Combined cervicothoracic approach in thymectomy. Acta Chir Scand 1990;156:53.

Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer J. F. Hamming, MD, PhD. J. A. Roukema, MD, PhD

The surgical management of patients with thyroid cancer continues to be a challenge. Over the last 3 decades surgeons have debated about the "best" management of patients with this disease. Randomized trials concerning the surgical treatment are nonexistent, because execution of such studies is hampered by the low incidence of thyroid carcinoma and the relatively indolent behavior. Treatment results are based on retrospective analysis of mostly heterogeneous groups of patients. The discussion section in publications almost invariably leads to the statement that the proposed and presented treatment modalities are to be preferred, but in fact only tentative conclusions can be drawn. Proponents of more extensive surgery can find theoretical arguments, and proponents of more conservative management refer to the lack of proven benefit of the aggressive approach. This is applicable to the extent of thyroidectomy as well as the approach toward the management of regional lymph nodes.' Nevertheless, progress has been made, and there is a tendency toward more selected management for the different types of thyroid cancer. Differences in opinion toward the management of regional lymph node metastases of thyroid cancer concern mainly papillary, follicular, and medullary thyroid cancer. The treatment of lymph node metastases of other less frequently occurring types of thyroid cancer is not discussed in this chapter. Well-differentiated, papillary, and follicular adenocarcinomas arise from follicular cells and are the most common types of thyroid cancer. Medullary carcinoma represents about 7% of all thyroid cancers, but 15% of deaths due to thyroid cancer. It is also considered to be a differentiated form of thyroid carcinoma, but it originates from parafollicular, or C, cells. Its biologic behavior is somewhat more aggressive than papillary or follicular thyroid cancer. The prognosis of patients with thyroid cancer correlates with histologic type, extrathyroidal growth of the primary tumor, and the presence of distant metastases at the time of

diagnosis. The prognosis of patients with intrathyroid papillary cancer differs only slightly from the average life expectancy. On the other hand, patients with distant metastases of medullary carcinoma have a short life expectancy. Patient-related factors such as age and-to a lesser extentgender are also important in assessing prognosis in an individual patient with thyroid cancer. The natural history of the three types of differentiated thyroid carcinoma differs from each other. Papillary cancer spreads predominantly to the regional lymph nodes. The influence of regional lymph node metastases on prognosis in patients with papillary cancer is questionable. Distant metastases occur in about 10% of patients and predict an unfavorable prognosis. Follicular cancer mostly spreads to distant sites; lymph node metastases are far less common than in papillary carcinoma and, when present, indicate a worse outcome. Medullary cancer frequently metastasizes to the regional lymph nodes and the presence of nodal involvement predicts a worse prognosis. Distant metastases, especially to the liver, are common. Although total thyroidectomy in patients with medullary cancer is widely accepted, the necessity of total thyroidectomy in all cases of papillary and follicular cancer remains controversial. Radical neck dissection for lymph node metastases in patients with differentiated thyroid cancer is no longer considered necessary. Modified radical neck dissection, also referred to as modified neck dissection, is usually recommended for patients with regional lymph node metastases due to papillary, follicular, and medullary cancer. For most patients with medullary cancer, standard modified neck dissection is advocated. Since the influence of regional lymph node metastases on the prognosis of patients with papillary cancer is debated, the benefit of prophylactic or elective neck dissection in these patients has not been established. The "best" management of lymph node metastases

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Thyroid Gland

is based on retrospective series and tradition. In this chapter we describe the rationale and technique of modified neck dissection for papillary, follicular, and medullary thyroid cancer. Although there are no major disagreements about the technique of modified neck dissection, the rationale and indications for prophylactic neck dissection remain controversial. To formulate a sensible approach for the treatment of patients with thyroid cancer metastatic to cervical and mediastinal lymph nodes, the lymphatic drainage and the incidence and localization of nodal metastases at the time of diagnosis must also be considered.

Lymphatic Drainage of the Thyroid The thyroid has an extensive lymphatic drainage, which may flow in a variety of directions.P Thyroid follicles are enveloped with lymphatic vessels. The intraglandular lymphatic connections are extensive and enable lymphatic drainage from one lobe to the other through a complex of intrathyroidal and pericapsular nodes." The major lymph vessels running efferently follow the branches of the thyroid arteries and veins in three main directions: superiorly, laterally, and inferiorly. The upper region of the thyroid is drained along the superior thyroid vessels to the upper jugular lymph nodes. From the isthmus, the lymph vessels run to the prelaryngeal, or Delphian, nodes, which are connected to the upper jugular nodes. Lateral lymph vessels follow the medial thyroid vein to the mid- and lower jugular nodes. The lower lymphatic drainage is to the pretracheal and paratracheal nodes and the lower jugular chain. Connections to the anterior mediastinal nodes and retropharyngeal nodes are common, but drainage to the submandibular and suprahyoid nodes is less common. Through the pericapsular, pretracheal, and prelaryngeal nodes, contralateral nodal involvement occurs.' The extensive intrathyroid and extrathyroid lymphatic connections probably contribute to the high incidence of multifocal intraglandular thyroid carcinoma." Initial lymph node metastases are most commonly observed in the central neck compartment (medially to the carotid sheet) in the pretracheal and paratracheal nodes and subsequently spread to the lateral compartment in the deep inferior and lateral cervical nodes.' In general, patients with larger primary thyroid tumors and multifocal intraglandular tumors have more extensive lymph node metastases," but patients may also present with nodal metastases and an occult thyroid cancer.

Applied Surgical Anatomy Anatomic subdivisions of the neck define its borders and are important to recognize." Recently, the Committee for Head and Neck Surgery and Oncology of the American Academy of Otolaryngology-Head and Neck Surgery has proposed an update of the neck dissection classification." The new guidelines present some minor revisions but do not differ substantially from the previous guideline. The sternocleidomastoid muscle is the most prominent landmark and covers the major vessels of the neck: the carotid artery and the internal jugular vein.

Six major nodal regions can be distinguished and are expressed as levels in the classification. A superior or submandibular and submental triangle (level l) is bounded by the mandible, the hyoid bone, and the posterior belly of the digastric muscle. The anterior belly of the digastric muscle divides the superior triangle in a submental part anteriorly and a submandibular part posteriorly. The submandibular gland is part of this region. Three jugular regions are anteriorly bound by the lateral margin of the sternohyoid muscle and the posterior edge of the sternocleidomastoid muscle. The upper jugular nodes (level 2) run down from the skull base to the level of the horizontal border of the hyoid bone, which forms the cranial limit of the midjugular region (level 3). The inferior border of the cricoid cartilage bounds the rnidjugular (level 3) from the lower jugular region (level 4); the lower jugular nodes are located between the inferior border of the cricoid cartilage and the clavicle. The superior boundary of the posterior triangle of the neck (level 5) is the apex formed by the convergence of the sternocleidomastoid and trapezius muscle. It is bounded anteriorly by the posterior border of the sternocleidomastoid muscle, posteriorly by the anterior margin of the trapezius muscle, and inferiorly by the clavicle. The anterior neck compartment (level 6) runs from the suprasternal notch to the hyoid bone and from the trachea to the carotid sheath. This compartment harbors the lymph nodes, which are most frequently involved in patients with thyroid cancer, and includes the lymph nodes around the thyroid, along the recurrent laryngeal nerve, the precricoid (Delphian) nodes, and the pretracheal and paratracheallymph nodes. The region from the lower neck, from the suprasternal notch to the innominate vein, is considered the superior mediastinum (level 7) and is considered separately from the six levels" but is also frequently involved in patients with thyroid cancer with metastatic nodes in the tracheoesophageal groove. Level 6 and the superior mediastinum together form the central neck compartment. Starting dorsally in the neck at the anterior border of the trapezius muscle, the deep layer or "floor" of the operating field consists of the splenius muscle of the head and the levator muscle of the scapula with the spinal accessory nerve. Then the scalenus muscles follow with the brachial plexus running between the anterior and middle scalenus muscles. The phrenic nerve runs across the anterior scalenus muscle. Anteriorly, one comes to the vagal nerve, the internal jugular vein, and the carotid sheath. The hypoglossal nerve passes under the digastric muscle. Ventrally, the laryngeal muscles, esophagus, trachea, and thyroid are located and in this area special attention has to be drawn to the superior laryngeal nerve, recurrent laryngeal nerve, and parathyroid glands. The surgical anatomy of the superior and recurrent laryngeal nerve as well as the parathyroids are discussed elsewhere (see Chapter 2). Lymph nodes can usually be removed from the superior mediastinum via the Kocher collar incision. The removal of lymph nodes caudal to the innominate vein in the mediastinum usually requires a median sternotomy. For lymph node dissections in patients with thyroid cancer, the neck should be divided into a central and a lateral neck compartment divided by the carotid sheath.' The fatty tissue encompassing the lymph nodes in the neck is situated between the first and third layers of deep

Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer - -

cervical fascia. The first layer of fascia is formed by the back side fascia of the sternocleidomastoid muscle; it runs posteriorly to the trapezius muscle and anteriorly to the digastric muscle and covers the strap muscles. The deep, or third, layer of cervical fascia covers the trachea and esophagus and runs laterally over the scalenus muscles, the levator muscle of the scapula, and the splenius muscle of the head to join the superficial cervical fascia at the trapezius muscle. The second layer of deep cervical fascia is also called the prethyroidalfascia. An aponeurotic sheet, which originates from the carotid sheet, runs sagitally to the fascia covering the strap muscles superficially and to the deep cervical fascia covering the scalenus muscles posteriorly. This aponeurotic sheet with the carotid artery as its predominant structure divides the fascia-covered tissue in a central and a lateral compartment. Because separate visceral compartments can be distinguished, the laterally located nodes cannot be truly resected en bloc with the thyroid."Consequently,the neck dissection is to be subdivided into a central neck dissection and a lateral neck dissection. In the central neck compartment, the thyroid is situated along with the trachea, esophagus, thyroid, parathyroids, and recurrent laryngeal nerves in one visceral space, which also contains the strap muscles. Superiorly it extends as far as the hyoid bone and inferiorly it runs into the superior mediastinum to the innominate vein. Laterally lies the carotid sheath, which serves as a medial border for the separate lateral compartment containing the lateral cervical lymph nodes. A modified neck dissection usually includes resection of the three jugular regions (levels 2 to 4) and the posterior triangle (level 5) as described earlier. The superior triangle or suprahyoid area harbors the submandibular and submental lymph nodes. It is usually not included in the modified neck dissection for thyroid cancer, because lymphatic spread to this region is rare.

Incidence and Localization of Lymph Node Metastases As mentioned before, papillary and medullary thyroid carcinomas frequently spread to the regional lymph nodes. Nodal involvement in follicular cancer is uncommon and when present one should consider that the tumor is a follicular variant of a papillary thyroid cancer. Although the presence and extent of initial lymph node metastases in patients with papillary thyroid cancer is correlated with tumor size,5.6,ID lymph node metastases often occur at an early stage of the disease.P'!' Even in patients with papillary carcinoma smaller than I em, metastases to the regional lymph nodes are not uncommon. I 1-13 Thus, lymphatic spread of papillary thyroid cancer is not always a sign of advanced primary disease. Lymph node metastases are sometimes the presenting symptom in patients without a palpable lesion in the thyroid.!"!? When prophylactic neck dissections are done in patients without clinical evidence of nodal involvement, 30% to 80% of patients are found to have lymph node metastases. 5,18-21 With more thorough examination, up to 90% of patients with papillary thyroid cancer have nodal involvement.5,18,19 Thus, most patients with papillary thyroid cancer have either clinical or occult regional lymph node metastases at the time of their primary treatment. Another interesting

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phenomenon is the fact that the incidence of cervical lymph node metastases is higher in young patients. 12.16, 17,22 In patients with intrathyroidal follicular cancer without distant metastases, lymph node metastases occur in about 5% of patients. Nodal involvement in patients with follicular carcinoma is associated with extrathyroidal extension of the primary tumor and is therefore a sign of advanced disease.F The presence of clinically enlarged lymph nodes in medullary thyroid cancer varies between 25% and more than 60%.23-27 More than half of the patients with medullary thyroid tumors have nodal involvement, but surprisingly about half the patients whose medullary thyroid cancers were detected by family screening also had lymph node metastases.24.26-28 Patients with hereditary medullary thyroid carcinoma may have more nodal involvement than patients with sporadic cancer.23,29 In familial disease the primary tumor is located bilaterally and lymph node metastases are also bilateral. Nodal involvement in patients with multiple endocrine neoplasia (MEN) 2B familial medullary thyroid carcinoma is more frequent than in the MEN 2A patients.'? Calcitonin is a sensitive and highly specific marker in persistent disease in patients with medullary thyroid cancer, especially after pentagastrin and/or calcium provocative testing. 31-34 Most patients with papillary and medullary thyroid cancer have unilateral lymph node metastases, but bilateral or contralateral spread occurs, especially in hereditary medullary thyroid cancer.5,6,16.19,23,35-37 Central neck nodes adjacent to the thyroid nodule are usually first involved.5,10,37-42 Metastases are found in the fatty tissue along the trachea, along the recurrent laryngeal nerves, and in the tracheoesophageal groove reaching laterally to the carotid artery (level 6). Metastatic nodes also occur in the pretracheal region and along the superior thyroid vessels. The lateral compartment along the jugular chain is usually not involved, until at least occult lymph node metastases exist adjacent to the thyroid gland.5.9,16,34,35 In the lateral compartment, the nodes along the mid and lower parts of the internal jugular vein (levels 3 and 4) are more frequently involved than those along the upper third of the vein (level 2) and those in the posterior triangle and supraclavicular region (level 5). Of all patients with nodal involvement, 80% of the metastases are found in the central neck compartment in level 6 and along the mid and lower internal jugular vein (levels 3 and 4). Unless there is extensive lymph node involvement, the submandibular and submental nodes (level I) in thyroid cancer are seldom affected. 5,16.19,43 Although lymphatic pathways to the retropharyngeal nodes are usually present.? lymph node metastases are rare in this area. The superior mediastinum is less frequently involved in patients with papillary than in patients with medullary carcinoma, although mediastinal nodal involvement is relatively common in both conditions. 6,22,24,43.44 Bilateral metastases are often found concomitantly with mediastinal nodes in patients with medullary carcinoma. 27,29,45 Metastases to the superior mediastinal lymph nodes occur most frequently when there is involvement along the internal jugular vein contralaterally to the primary tumor. 17,44,46 More distant mediastinal nodal metastases are rare, except in patients with advanced locoregional disease."

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Prognostic Significance of Regional Lymph Node Metastases In epidermoid cancers of the head and neck, the presence of regional lymph node metastases is associated with an unfavorable prognosis. In papillary thyroid cancer, nodal metastases appear to be a minor rather than a major risk factor. The prognostic significance of lymph node metastases is different for the three types of thyroid cancer. In general, nodal involvement at the time of diagnosis in papillary cancer increases the risk of recurrent cancer but has only a minor influence on overall survival. Regional lymph nodes are not commonly involved in patients with follicular thyroid cancer, but in these patients the tumor tends to behave more aggressively. Lymph node metastases in patients with medullary thyroid cancer adversely influence survival. The most important determinants for survival in thyroid cancer of follicular cell origin are tumor stage, age, histologic type, local invasiveness, and to a lesser extent gender. 12,15,22,26,47-57 Some studies suggest that the presence of clinically evident lymph node metastases in patients with papillary and follicular carcinoma has an adverse effect on survival.6,49,53,58-60 Other authors have reported that patients with nodal metastases have an increased recurrence rate, but survival is not adversely affected,15,48,51,56,61-63 Only patients with stage tumor growth beyond the lymph node capsule (pN3) have an impaired survival.>' Other studies suggest that lymph node metastases in patients with papillary carcinoma have no adverse effect on survival or recurrence rate in their patients. 12,17,47,50,55 In one study, even a slightly better prognosis in these patients was suggested.P However, these authors did not account for the fact that young patients are more likely to have nodal metastases and that the prognosis is more favorable in younger than older patients with papillary thyroid cancer. 22.58,59 In one study, which contained a relatively high proportion of node-positive patients with papillary thyroid cancer older than 45 years of age, nodal involvement was a strong independent risk factor for survival. 6 The difference in frequency of lymph node metastases in younger versus older patients with papillary thyroid cancer could explain the varying influence of lymph node metastases on prognosis. Other authors noticed that, when patients were matched by age, the presence of positive lymph nodes did have an adverse effect on the survival and recurrence rate." However, in this study 12% of the patients with nodal involvement had a follicular carcinoma and the lymph node metastases in patients with this type of thyroid cancer are known to have a more ominous effect on prognosis than in patients with papillary carcinoma. 13,56,60,64 The prognostic significance of lymph node metastases from papillary and follicular carcinoma should therefore be considered separately. Also, other authors do not discriminate between lymph node metastases from papillary or follicular carcinoma,14,36.53,59.65,66 which hampers comparative evaluation of survival analyses and does not justify selecting one type of neck dissection over another. Although most patients with papillary thyroid carcinoma have at least microscopic lymph node metastases, the recurrence rate in patients without macroscopic nodal involvement,

who are not treated with a prophylactic neck dissection, is low and usually does not exceed 20%,10,13,15.21.36,48,51,67-70 Moreover, the presence of metastatic nodes in the central neck makes nodal metastases in the lateral neck more likely, but subsequent development of recurrent disease in the lymph nodes in the jugular chain or lateral neck is relatively uncommon." Apparently, most of these occult metastases fail to grow and some may regress, The development of lymph node recurrence after primary treatment of papillary carcinoma seems to have an independent significant effect on survival in older patients, whereas the effect in younger patients is less evident. 71 As already mentioned, the presence of lymph node metastases in patients with medullary carcinoma is associated with a poorer prognosis,23,24,26,27,72 especially when metastases are found in the mediastinum.Pv' In fact, the presence of more than three nodes and nodes larger than 1 em correlate with a worse prognosis." Measurement of plasma calcitonin levels after administration of calcium and/or pentagastrin is a sensitive method of documenting when persistent disease is present. 31-33 Elevated calcitonin and carcinoembryonic antigen (CEA) levels are associated with residual or recurrent disease.

Choice of Neck Dissection Operations used to remove cervical lymph nodes vary from removing only grossly affected lymph nodes ("node picking") to the classic radical neck dissection. Crile in 1906 developed the classic radical neck dissection for local control of head and neck cancers.P Although this operation became the standard operation for most head and neck cancers, it is not used today for patients with thyroid cancer. Radical .neck dissection is associated with disfiguring cosmetic and functional results, and equally good local control and cure can be obtained with less extensive operations. 9.14,15,18.26,35.38,55,74,75 The modified neck dissection, which is called "functional" neck dissection by other surgeons." allows for an en bloc dissection ofthe lymphatic network of the neck, while preserving the functionally important structures (muscles, vessels, and nerves). The technique of modified neck dissection for thyroid carcinoma has been described,9,18,74 and the operation can be performed with minimal morbidity and favorable cosmetic results. 9,I0,36 During dissection of the central neck, it is essential to preserve the recurrent laryngeal nerve and the blood supply to the parathyroid glands. The dissection of the superior mediastinum is part of the central neck compartment dissection, including removing nodes from around the thymus gland. In patients with extensive invasive papillary and follicular thyroid cancers and more commonly with medullary cancer, it is sometimes necessary to perform a median sternotomy and remove all fatty tissue, thymus, and lymph nodes from the anterosuperior mediastinum." A modified neck dissection can be done, because most nodal metastases from thyroid carcinoma do not invade adjacent anatomic structures. Lymph node metastases are rarely found within the substance of the sternocleidomastoid muscle, even when there is extensive nodal involvement.P-" It is therefore unnecessary to sacrifice this muscle. In most

Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer - -

cases, it is possible to dissect the spinal accessory nerve free from surrounding tissue. Deformity of the neck, shoulder, and subsequently the back is reduced by the preserving the spinal accessory nerve. The internal jugular vein can also usually be preserved, but it is essential to dissect all nodes along the vein, especially behind the lower end." During bilateral modified neck dissection it is important to preserve at least one internal jugular vein to avoid possible severe facial swelling and edema. A modified or functional neck dissection is the treatment of choice for patients with metastatic thyroid cancer in the cervical nodes. It benefits especially young women, which form the largest group of patients with papillary, follicular, and medullary thyroid cancer. Sentinel lymph node dissection is now used to assess the status of lymph nodes in patients with breast cancer and melanoma and has changed the surgical management. Intraoperative lymphatic mapping has also been investigated in thyroid cancer.76-78 The technique has been carried out with a vital dye technique and/or a radiotracer technique. The sentinel node dissection seems feasible, although the false-negative rate is difficult to establish since not all patients undergo a central and modified neck dissection. As mentioned previously, the influence of occult lymph node metastases on prognosis of papillary cancer is the most questionable. Therefore, the usefulness in papillary cancer is limited because most surgeons would agree that systematic surgical resection of lymph nodes should be limited to therapeutic dissection in patients with enlarged lymph nodes. Sentinel lymph node studies might be helpful in patients with medullary cancer and small primary tumors since surgeons advocate a standard lateral neck dissection in these patients. The identification of a sentinel node in the lateral neck compartment in patients without central neck involvement might provide arguments to perform a lateral neck dissection. Further information should be obtained to clarify this issue.

Papillary and Follicular Thyroid Carcinoma A prophylactic modified neck dissection is not generally advocated. Only a few authors advocated prophylactic neck dissections, 18.62 and most recommend a more disease-related strategy. Systematic neck dissection in patients with nodal involvement and papillary or follicular thyroid cancer reduces regional tumor recurrence compared to limited nodal excision ("node picking"), but the extent of neck dissection has no proven influence on overall surviva1. 55,66,68,75 Although in one study nodal involvement of papillary carcinoma adversely influenced survival as well as the recurrence rate, more aggressive treatment did not appear to have any influence on prognosis."? Therefore, an attempt to eradicate all lymph node tissue to eliminate tumor in patients with papillary and follicular thyroid cancer seems unjustified, and it increases the risk of morbidity. However, evident metastatic disease should be resected when this can be done with minimal increased morbidity. Some surgeons6,18,62,80,8! have recommended routine removal of cervical lymph nodes from the central neck compartment concomitant with the total thyroidectomy, Other surgeons 38,49,69,82 mention careful inspection of the central neck with removal of suspicious nodes for frozen

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section; if positive, the lymph nodes in the central neck compartment are removed. Most surgeons 1,9,14,39,41,48,52,58,62,69,82-84 use the latter strategy in patients with papillary and follicular carcinoma and reserve modified neck dissection for patients with clinically evident lymph node metastases in the lateral neck. In patients without nodal involvement in the lateral neck, a therapeutic modified neck dissection can be performed later, if recurrence occurs in the lateral neck, A subsequent neck dissection is not difficult because this area has not previously been explored. Some authorities on thyroid cancer advocate mid- and lower jugular sampling in patients without clinically evident nodal involvement to decide whether a modified neck dissection is necessary.36,65,66,70,80 When these nodes are positive, a modified neck dissection is performed. They argue that lymph node metastases are associated with more aggressive differentiated thyroid cancer even though most studies using multivariate analysis fail to show an adverse effect on prognosis. A few surgeons reserve the modified neck dissection for patients with more extensive nodal involvement rather than for all patients with nodal metastases and use a limited resection or node picking for patients with limited nodal involvement. 39,47,73,81

MedUllary Thyroid Carcinoma Medullary thyroid carcinoma is biologically more aggressive than papillary or follicular thyroid carcinoma, and the presence of lymph node metastases correlates with a poorer prognosis. Medullary thyroid cancer in contrast with papillary and follicular cancer usually does not concentrate radioactive iodine,26,57,85 so this form of adjuvant therapy is usually ineffective to treat persistent or recurrent disease. Most medullary thyroid cancers are also resistant to chemotherapy or external irradiation. For these reasons, a more extensive surgical approach is warranted than in patients with papillary or follicular thyroid cancer. In patients with medullary thyroid cancer, a bilateral central neck dissection concomitantly with the total thyroidectomy is essential and uniformly advocated by experts in the field. 25,28,29,34,35,45,57,63,65,86-92 There is a potential risk of recurrent disease in the central neck in these patients, because micrometastases are frequently present in clinically node-negative patients and secondary surgery in the central neck area is associated with a high complication rate." Standard modified neck dissectionin patients with medullary thyroid cancer is controversial. Some authors45,57,65 advocate modified neck dissection directed by sampling of the lymph nodes along the ipsilateral lower and middle parts of the internal jugular vein during primary surgery in all patients. Other surgeons88,89 do not advocate jugular sampling and recommend an ipsilateral modified neck dissection when the primary thyroid cancer is 1.5 em or larger. Most surgeons29,37,90 would recommend at least ipsilateral modified neck dissection in all patients with any nodal involvement in the central neck compartment. In addition, standard ipsilateral or bilateral lateral neck dissection is advocated by some authors in all patients with medullary thyroid cancer.91,92 More evidence is necessary to determine whether extensive cervical lymphadenectomy improves overall survival. However, a normal basal and stimulated calcitonin level after completion of the neck dissection suggests a better long-term outcome.

200 - - Thyroid Gland A common problem arises when the serum calcitonin level remains elevated despite adequate surgery including total thyroidectomy, and bilateral central and lateral neck dissection including the upper mediastinum. Noninvasive and invasive imaging studies as well as venous sampling of calcitonin have been used to try and identify site or sites of persistent disease. When the localization studies are negative and the patient has had definitive surgery (total thyroidectomy, central neck dissection and a modified neck dissection), there is no consensus about how to best manage these patients. Prophylactic re-explorations have only infrequently resulted in normalization of calcitonin levels in patients who have already had appropriate dissections.W" Nevertheless long-term survival is relatively good in this group of patients without reoperations.t-P-" In medullary thyroid carcinoma, a systematic microdissection of the neck has been recommended. A thorough neck dissection using microdissection techniques with the help of magnifying glasses is performed to remove all identifiable metastatic tissue from the neck. 28,29.34 Meticulous dissection of regional lymph nodes in the central neck compartment including the superior mediastinum as well as a bilateral modified neck dissection has been shown to be superior compared to less systematic procedures with regard to the normalization of calcitonin levels and survival. 28,29,34 Some surgeons have extended the operation with a dissection of the mediastinum using median sternotomy when positive nodes were found in the superior mediastinum, but this extension has not improved their results." A longer follow-up period is necessary to confirm the merit of these procedures, but the results are promising, with serum calcitonin levels becoming undetectable in about 25% of these patients. Microdissection of the neck is time consuming, and meticulous dissection is best performed at the primary procedure before adhesions make dissections more difficult.P Medullary thyroid cancer is a relatively rare tumor, and patients with these tumors require the most experienced thyroid surgeons for the best results.

Operative Technique The lymph nodes in the central neck compartment are usually resected in continuity with the thyroid itself. The strap muscles are retracted laterally during the dissection. When the strap muscles inhibit exposure, they can be divided superiorly, since they are innervated from below. The technique of the total thyroidectomy has been described in previous chapters. As mentioned earlier, the central neck dissection puts the recurrent laryngeal nerve and the blood supply to the parathyroids at risk. The parathyroid glands are delicately dissected away from the thyroid, preserving their vascular pedicles during thyroidectomy. When they cannot be kept on a vascular pedicle, they should be removed, biopsied with frozen section, and autotransplanted.All fatty tissue and lymph nodes between the carotid sheath and the esophagus can be removed from the recurrent laryngeal nerve along the trachea and from the tracheoesophageal groove (Fig. 22-1). The recurrent laryngeal nerves must be identified to minimize the risk of injury and consequent paralysis of the vocal cords. When lymph nodes are extensively involved,

the position of the recurrent laryngeal nerve can be displaced and identification can be more difficult. In most patients removal of nodes from the recurrent nerve can be done safely. When there is extensive nodal involvement, it may be difficult to preserve the lower parathyroid gland on this side. The upper parathyroid gland is usually easier to preserve because it is situated more dorsally. Positive identification and preservation of the contralateral parathyroid glands are essential. The central neck dissection is continued into the superior mediastinum while dissecting along the recurrent laryngeal nerves bilaterally. The superior mediastinum can be dissected by removing the upper thymus with the fatty tissue after determining its relation with the inferior parathyroid glands. When the inferior parathyroid glands have not been found during thyroidectomy, they are probably embedded in the cranial portion of the thymus. Opening of the capsule of the cranial part of the thymus usually uncovers the intrathymic parathyroid gland. When another parathyroid gland has not been positively identified, it is best to leave the thymus in situ or to autotransplant the identified intrathymic parathyroid gland. The dissection is extended toward the innominate vein. Occasionally it is necessary to split the sternum (median sternotomy) for invasive or extensive tumors. When a modified neck dissection is planned, the Kocher transverse collar incision is extended laterally (MacFee extension), which provides adequate exposure in most cases. The cosmetic results of this extension are favorable. Good exposure can also be achieved by a vertical extension toward the angle of the jaw, but this extension is cosmetically less favorable. A second horizontal incision high in the neck and parallel to the initial incision is preferable cosmetically. The dissection plane of the skin flaps continues just deep to the platysma muscle and anterior to the external jugular vein. Special attention must be given to the retraction of the cranial skin flap: the mandibular marginal branch of the facial nerve runs just below the mandibula and can be compressed by retractors. This must be avoided because it results in drooling from the comer of the mouth. It is usually not necessary to transect the sternocleidomastoid muscle. The neck dissection can be performed adequately by retracting the muscle medially and laterally and working beneath it. This can be done with retractors or a rubber cord. Alternatively,the muscle can temporarily be disconnected just caudal to its insertion to the clavicle and sternum. In this situation the muscle is dissected and elevated toward the mastoid region. The superficial cervical fascia covering the sternocleidomastoid muscle is incised longitudinally over the whole length of the muscle and dissected away. When possible the external jugular vein and greater auricular nerve are preserved and retracted posteriorly by a separate vessel loop. The anterior part of the superficial fascia is dissected from the muscle and is left in continuity with the fascia, which covers the internal jugular vein and its contiguous chain of lymph nodes. The dissection either commences medially at the junction of the lower part of the internal jugular vein and the clavicle or laterally at the junction of the anterior border of the trapezius muscle and the clavicle. We prefer the medial approach where the fatty tissue and embedded lymph nodes are dissected from the internal jugular vein starting just above the sternoclavicular joint. On the left side, one should identify the thoracic duct just above the junction of the

Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer - -

201

FIGURE 22-1. Total thyroidectomy with dissection of central neck compartment and midjugular sampling.

innominate vein and the internal jugular and subclavian veins. The duct can be distended by compression of the areolar tissue near the bifurcation, which facilitates its identification. The thoracic duct must be divided and ligated when injured or the patient may develop a chyle fistula. The internaljugular vein is dissected free from its surrounding lymph node-bearing tissue, which contains the beginning of the modified neck dissection. Special attention must be drawn to the lower jugular nodes, which are located behind the vein. The vein should be retracted either medially or laterally to obtain a good view of this area. This retraction should be done gently to avoid tearing the vein, which might cause air embolism. The dissection is continued by exposing the

carotid artery, sympathetic chain, and vagus nerve. The lymph node containing fatty tissue is mobilized laterally and superiorly along the clavicle, creating the inferior border of the lateral compartment dissection specimen. Care is taken to avoid injury to the pleura. The specimen is gradually dissected upward from the floor of the lateral compartment. The phrenic nerve is identified running obliquely on the scalenus anticus muscle, and the brachial plexus is identified between the scalenus anticus and medius muscles (Fig. 22-2). The anterior border of the trapezius muscle is dissected and the spinal accessory nerve is identified approximately 1 em anteriorly from the margin of the muscle. The trapezius muscle represents the lateral border of the lateral

202 - - Thyroid Gland

FIGURE 22-2. Modified dissection of central neckcompartment.

neck compartment. The spinal accessory nerve runs parallel to the trapezius muscle over the levator muscle of the scapula. The nerve itself is rarely invaded by tumor but is often surrounded by lymph nodes. It should be carefully dissected from the adjacent tissues upward to the cranial part of the sternocleidomastoid muscle. The spinal accessory nerve is in a superficial position in the posterior triangle of the neck. A plexus of branches from the cervical sensory nerves is located caudal and parallel to the spinal accessory nerve and the phrenic nerve, and these nerves should be preserved when possible. The greater auricular nerve turns toward the sternocleidomastoid muscle near this point. In this area, too, care must be taken to preserve the branch of the occipital artery, which vascularizes partly the sternocleidomastoid muscle. The occipital artery represents the upper posterior limit of

the dissection of the lateral compartment. The dissection continues to the prevertebral fascia. The tissue behind and above the spinal accessory nerve is mobilized from the nerve itself and is dissected upward from the levator muscle of the scapula and splenius muscle of the head. The inferior, lateral, and upper posterior parts of the dissection are completed, and the specimen is passed underneath the sternocleidomastoid muscle, which is now retracted laterally. The anterior part of the specimen is freed from the carotid sheet and jugular vein, and the dissection continues superiorly along the jugular vein, mobilizing the mid- and upper jugular lymph nodes. The hypoglossal nerve, which runs behind the facial vein, is identified. Sometimes the facial vein has to be ligated and transected to obtain an adequate exposure to the hypoglossal nerve while removing the upper jugular lymph nodes.

Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer - -

203

Macroscopic lymphadenopathy

FIGURE 22-3. Proposed strategy for management of regional lymph nodes in papillary and follicular thyroid carcinoma. Modified neck dissection includes a central neck dissection. Central neck dissection includes a dissection of the superior mediastinum. Middle and lower jugular sampling is optional. See additional considerations in the section "Therapeutic Strategy."

Modified neck dissection

Central neck dissection

(Positive jugular sampling)

The dissection is terminated at the posterior belly of the digastric muscle. The lymph nodes in the submandibular region are rarely involved in patients with thyroid cancer and are therefore not removed unless there is extensive lymphadenopathy adjacent to this area. The digastric muscle marks the upper border of the dissection. The specimen can now be removed. Careful hemostasis is performed, and suction drains are often used. The heads of the sternocleidomastoid muscle, when previously divided, are reapproximated. The platysma muscle is approximated and the skin is closed.

Complications of Neck Dissection More extensive neck dissections, especially in the central neck compartment, are associated with a higher risk of hypoparathyroidism and other complications.tv" With complete resection of all fatty and lymph node tissue from the central neck, the recurrent laryngeal nerves and the vascular supply to the parathyroid glands are at risk, especially when combined with total thyroidectomy.14,47,62,69,94-96 Awareness of these potential problems emphasizes the importance of meticulous dissection and positive identification of the recurrent laryngeal nerves and parathyroid glands. Magnifying glasses (x2.5) and bipolar coagulation are helpful. The patient should not receive muscle relaxants. The recurrent laryngeal nerve should be dissected over its complete length with special care for the part caudal to the thyroid. Unilateral paralysis causes hoarseness, which is inconvenient to the patient. Bilateral injury is a life-threatening complication that may make an emergency tracheostomy necessary. Resection of the trachea and esophagus muscle wall is occasionally necessary in patients with extensive extracapsular tumor growth. The modified neck dissection is designed to remove all of the metastatic lymph nodes in the lateral neck yet minimize morbidity. In experienced surgical hands, modified neck dissection is a safe procedure with minimal morbidity. 10.36.94 Resection of the spinal accessory nerve results in paralysis of the trapezius muscle with a shoulder drop and decreased abduction of the arm. Besides loss of function, paralysis of the trapezius muscle is disfiguring. The choice of the incision as well as the preservation of the sternocleidomastoid

muscle and the spinal accessory nerve is an important aspect for a favorable cosmetic result of a modified neck dissection. Injury to the phrenic nerve can result in paralysis of the diaphragm, whereas injury to the sympathic ganglion leads to Homer's syndrome. Resection of branches of the cervical sensory nerves can cause sensory loss of the shoulder. As previously stated, the identification of the thoracic duct on the left side can be difficult. When the duct is injured, chylous fluid collection or cyst occurs. The duct should therefore be ligated to prevent postoperative chylous fistula or chylothorax. When such a complication occurs, reoperation and ligation of the duct are often necessary. Both modified neck dissection and dissection of the superior mediastinum can cause a pneumothorax. A postoperative chest radiograph is recommended. When a pneumothorax is present, a chest catheter is placed under water seal. Bilateral neck dissection can cause significant postoperative edema, and a temporary tracheostomy is rarely necessary. When one internal jugular vein is resected, the contralateral neck dissection should be delayed for at least 6 weeks to avoid this problem. Wound infections are uncommon (Figs. 22-3 and 22-4).

Bilateral central neck dissection

FIGURE 22-4. Proposed strategy for management of regional lymph nodes in medullary thyroid carcinoma. Ipsilateral neck dissection is advocated if central neck nodes are involved with tumor. All patients with tumors larger than 2 cm should undergo standard ipsilateral neck dissection. Central neck dissection includes dissection of the superior mediastinum. See additional considerations in the section "Therapeutic Strategy."

204 - - Thyroid Gland

Therapeutic Strategy Papillary and Follicular Thyroid Carcinoma Figure 22-3 shows our strategy for the management of the regional lymph nodes in patients with papillary or follicular thyroid carcinoma. The object is to remove fatty and lymphatic tissue with minimal risk of complications. As mentioned previously, prophylactic neck dissections for probable microscopic nodal involvement do not appear to be indicated, except possibly in older male patients with central node involvement. While performing total thyroidectomy, the central neck compartment is carefully examined. Enlarged nodes are removed and sent for frozen section analysis. When positive, a central neck dissection is performed, including removing nodal tissue from the superior mediastinum. When there are numerous lymph node metastases in the central neck, the lateral lymph nodes are palpated, and, if present, they are removed (levels 2 to 5). Modified neck dissection can usually be performed with minimal associated morbidity. When there is nodal involvement in the lateral neck compartment without evident involvement in the central neck, a modified neck dissection as well as a central neck dissection, including removing the lymph nodes from the superior mediastinum, is performed. En bloc or compartment dissections are preferable to limited dissections or node picking to decrease the likelihood of recurrent disease. Repeat operations in previously explored areas are associated with increased morbidity but can offer significant palliation.

Medullary Thyroid Carcinoma Figure 22-4 shows the strategy for the management of the regional lymph nodes in patients with medullary carcinoma. Total thyroidectomy with bilateral central neck dissection, including the dissection of the superior mediastinum, is recommended. Microdissection is helpful for identifying all lymph node-bearing tissue so that it can be removed from the central neck compartment bilaterally. When nodes contain medullary thyroid cancer in the central neck, a modified neck dissection is performed on the involved side. Although we formerly advocated jugular node sampling, we now recommend either leaving the lateral compartment alone or proceeding with a systematic modified neck dissection. Formation of scar tissue after jugular sampling make a subsequent dissection of levels 3 and 4 more difficult. Patients with large tumors (> 1.5 ern) should have standard prophylactic ipsilateral modified neck dissection, and this should be done bilaterally in patients with familial disease or with bilateral tumor involvement. When at the initial operation the central neck nodes are not involved, the operation can be limited to the central neck dissection. If a subsequent modified neck dissection is required, adhesions will not be a problem. Nevertheless, elective modified neck dissection should be performed in a secondary session, when central neck nodes are involved with medullary thyroid cancer at final histology and the basal or stimulated serum calcitonin level is elevated. Postoperatively, patients should be followed cautiously by monitoring the serum calcitonin and CEA levels. In patients with persistent elevated basal or stimulated calcitonin levels, noninvasive studies such as magnetic resonance imaging of the neck and

mediastinum should be performed. Selective venous sampling for calcitonin'? or microdissection of nonpreviously explored compartments of the neck is useful in selected patients.28.29.34 Microdissection by experienced surgeons has reduced serum calcitonin levels to normal in about one third of the patients. In patients with distant metastases, local control is important and therapeutic but not prophylactic nodal resections are recommended.

Treatment of Regional Recurrences in the Neck Recurrent thyroid cancer most commonly occurs in the cervical lymph nodes.47.66.69 Recurrent disease in the lateral neck should be treated by modified neck dissection. When a recurrence occurs after neck dissection, a repeat neck dissection or local excision should be performed. Central neck re-explorations are hazardous, and although excellent results have been reported." the recurrent laryngeal nerve and the parathyroid glands are at increased risk of injury in secondary explorations. Recurrences in the central neck in patients with papillary and follicular cancer can be treated with surgical excision and/or radioactive iodine. If the recurrence is small « I em) and located in the thyroid bed, the tumor is often best controlled by radioactive iodine or external irradiation. Larger tumor deposits should be resected. Follicular cancers appear to be more amenable to radioactive iodine treatment than papillary cancers.l.85.99 Medullary cancer is usually insensitive to radioactive iodine therapy, and patients with nonresectable cancer should be treated with external radiation.v" Median sternotomy should be done for patients with elevated serum calcitonin levels and a mediastinal mass. Prophylactic median sternotomy is more controversial.34 Esophageal or tracheal resection is indicated in selected patients and can usually be accomplished with minimal morbidity.

Summary and Conclusions The extent of lymph node dissection must be based on individual tumor type and stage, extent of nodal involvement at the time of operation, and patient-related factors such as age and general condition. The surgeon's experience should also be taken into account. As mentioned previously, more aggressive surgical procedures do not always influence overall survival in patients with papillary and follicular thyroid cancer. Most patients with well-differentiated thyroid cancer of follicular cell origin benefit from therapeutic nodal dissection, but prophylactic node dissection is not necessary. An extensive search for micrometastases also does not seem warranted. Although most patients with papillary carcinoma have at least microscopic nodal involvement, the recurrence is low even in patients not treated with prophylactic neck dissection. Compartment-related dissections appear to be preferable to local excision of lymph nodes to minimize local recurrence: central neck dissection in case of lymph node metastases in the central neck medially to the carotid arteries (level 6 and the superior mediastinum) and modified

Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer - -

neck dissection of levels 2 to 5 for nodal involvement of the lateral neck. In patients with medullary thyroid carcinoma, a more extensive surgical approach is warranted. Medullary carcinoma is more aggressive than papillary and follicular thyroid cancer and ablative treatment with 1311 is generally not effective. A total thyroidectomy and bilateral central neck dissection are therefore recommended for most patients with medullary thyroid cancer. Ipsilateral modified neck dissection of levels 2 to 5 is indicated in all patients with primary tumors larger than 1.5 em and bilateral neck dissection in patients with bilateral thyroid tumors and hereditary medullary thyroid cancer. Postoperatively, patients should be followed cautiously by monitoring the serum calcitonin and CEA levels. Some patients without demonstrable tumor but with elevated calcitonin levels benefit from repeat central and bilateral modified neck dissection of renewed surgery in the neck using microsurgical techniques if this has not already been done.

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206 - - Thyroid Gland 48. Rossi RL, Cady B, Silverman ML, et al. Current results of conservative surgery of differentiated thyroid carcinoma. World J Surg 1986;10:612. 49. Byar DP, Green SB, Dor P, et al. A prognostic index for thyroid carcinoma: A study of the EORTC Thyroid Cancer Cooperative Group. Eur J Cancer 1979;15:1033. 50. Franssila KO. Prognosis in thyroid carcinoma. Cancer 1975;36: 1138. 51. Mazzaferri EL, Young RL. Papillary thyroid carcinoma: A IO-year follow-up report of the impact of therapy in 576 patients. Am J Med 1981;70:511. 52. Tennvall J, Biorklund A, Moller T, et al. Prognostic factors of papillary, follicular, and medullary carcinomas of the thyroid gland. Acta Radiol OncoI1985;24:17. 53. Tubiana M, Schlumberger M, Rougier PH, et al. Long-term results and prognostic factors in patients with differentiated thyroid carcinoma. Cancer 1985;55:794. 54. Schelfhout LJDM, Creutzberg CM, Hamming JF, et al. Multivariate analysis of survival in differentiated thyroid cancer: The importance of the factor age. Eur J Cancer Clin Oncol 1988;24:331. 55. Cunningham MP, Duda RB, Recant W, et al. Survival discriminants for differentiated thyroid cancer. Am J Surg 1990;160:344. 56. Simpson WJ, McKinney SE, Carruthers JS, et al. Papillary and follicular thyroid cancer: Prognostic factors in 1,578 patients. Am J Med 1987;83:479. 57. Brunt LM, Wells SA Jr. Advances in the diagnosis and treatment of medullary thyroid carcinoma. Surg Clin North Am 1987;67:263. 58. Harwood J, Clark OH, Dunphy JE. Significance of lymph node metastasis in differentiated thyroid cancer. Am J Surg 1978;136:107. 59. Sellers M, Beenken S, Blankenship A, et al. Prognostic significance of cervical lymph node metastases in differentiated thyroid cancer. Am J Surg 1992;164:578. 60. Witte J, Goretzki PE, Dieken J, et al. Importance of lymph node metastases in follicular thyroid cancer. World J Surg 2002;26:1017. 61. Block MA. Management of carcinoma of the thyroid. Ann Surg 1977; 185:133. 62. Noguchi S, Noguchi A, Murakami N. Papillary carcinoma of the thyroid: II. Value of prophylactic lymph node excision. Cancer 1970;26:1061. 63. Salvesen H, Njolstad PR, Akslen LA. Papillary thyroid carcinoma: A multivariate analysis of prognostic factors including an evaluation of the p-TNM staging system. Eur J Surg 1992;158:583. 64. Lang W, Choritz H, Hundeshagen H. Risk factors in follicular thyroid carcinomas: A retrospective follow-up study covering a 14-year period with emphasis on morphological findings. Am J Surg Pathol 1986;10:246. 65. Rosen IB, Maitland A. Changing the operative strategy for thyroid cancer by node sampling. Am J Surg 1983;146:504. 66. McHenry CR, Rosen IB, Walfish PG. Prospective management of nodal metastases in differentiated thyroid cancer. Am J Surg 1991;162:353. 67. Farrar WB, Cooperman M, James AG. Surgical management of papillary and follicular carcinoma of the thyroid. Ann Surg 1980;192:701. 68. Hamming JF, Van de Velde CJH, Fleuren OJ, et al. Differentiated thyroid cancer: A stage-adapted approach to the treatment of regional lymph node metastases. Eur J Cancer Clin OncoI1988;24:325. 69. Hamming JF, Van de Velde CJH, Goslings BM, et al. Perioperative diagnosis and treatment of metastases to the regional lymph nodes in papillary carcinoma of the thyroid gland. Surg Gynecol Obstet 1989;169:107. 70. Proye C, Carnaille B, Vix M, et al. Recidives ganglionnaires cervicales des cancers thyroidiens operes: De I'inutilite du curage ganglionnaire de principe (carcinomes medullaires exclus). Chirurgie 1992;118:448. 71. Voutilainen PE, Multanen MM, Leppaniemi AK, et al. Prognosis after lymph node recurrence in papillary thyroid carcinoma depends on age. Thyroid 2001 ;11:953. 72. Rossi RL, Cady B, Meissner WA, et al. Nonfamilial medullary thyroid carcinoma. Am J Surg 1980;139:554.

73. Crile G. Excision of cancer of the head and neck with special reference to the plan of dissection based on one hundred and thirty-two operations. JAMA 1906;47:1780. 74. Bocca E, Pignataro 0, Oldini C, Cappa C. Functional neck dissection: An evaluation of review of 843 cases. Laryngoscope 1984;94:942. 75. McGregor or, Luoma A, Jackson SM. Lymph node metastases from well-differentiated thyroid cancer: A clinical review. Am J Surg 1985;149:610. 76. Kelemen PR, Van Herle AJ, Giuliano AB. Sentinel lymphadenectomy in thyroid malignant neoplasms. Arch Surg 1998;133:288. 77. Arch-Ferrer J, Velazquez D, Fajardo R, et al. Accuracy of sentinel lymph node in papillary thyroid carcinoma. Surgery 2001;130:907. 78. Wiseman S, Hicks W, Chu Q, Rigual N. Sentinel lymph node biopsy in staging of differentiated thyroid cancer: A critical review. Surg Oncol 2002;11:137. 79. Noguchi M, Earashi M, Kitagawa H, et al. Papillary thyroid cancer and its surgical management. J Surg OncoI1992;49:140. 80. Boom RPA. Problemen bij de chirurgische behandeling van het gedifferentieerde schildkliercarcinoom, in het bijzonder bij remterventie, [Dissertation]. Amsterdam, University of Amsterdam, 1982. 81. Gemsenjager E. Zur chirurgischen therapie der differenzierten schilddrusenkarzinome. Dtsch Med Wochenschr 1978;103:749. 82. Sisson GA, Feldman DE. The management of thyroid carcinoma metastatic to the neck and mediastinum. Otolaryngol Clin North Am 1980;13:119. 83. Lennquist S. Surgical strategy in thyroid carcinoma: A clinical review. Acta Chir Scand 1986;152:321. 84. Ballantyne AJ. Neck dissection for thyroid cancer. Semin Surg Oncol 1991;7:100. 85. Tubiana M. External radiotherapy and radioiodine in the treatment of thyroid cancer. World J Surg 1981;5:75. 86. Clark OH. Total thyroidectomy: The treatment of choice for patients with differentiated thyroid cancer. Ann Surg 1982;196:361. 87. Block MA. Surgical treatment of medullary carcinoma of the thyroid. Otolaryngol Clin North Am 1990;23:453. 88. Duh QY, Sancho JJ, Greenspan FS. Medullary thyroid carcinoma: The need for early diagnosis and total thyroidectomy. Arch Surg 1989;124:1206. 89. Moley JF. Medullary thyroid cancer. Surg Clin NorthAm 1995;75:405. 90. Kebebew E, Clark OH. Curr Treat Options Oncol 2000; I:359. 91. Fleming JB, Lee, JE, Bouvet M, et al. Surgical strategy for the treatment of medullary thyroid carcinoma. Ann Surg 1999;230:697. 92. Dralle H. Lymph node dissection and medullary thyroid carcinoma. Br J Surg 2002;89: 1073. 93. Norton JA, Doppman JL, Brennan MD. Localization and resection of clinical inapparent medullary carcinoma of the thyroid. Surgery 1980;87:616. 94. Cheah WK, Arici C, Ituarte PHG, et al. Complications of neck dissection for thyroid cancer. World J Surg 2002;26: 1013. 95. Scanlon EF, Kellogg JE, Winchester DP, et al. The morbidity of total thyroidectomy. Arch Surg 1981;116:568. 96. Harness JK, Fung L, Thompson NW, et al. Total thyroidectomy: Complications and technique. World J Surg 1986;10:781. 97. Wells SA Jr, Baylin SB, Johnsrude IS, et al. Thyroid venous catheterization in early diagnosis of familial medullary thyroid carcinoma. Ann Surg 1982;196:505. 98. Levin KE, Clark AH, Duh QY, et al. Reoperative thyroid surgery. Surgery 1992; III :604. 99. Schlumberger M, Tubiana M, DeVathaire F, et al. Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinomas. J Clin Endocrinol Metab 1986;63:960.

Occurrence and Prevention of Complications in Thyroid Surgery Job Kievit, MD, PhD • Bert A. Bonsing, MD, PhD • Ilfet Songun, MD, PhD • Comelis J.H. van de Velde, MD, PhD

The first surgeon to receive the Nobel Prize in medicine was Theodor Kocher (1841-1917) in 1909, a pioneer in thyroid surgery. One of his accomplishments was to reduce the frequency of thyroid surgery complications. The refinements of his surgical methods from his first important article on thyroidectomy (1878) led to a reduction in mortality from high initial figures (50%) to less than 4.5%. Currently, the mortality rate of thyroidectomy, as reported in several large series, approaches zero. The morbidity of thyroidectomy, however, continues to be a matter of concern. Meticulous attention to operative technique is required, as is a flexible approach that balances the requirements of resection to avoid recurrences against the risk of complications. In 1989, in the United Kingdom, surgical claims for thyroidectomy complications accounted for 4% of general surgical claims, all of which involved recurrent laryngeal nerve injury.' Claims underrepresent complications, and complications in routine care may occur more frequently than in published series. Most complications of thyroidectomy can be avoided by detailed knowledge of the anatomy and careful surgical technique. Although it is a surgical truism that volume generally improves quality, recent research suggests that surgeons may differ in their ability to perform this refined surgery with sufficient care.' Regardless of the background of the surgeon (general surgeon, head and neck surgeon, or endocrine surgeon), the collaboration with an endocrinologist and broad experience in thyroid surgery not only will improve quality but will give confidence in any legal challenge and will help educate future surgeons in proper surgical decision making and technique.

Surgery for Thyroid Disease In the foregoing chapters, the indications for thyroid surgery for different pathologic entities have been discussed. Naturally, benefits of surgical therapy must outweigh the

risks involved. About 1 in 10 solitary thyroid nodules is malignant.' Therefore, a selective approach must be used to determine who will benefit from thyroidectomy and who can be safely observed. The same applies to the extent of thyroid surgery (e.g., total vs. subtotal thyroidectomy) or of surgery for lymph node metastases (node picking or radical neck dissection).

Complications in Patients Undergoing Thyroid Surgery In this chapter, we discuss "complications," being defined as unfavorable and unintended outcomes of care-in short, adverse outcomes. Complications of thyroid surgery can be divided into general or specific complications, the latter being directly related to surgical technique, and the former being more or less independent of the surgical technical procedure itself. Examples of general complications are circulatory and respiratory problems and urinary tract infections. Specific complications include vocal cord dysfunction resulting from injury to the recurrent or external laryngeal nerves, hypoparathyroidism, bleeding, serous or lymphatic leakage, and hypoparathyroidism (origination from damage or ischemia to the parathyroid glands). The nerves at risk during thyroid operations are the external branch of the superior laryngeal nerve (EBSLN), the recurrent laryngeal nerve, and, depending on the surgical approach chosen, the various branches of the hypoglossal ansa. Other complications, such as lesions of the esophagus, thoracic duct, jugular vein, and carotid artery, are extremely rare and are likely to occur only in patients with large, invasive tumors requiring more extensive surgery. In the next sections, we deal with most general and specific complications, drawing both from literature data and from a series of 752 patients undergoing thyroid surgery at the Leiden University Medical Center (27% of them being reoperations). Attention is paid especially to the local anatomy,

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208 - - Thyroid Gland surgical techniques that can prevent damage to the structures at risk, and handling of complications.

General Complications The most frequent general complications involve the heart and the lungs. In our series, benign cardiac arrhythmias occurred in 0.4% of patients; however, one patient (0.1 %) died because of a cardiac arrest. Pulmonary complications involved bronchitis or pneumonia (0.5%); none of these caused severe morbidity or mortality. Other general complications were cystitis (0.2%) and fever (0.2%).

Specific Complications Edema Facial, neck, or tracheal edema may be caused by decreased venous or lymphatic drainage from the operating field. It may interfere with inspiration and occurs especially if thyroidectomy is combined with bilateral lymphadenectomy, such as may be required in patients with medullary cancer.t-' Severe edema in the case of isolated thyroid surgery is rare; none of our patients needed treatment for this complication. It is more common in patients with neck dissections, and it can be prevented or reduced by keeping the head elevated and applying cortisone preparations.

Bleeding Bleeding in the operating field may occur from superficial arteries and veins in the neck, lying on the superficial cervical fascia and from vessels around the thyroid. Such bleeding occurred in nine patients (1.2%) in our series, half of them requiring reoperation. Ligatures tied around the superficial neck veins may come loose and cause subcutaneous bleeding or hematoma. The rich vascular supply of the thyroid gland contributes to its bleeding tendency and stresses the need for meticulous hemostasis. Perioperative bleeding may be decreased by having the patient in a reverse Trendelenburg position, with the head elevated 20 degrees. To test for possible bleeding at the conclusion of the thyroidectomy, the head can be tilted down and the lungs hyperinflated by the anesthetist to increase intrathoracic pressure as well as blood pressure in the neck veins. After thyroid surgery, patients should be kept in a low Fowler position with the head and shoulders elevated 10 to 20 degrees to keep a negative pressure in the veins; they should be observed in the postanesthesia care unit for several hours because most significant hemorrhages with evident tracheal compression occur within hours after operation. In accordance with recent research, we do not routinely use drains, but only if bleeding during or at the end of surgery causes concem.v!" If used at all, drains should be at least be 14 gauge. Drains are certainly not a reason to decrease concern: clots may form and prevent adequate drain function of the placed drains. Extensive dressings may hide the complication and prevent inspection of the contour of the neck and are, therefore, not advised. In the case of symptomatic postoperative hematomas, a liberal attitude toward re-exploration is justified. Hematoma or seroma

occurring after several days is uncommon and generally can be managed expectantly.

Wound Healing Disorders and Infection A well-positioned collar incision, approximately 2 em above the jugulum or 1 em below the cricoid cartilage, extended laterally and closed by intracutaneous running suture, gives the best cosmetic result. A lower incision is more prone to keloid development. If this occurs, excision of the scar after I year may reduce the size of the deformity. Infections occur rarely in thyroid surgery, most often when combined with lymph node dissection (3 patients [0.4%1 in our series, one of whom also had a tracheostomy). Apart from normal surgical hygiene and disinfection and the avoidance of operations in patients with acute sore throats, no additional preventive measures are required. Infections should be treated by opening the wound and evacuating the pus. After adequate drainage, when granulation starts, the wound can be excised and closed secondarily by intracutaneous suture, which gives the same excellent aesthetic result as in uncomplicated primary closure. Seroma can be treated by aspiration.

Vascular and Lymphatic Lesions Other specific surgical complications, typical for thyroid surgery, involve the thyroid vessels and the thoracic duct. The vessels most easily damaged during thyroidectomy are the middle and inferior thyroid veins, which may be severed between their origin from the internal jugular vein and their entrance into the lateral margin of the thyroid lobe. This is especially the case when very large goiters obscure the trajectory of these vessels. Bleeding is easily controlled by ligation and has no adverse effects. Damage to the thyroid arteries rarely occurs accidentally but generally occurs on purpose to devascularize the thyroid lobe. Ligation of both arteries, but more so of the inferior than of the superior thyroid artery, may cause parathyroid ischemia. Some authors contend that ligation of the inferior thyroid artery causes ischemia to both the inferior and the superior parathyroid glands, especially if the artery is ligated far away from the thyroid gland. Lesions to the thoracic duct may occur when thyroid surgery is combined with lymph node dissection (Fig. 23-1). The duct is most frequently damaged at its craniolateral aspect, where lymphatic vessels from the neck enter into the duct, resulting in leakage of clear or milky chylous fluid. If the thoracic duct, or one of its branches, is injured intraoperatively, it should be ligated. Ligation is sometimes difficult because it may be hard to identify the duct. In such cases, suturing the surrounding middle or deep cervical fascia over the duct leak is often possible. Alternatively, the investing fascia of the anterior scalenus muscle may be mobilized in a craniocaudal direction and used to cover the site of leakage. In that case, extreme care should be paid to the phrenic nerve, and its prescalenal trajectory may obviate usage of the anterior scalenus fascia. After successful suture ligation treatment of leakage, any coverage achieved should be reinforced with the use of fibrin sealant in combination with collagen (e.g., Tissuecol).

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FIGURE 23-1. Extensive lymphatic branching of the thoracic duct in a patient undergoing neck dissection for thyroid cancer.

If leakage of the thoracic duct is recognized postoperatively (because of the production of clear or milky fluid from the wound drain), it may be treated conservatively (by total parenteral nutrition for several weeks) or surgically. Surgery is the most effective treatment and involves reopening the neck, identifying the lesion, and treating it as described previously. In our series, we were able to obtain surgical control of the duct in all cases in which leakage occurred both intraoperatively (1.2% of our patient series) and postoperatively (0.4% of patients in our series).

Nerve Damage to the Recurrent Laryngeal Nerve The recurrent laryngeal nerve is involved in most claims concerning complications of thyroid surgery.' Morbidity related to this injury ranges from minimal changes in voice quality to recurrent tracheal aspiration and/or severe dyspnea requiring tracheostomy. The incidence of injury to the recurrent laryngeal nerve(s) during thyroid surgery is influenced by many factors. The risk is higher in more extended thyroid resections, in patients with malignant thyroid disease, in patients in whom the recurrent laryngeal nerves could not be identified, and in re-operations due to recurrent thyroid disease.'!"? Although it is recognized that experience reduces complication rates in surgery in general and reoperations on thyroid disease specifically, reports concerning this topic in primary thyroid surgery are conflicting and emphasize the importance of individual surgical skill and performance. I 1.12.14,16.18,19 Use of a harmonic scalpel reduces operating time but was not shown in small studies to be safer in avoiding recurrent laryngeal nerve injury than bipolar coagulation and ligatures. 20 -22 The same is true for use of minimally invasive video-assisted procedures.P:" At present, there are mainly three strategies that can reduce the risk of recurrent laryngeal nerve injury. The first and most frequently used method is visual control by complete dissection of the full extralaryngeal trajectory of the recurrent laryngeal nerve. I I Second, intraoperative electrical nerve stimulation of the surgical field in addition to visual control can be used to delineate the presence, function, and

FIGURE 23-2. Right-sided non-recurrent recurrent laryngeal nerve in a woman with tertiary hyperparathyroidism.

possibly the course of the recurrent laryngeal nerves by observing contractions of the cricopharyngeus muscle. 27- 32 Third, uninterrupted monitoring of laryngeal electromyographic activity through electrodes placed against the posterior cricoarytenoid muscles can be used. It reveals changes in mechanical activation by manipulation of the recurrent laryngeal nerves during dissection. 27,33-36 Either way, detailed knowledge of the anatomy is of paramount importance to avoid damage to the recurrent laryngeal nerve. The anatomy of the recurrent laryngeal nerves can be quite variable, especially in patients with large goiters, and in cases of "redo" surgery for recurrent thyroid outgrowth. Normally, the right laryngeal nerve arises anterior to the right subclavian artery or brachiocephalic trunk, ascends in the neck behind the common carotid artery, and then curves medially and ventrally, running obliquely and superiorly toward the cricoid cartilage and inferior constrictor. In less than I % of patients, the right recurrent nerve is nonrecurrent and may enter the thyroid from a superior or lateral direction. I I ,37-39 Combinations of recurrent and nonrecurrent branches do also occur (Figs. 23-2 to 23-4).11

FIGURE 23-3. Right-sided partially non-recurrent recurrent laryngeal nerve in young woman with multiple endocrine neoplasia type I hyperparathyroidism.

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FIGURE 23-4. Right-sided partially non-recurrent recurrent laryngeal nerve in a young woman with severe Hashimoto's thyroiditis.

The left recurrent nerve arises from the nervus vagus on the left side of the aortic arch and winds around the arch behind the attachment of the ligamentum arteriosum. It then ascends in the anterior mediastinum and neck in a more medial position, running in the left tracheoesophageal groove. Both nerves subsequently ascend in the neck and cross the lower lateral border of the thyroid at the level of the inferior thyroid artery. They then pass behind the thyroid lobe and laterodorsally to Berry's ligament before they penetrate the cricothyroid muscle to enter the larynx.4o•42 Inside the larynx, the nerve divides into two or three branches-a lateral and a medial branch-that innervate different laryngeal muscles. In addition to this normal rarnification pattern within the larynx, the recurrent nerve may also give off branches in its extralaryngeal ascent in the neck in 60% to 75% of the patients." In the first place, the nerve may divide at any level between its origin and its entry in the larynx, resulting in a full or partial duplication of the nerve within the neck. These branches then ascend in the neck in a parallel course until their entry in the larynx. Besides duplication of the recurrent laryngeal nerve itself, the nerve may give off branches that do not enter the larynx but connect the nerve to other structures within the neck. In the lower part of the neck, small branches may divert from the lateral aspect of the nerve to reach the sympathetic chain, where they connect to the cranial and medial cardiac nerves. Other small branches separate from the nerve medially to innervate the trachea, esophagus, and larynx. Finally, the recurrent nerve may infrequently give off a large lateral branch that runs in a cranial and lateral direction and connects with the superior laryngeal nerve: the communicating branch of the recurrent laryngeal nerve. In conclusion, the recurrent nerve is not always a single strand that ascends in the neck to enter the larynx. It may exhibit a relatively complicated pattern of branches. The easiest site at which to identify the recurrent nerve is near where the inferior thyroid artery (which can easily be seen or palpated between the carotid artery and the lateral aspect of the lower pole of the thyroid) crosses the lateral border of the lower pole of the thyroid gland. The recurrent nerve or one of its branches may pass behind, between, or before the branches of the artery, with at least one nerve branch passing before the artery in about 40% of cases. An advantage of this approach is its relative ease; a slight disadvantage is the risk that the nerve has already given off

one or more branches at a more caudal level that are missed. A result of such variation may be that if only one of two or more branches of the recurrent nerve is identified, it may be falsely assumed that "the" recurrent nerve has been found, and the other branches may inadvertently be severed. Fortunately, this situation is quite uncommon. There are four other ways of identifying the recurrent nerve. 1. The nerve can be located most caudally where it crosses behind the cranial and medial curves of the common carotid artery. At this level, the nerve lies further dorsally than at more cranial levels, but it can always be identified if dissection is performed along the mediocranial surface of the artery, exploring from a lateral to a medial and dorsal direction toward the trachea and esophagus. An advantage of this approach is that the nerve is larger because it has not given off branches. A second advantage is that, in case of reoperation, the neck at this level may be unviolated, facilitating identification of the recurrent nerve with a lower risk of injury. A minor disadvantage of this procedure is its slightly more cumbersome nature, necessitating dissection of the loose connective, fatty, and lymphoid tissues caudally in the neck. 2. The recurrent nerve can be identified at the level of Berry's ligament, just caudal to its level of entry through the cricothyroid muscle into the larynx. The advantage of this approach is that the location of the nerve at this level is fairly fixed. An important disadvantage is that it is located behind the thyroid, which makes access difficult. In addition, this area is hypervascular, and annoying bleeding may easily occur, especially from a small branch of the inferior laryngeal artery, which runs on the cranial border of Berry's ligament and bleeds in close approximation to the entry of the recurrent laryngeal nerve. Bleeding from this artery should be treated with fine (5-0 or 6-0 Prolene) sutures or a hemoclip, a technique that is preferable in all cases of bleeding close to the recurrent laryngeal nerve. Coagulation with bipolar diathermy is acceptable at distances of at least 5 mm from the nerve and is therefore not the preferred method of hemostasis in this area. 3. The recurrent laryngeal nerve can be identified with the use of palpation instead of visually guided dissection. By gently pressing the loose connective, fatty, and lymphoid tissues below the lower thyroid pole against the trachea and moving the finger slowly ventrally and dorsally and back and forth, the nerve can often be felt as a string that moves on the surface of the trachea and tends to "snap" from underneath the palpating finger. Once this sensation has been felt, the connective tissue can be separated carefully in the direction of the nerve. Careful alternation between palpation and dissection prevents injury to the nerve. 4. Finally, neuromonitoring such as described earlier can be used to identify the recurrent laryngeal nerve and its course. 27. 37,46 Especially in reoperations, this can be helpful, as are alternative surgical approaches to the thyroid using previously undissected surgical planes (i.e., an approach around the lateral border of the sternohyoid and sternothyroid muscles)."

Occurrence and Prevention of Complications in Thyroid Surgery - - 211

Complications concerning the laryngeal nerve cause considerable morbidity and occur in 0% to 5% of the patients. 11,27.44-48 In our series involving 755 nerves at risk, the overall risk of permanent injury was 0.5%. Postoperative hoarseness may be caused by several mechanisms. If it occurs in the first 2 to 5 days postoperatively, it is most likely caused by edema in the operating field as a selflimited, innocent process. Long-term hoarseness (~6 months) may occur if the recurrent nerve has been kept intact, whereas stretching it too forcefully has damaged its axons. This can be avoided by handling the nerve gently in all stages of the operation. The nerve should be separated carefully from the thyroid gland before the gland is retracted medially or otherwise manipulated. Vessel loops, put around the nerve for better anatomic identification, should never be kept in hemostats or otherwise fixated, because traction on the loop may cause nerve damage. In the case of nerve stretching, new axon ends need to grow into the axon sheath, a process that takes 1 day to grow 1 mm. Inadvertent cutting or clamping the recurrent laryngeal nerve may cause permanent hoarseness. If this is observed perioperatively, reanastomosis can be performed using the operating microscope and 10-0 Prolene sutures, but the outcome is often unsatisfactory.f'?' When lesions of both recurrent laryngeal nerves occur, patients have dyspnea and difficulty in breathing. These patients should be reintubated or should have a tracheostomy. Most recover some function, but if dysfunction is permanent, a lateralization or laser treatment of the vocal cords is mandatory. Preoperative direct or indirect laryngoscopy should be performed in all patients with a voice change, with proven malignancy, or with a history of neck exploration. In our opinion, postoperative laryngoscopy does not need to be performed routinely but instead may be reserved for patients with vocal cord dysfunction seen at laryngoscopy during extubation and for patients with voice change after thyroid surgery. When vocal cord dysfunction continues for 1 year, it is most likely permanent. However, in cases of nerve reanastomosis, improvement is still possible, even after 1 to 2 years, in our own experience.

artery, and divides into terminal branches. Some of these branches may communicate with branches of the recurrent laryngeal nerve, either within the larynx, or externally. The internal branch provides sensory innervation of the pharyngeal and laryngeal mucosa, extending from the base of the tongue to the glottis and subglottic region. Lesion of the nerve causes loss of sensation of the ipsilateral mucosa. This loss is manifested clinically by aspiration of food and drink on swallowing, caused by the defective sensori motor coordination of the glottis. Treatment consists of specialized physiotherapy, in which the patient is trained to exhale while swallowing. The EBSLN takes a more caudal course, running in close proximity to the medial aspect of the superior thyroid artery. Cranial to the superior pole of the thyroid lobe, it curves medially to innervate the cricothyroid muscle, which regulates the tension in the ipsilateral vocal cord. Two aspects of its anatomy are important determinants of the risk of it being injured during surgery at the upper pole of the thyroid: (1) the level at which it crosses the (vessels of) the upper pole of the thyroid and (2) whether it runs superficial to, or is covered by, the inferior constrictor of the pharynx. Cernea and associates have provided a classification system for the course of the EBSLN that is widely accepted.52-54 Cernea type 1 means that the nerve crosses medially into the cricothyroid muscle more than 1 em cranially to the upper pole of the thyroid lobe; it occurs in about two thirds of cases. Cernea type 2 means that the EBSLN runs within a distance less than 1 em from the upper pole of the thyroid gland, or passes even more caudally, thereby being at risk during surgery at or near the upper pole; it occurs in the remaining one third of cases. Depending on how far caudally the nerve extends, Cernea type 2 is subdivided into types 2a and 2b. In Cernea type 2a, the nerve remains cranial to the upper pole of the thyroid lobe. A nerve that in its most caudal position comes to lie below the upper pole of the thyroid lobe is considered Cernea type 2b (Figs. 23-5 and 23-6). This location has clear surgical importance

Nerve Damage to the External Branch of the Superior Laryngeal Nerve Damage to the EBSLN causes less severe symptoms than damage of the recurrent laryngeal nerve and is therefore less easily recognized and documented. Because the course of this nerve varies even more than that of the recurrent nerve, knowledge of its anatomy is vital. The superior laryngeal nerve, like the recurrent laryngeal nerve, originates from the vagus nerve, in this case close to the caudal end of the nodose ganglion above the hyoid bone. The nerve subsequently descends in the neck in a caudal, medial, and ventral direction, crossing behind the external carotid artery or the carotid bifurcation, where it gives off branches to the carotid body. At the level of the hyoid bone, it divides into an internal (sensory) branch and an external (motor) branch. The common trajectory of the superior laryngeal nerve and its internal branch is positioned cephalad to the dissection area used during thyroidectomy and is therefore not encountered in standard thyroid surgery. The internal branch of the superior laryngeal nerve curves medially, perforates the thyrohyoid membrane above the superior laryngeal

FIGURE 23-5. External branch of superior laryngeal nerve (EBSLN) passing below the left upper pole in a case of enlarged dysplastic thyroid (Cernea type 2b).

212 - - Thyroid Gland

FIGURE 23-6. External branch of superior laryngeal nerve

(EBSLN) running on the mediodorsal surface of the left upperpole in a patient operated on acutely for asphyxia caused by a grossly enlarged thyroid (Cernea type 2b).

because of an increased risk of injury during the dissection and ligation of the superior thyroid pedicle during thyroidectomy (so-called high-risk nervesj." It goes without saying that, especially in cases of type 2 crossing, the nerve is at risk for inadvertent damage if the superior thyroid vessels are clamped en masse and divided before the nerve is freed. The technique of identification of the EBSLN has been described by several authors. 55-62 Of course, one should first of all have adequate cranial exposure of the upper pole of the thyroid by an adequate skin incision and by a sufficiently high division of the linea alba cervicalis. Subsequently, the sternohyoid and sternothyroid muscles are carefully dissected free from the underlying thyroid and are retracted laterally. An excellent procedure for identifying the EBSLN is Lennquists's stepwise method, using (1) a midline incision between the strap muscles, (2) opening of the space between the upper pole and the cricothyroid muscle by laterocaudal traction of the thyroid, (3) careful dissection of the thyroid vascular pedicle, and (4) careful inspection of the inferior pharyngeal constrictor." Most essential is step 2, in which the upper part of the sternothyroid muscle is retracted laterally and cranially to free the upper pole of the thyroid. While this traction is continued, the loose connective tissue located medial to the superior thyroid vessels is opened, and the entire medial border of the thyroid lobe is carefully inspected from the thyroid isthmus to the upper pole. One should keep in mind that, if there are no nerve branches crossing from the thyroid surface medially to enter the cricothyroid muscle, one should not fear an EBSLN entering the thyroid vascular pedicle more cranially. For that reason, we prefer freeing the cricothyroid space in a mediocaudal to laterocranial direction. Dissection is continued up to 1 em cranially from the end of the upper pole, until the EBSLN is either identified and freed, or the superior thyroid vessels are freed over a sufficiently long course to make certain that an unidentified nerve is not included in the vascular pedicle. In cases in which sparing of the EBSLN is crucial (e.g., in professional singers), use of the nerve stimulator should be considered, especially in those cases where

anatomic identification of the nerve fails. Effective prevention of iatrogenic lesions during thyroidectomy by intraoperative identification of the external branch with a nerve stimulator is described by Cernea and colleagues'? and Eisele. 63 However, identifying the nerve is not sufficient as long as other important principles are forgotten. Lennquist and coworkers reported that inappropriate use of diathermy close to the external branch can cause damage, which also occurs to the recurrent laryngeal nerves, and should therefore be avoided, in favor of ligatures." In all cases in which sparing the EBSLN is considered relevant, the vessels of the upper pole should be dissected individually and be ligated as caudally as possible on the surface of the thyroid. The use of clamps should be avoided in favor of suture ligation between thin (4-0 or 5-0) absorbable ligatures. The variations just described must be kept in mind when one performs this procedure. Another important finding is considerable asymmetry of the left and right EBSLNs. Iatrogenic lesions of the external branch during thyroidectomy are not infrequent because of the anatomic variations in relation to the superior thyroid vessels. The importance of preserving the external branch during thyroidectomy was dramatically demonstrated in 1935, when the famous opera soprano Amelita Galli-Curci sustained injury to a superior laryngeal nerve during thyroidectomy for an enlarged toxic goiter, which ended her career. In singers, injury to this nerve is a serious problem, although for some patients symptoms are minimal and are often overlooked. Some patients complain of mild hoarseness, voice weakness or fatigue, loss of voice range (especially upper singing registers), and lower voice volume. When both left and right superior laryngeal nerves are injured, patients experience swallowing disorders, which make them vulnerable to pneumonias. The most accurate test for postoperative assessment of superior laryngeal nerve paralysis is laryngeal electromyography; evaluation by laryngoscopy can be quite difficult. The vocal cord on the involved side is usually bowed and at a lower level than the contralateral vocal cord. In addition, the anterior larynx is slightly rotated to the contralateral side because of the action of the intact contralateral cricothyroid muscle.

Hypoparathyroidism Most individuals have four parathyroid glands situated on the posterolateral capsule of the thyroid. Anatomic studies have demonstrated that 80% to 86% of upper parathyroid arteries and 90% to 95% of lower parathyroid arteries originate from the inferior thyroid artery. Truncal ligation of the inferior thyroid arteries during thyroidectomy, however, does not cause more hypoparathyroidism compared with ligation of the branches of these arteries at the resection margin of the thyroid capsule.v' Becuase superior thyroid arteries may contribute significantly to the parathyroid blood supply, and sufficient parathyroid blood supply may be ensured by collaterals between thyroid vessels and neighboring esophageal and tracheal arteries. The upper parathyroid glands are usually located lateral to the recurrent laryngeal nerve at the level of Berry's ligament and are the glands that are usually the easiest to preserve

Occurrence and Prevention of Complications in Thyroid Surgery - - 213

during thyroidectomy because of their more lateral and posterior position. The lower parathyroid glands are almost always situated anterior to the recurrent laryngeal nerves and caudal to where the recurrent laryngeal nerve crosses the inferior thyroid artery. Permanent hypoparathyroidism occurs in less than 3% ~f the patients, whereas transient postoperative hypocalcemia is much more common. 65-69 Ischemia or removal of the parathyroid glands results in temporary or per~anent hypoparathyroidism and may be caused ~y ?ccIdental coagulation by heat induction, by devascularization, or by accidental removal of the parathyroid glands. For better identification of the vascularization of the gland, magnifying glasses (x2.5) are helpful. The parathyroid glands should not be mobilized extensively, or they may be devascularized during the dissection. When a parathyroid gland cannot be safely dissected from the thyroid gland on a good vascular pedicle, it should be removed and then autotransplanted into the sternocleidomastoid muscle or into t~e brachioradial muscle of the nondominant arm. Parathyroid glands should be inspected carefully with m~gnifying glasses both during and at the end of the operatron. Any gland that appears ischemic should be removed and aut.otransplanted because there is no reason to assume that Its vascular supply will recover. Not doing so means unnecessarily running the risk of hypoparathyroidism. On the other hand, there is no reason to perform biopsy of normalappearing parathyroid glands durin~. thyroid. su.rgery because this obviously subjects them to injury. Earlier III our patient series, when parathyroid biopsy was regularly used, symptomatic hypocalcemia requiring supplementation occurred in about 10% of patients, and permanent hypocalcemia (6 weeks to 6 months after thyroid surgery) was seen in 3.5%. In later years, we have more and more come to rely on surgical identification of the parathyroids. The criteria ~e use are (1) position; (2) mobility independent of the thyroid gland; (3) brownish color; (4) smooth, finely granular surface; (5) presence of vascular pedicle; (6) easy bleeding on manipulation, in particular the rapid spread of a subcapsular hematoma in case of manipulation with forceps; and (7) the presence of a small "fatty hood." With these seven criteria, we rarely need frozen section biopsy to identify parathyroids. Permanent hypoparathyroidism has thereby decreased to below 2%. Preoperative serum calcium levels should be checked routinely in each patient undergoing bilateral thyroid procedures. Postoperative hypocalcemia resulting from hypoparathyroidism is seen after bilateral thyroidectomy but almost never after unilateral thyroidectomy unless the patient has had previous thyroid surgery. If there are clinical symptoms, oral calcium should be given. Permanent hypoparathyroidism is evident when, after 1 year: serum calcium levels are below 2.25 mmol/L and the patIent has symptoms and requires treatment with vitamin D and calcium. Such patients also have high phosphate levels. Permanent hypoparathyroidism results in lifetime disability. Despite frequent testing and adjustments in therapy, fatigue, paresthesias, and irritability are common. Cata~acts h~ve been reported in as many as 70% to 80% of patients WIth permanent hypoparathyroidism, despite laboratory evidence of normocalcemia.s?

Hypothyroidism Hypothyroidism occurs after total or near-total thyroidectomy and increases in frequency after subtotal procedur~s as the size of the remnant decreases. Menegaux and associates compared the outcome of surgical treatment for Graves' disease from 1966 to 1980 and from 1981 to 1988. 70 During the second period, in which bilateral subtotal thyroidectomy was abandoned for unilateral total lobectomy and a subtotal lobectomy on the other side (Dunhill procedure), the rate of permanent recurrent laryngeal nerve and recurrent hyperthyroidism decreased (from 1% to 0% and from 11% to 3.7%, respectively), whereas the rate of permanent hypoparathyroidism and hypothyroidism increased (from 1% to 1.9% and 13% to 48.7%, respectively).

Summary During thyroid operations, it is important to achieve a balance between the benefits of extensive resection for cure and the increased potential for complications. More extensive thyroid resections, especially when combined with bilateral and central neck and modified radical neck dissections, are associated with more postoperative complications, as are reoperations.":" However, the literature contains numerous reports of total thyroidectomy and reintervention by experienced surgeons in which the prevalence of recurrent laryngeal nerve injury and permanent hypoparathyroidism is 2% or less, demonstrating that these operations can be done with minimal morbidity." Total thyroidectomy has been proposed for multinodular goiters involving the entire g~a.nd, Graves' disease, and malignancies by a few authorities, because total thyroidectomy eliminates the possibility of recurrence. However, complications may occur, even in experienced hands, and in the same surgeon's hands more extensive thyroid operations are associated with more complications. To keep morbidity to a minimum, thyroid operations for patients with cancer or large goiters should be performed by surgeons trained in endocrine surgery, with extensive knowledge of the topographic anatomy and its variations. To maintain surgical skills, we believe that individual surgeons bearing responsibility for surgical outcomes should perform no fewer than 10 thyroidectomies annually. If these principles are followed, thyroid surgery can be performed in teaching hospitals such as ours with minimal morbidity and almost zero mortality.18,74-76

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214 - - Thyroid Gland 6. Joudinaud T, Corre FL, Pages JC, et al. [Drainage after thyroid surgery: 264 patients.] Ann Otolaryngol Chir Cervicofac 2002;119:146. 7. Tugergen D, Moning E, Richter A, Lorenz D. [Assessment of drain insertion in thyroid surgery?] Zentralbl Chir 2001;126:960. 8. Hurtado-Lopez LM, Lopez-Romero S, Rizzo-Fuentes C, et al. Selective use of drains in thyroid surgery. Head Neck 2001;23:189. 9. Tabaqchali MA, Hanson 1M, Proud G. Drains for thyroidectomy/ parathyroidectomy: Fact or fiction? Ann R Coli Surg Engl 1999;81:302. 10. Karayacin K, Besim H, Ercan F, et aI. Thyroidectomy with and without drains. EastAfr Med J 1997;74:431. 11. Hermann M, Alk G, Roka R, et al. Laryngeal recurrent nerve injury in surgery for benign thyroid diseases: Effect of nerve dissection and impact of individual surgeon in more than 27,000 nerves at risk. Ann Surg 2002;235:261. 12. Hermann M, Keminger K, Kober F, Nekahm D. [Risk factors in recurrent nerve paralysis: A statistical analysis of 7566 cases of struma surgery.] Chirurg 1991;62:182. 13. Lo CY, Kwok KF, Yuen pw. A prospective evaluation of recurrent laryngeal nerve paralysis during thyroidectomy. Arch Surg 2000;135:204. 14. Menegaux F, Turpin G, Dahman M, et al. Secondary thyroidectomy in patients with prior thyroid surgery for benign disease: A study of 203 cases. Surgery 1999;126:479. 15. Misiolek M, Waler J, Namyslowski G, et al. Recurrent laryngeal nerve palsy after thyroid cancer surgery: A laryngological and surgical problem. Eur Arch Otorhinolaryngol 2001;258:460. 16. Moley JF, Lairmore TC, Doherty GM, et al. Preservation of the recurrent laryngeal nerves in thyroid and parathyroid reoperations. Surgery 1999;126:673. 17. Steurer M, PassIer C, Denk DM, et al. Advantages of recurrent laryngeal nerve identification in thyroidectomy and parathyroidectomy and the importance of preoperative and postoperative laryngoscopic examination in more that 1000 nerves at risk. Laryngoscope 2002;112:124. 18. Lamade W, Renz K, Willeke F, et al. Effect of training on the incidence of nerve damage in thyroid surgery. Br J Surg 1999;86:388. 19. Thomusch 0, Machens A, Sekulla C, et al. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: A multivariate analysis of 5846 consecutive patients. Surgery 2003;133:180. 20. Siperstein AE, Berber E, Morkoyun E. The use of the harmonic scalpel versus conventional knot tying for vessel ligation in thyroid surgery. Arch Surg 2002;137:137. 21. Vach B, Fanta J, Velenska Z. [The harmonic scalpel and surgery of the thyroid gland.] Rozhl Chir 2oo2;81(Suppll):S3-S7. 22. Voutilainen PE, Haglund CH. Ultrasonically activated shears in thyroidectomies: A randomized trial. Ann Surg 2000;231:322. 23. Bellantone R, Lombardi CP, Bossola M, et al. Video-assisted versus conventional thyroid lobectomy: A randomized trial. Arch Surg 2002;137:301. 24. Bellantone R, Lombardi CP, Raffaelli M, et al. Minimally invasive, totally gasless video-assisted thyroid lobectomy. Am J Surg 1999; 177:342. 25. Miccoli P, Bellantone R, Mourad M, et al. Minimally invasive videoassisted thyroidectomy: Multi-institutional experience. World J Surg 2002;26:972. 26. Yeh TS, Jan YY, Hsu BR, et aI. Video-assisted endoscopic thyroidectomy. Am J Surg 2000;180:82. 27. Marcus B, Edwards B, Yoo S, et al. Recurrent laryngeal nerve monitoring in thyroid and parathyroid surgery: The University of Michigan experience. Laryngoscope 2003;113:356. 28. Hillermann CL, Tarpey J, Phillips DE. Laryngeal nerve identification during thyroid surgery: Feasibility of a novel approach. Can J Anaesth 2003;50: 189. 29. Scheuller MC, Ellison D. Laryngeal mask anesthesia with intraoperative laryngoscopy for identification of the recurrent laryngeal nerve during thyroidectomy. Laryngoscope 2002; 112:1594. 30. Eltzschig HK, Posner M, Moore FD Jr. The use of readily available equipment in a simple method for intraoperative monitoring of recurrent laryngeal nerve function during thyroid surgery: Initial experience with more than 300 cases. Arch Surg 2002;137:452. 31. Dimov RS, Mitov FS, Deenichin GP, et al. Stimulation electromyography as a method of intraoperative identification of the recurrent laryngeal nerve in thyroid surgery. Folia Med (Plovdiv) 2001;43:17.

32. Jonas J, Bahr R. [Intraoperative electromyographic identification of the recurrent laryngeal nerve.] Chirurg 2000;71 :534. 33. Lambert AW, Cosgrove C, Barwell J, et al. Vagus nerve stimulation: Quality control in thyroid and parathyroid surgery. J Laryngol Otol 2000;114:125. 34. Otto RA, Cochran CS. Sensitivity and specificity of intraoperative recurrent laryngeal nerve stimulation in predicting postoperative nerve paralysis. Ann Otol Rhinol Laryngol 2002;111:1005. 35. Timon Cl, Rafferty M. Nerve monitoring in thyroid surgery: Is it worthwhile? Clin Otolaryngol 1999;24:487. 36. Thomusch 0, Sekulla C, Walls G, et al. Intraoperative neuromonitoring of surgery for benign goiter. Am J Surg 2002;183:673. 37. Vuillard P, Bouchet A, Gouillat C, Armand D. [Non-recurrent inferior laryngeal nerve: 15 operative cases.] Bull Assoc Anat (Nancy) 1978;62:497. 38. Wijetilaka SE. Non-recurrent laryngeal nerve. Br J Surg 1978;65:179. 39. Ardito G, Manni R, Vincenzoni D, et aI. [The non-recurrent inferior laryngeal nerve: Surgical experience.] Ann Ital Chir 1998;69:21. 40. Lekacos NL, Tzardis PJ, Sfikakis PG, et al. Course of the recurrent laryngeal nerve relative to the inferior thyroid artery and the suspensory ligament of Berry. Int Surg 1992;77:287. 41. Leow CK, Webb AJ. The lateral thyroid ligament of Berry. Int Surg 1998;83:75. 42. Sasou S, Nakamura S, Kurihara H. Suspensory ligament of Berry: Its relationship to recurrent laryngeal nerve and anatomic examination of 24 autopsies. Head Neck 1998;20:695. 43. Katz AD, Nemiroff P. Anastomoses and bifurcations of the recurrent laryngeal nerve: Report of 1177 nerves visualized. Am Surg 1993;59:188. 44. Calrk OH, Levin K, Zeng QH, et al. Thyroid cancer: The case for total thyroidectomy. Eur J Cancer Clin Oncol 1988;24:305. 45. de Roy van Zuidewijn DB, Songun I, Kievit J, van de Velde CJ. Complications of thyroid surgery. Ann Surg Oncol 1995;2:56. 46. Dralle H. [Intraoperative neuromonitoring in thyroid surgery and surgery of the parathyroid gland.] Zentralbl Chir 2002;127:393. 47. Martensson H, Terins J. Recurrent laryngeal nerve palsy in thyroid gland surgery related to operations and nerves at risk. Arch Surg 1985;120:475. 48. Shindo ML, Sinha UK, Rice DH. Safety of thyroidectomy in residency: A review of 186 consecutive cases. Laryngoscopy 1995;105:1173. 49. Chou FF, Su CY, Jeng SF, et al. Neurorrhaphy of the recurrent laryngeal nerve. J Am Coli Surg 2003;197:52. 50. Damrose EJ, Huang RY,Ye M, et al. Surgical anatomy of the recurrent laryngeal nerve: Implications for laryngeal reinnervation. Ann Otol Rhinol Laryngol 2003;112:434. 51. Maronian N, Waugh P, Robinson L, Hillel A. Electromyographic findings in recurrent laryngeal nerve reinnervation. Ann Otol Rhinol LaryngoI2003:112:314. 52. Cernea CR, Ferraz AR, Furlani J, et al. Identification of the external branch of the superior laryngeal nerve during thyroidectomy. Am J Surg 1992;164:634. 53. Cernea CR, Ferraz AR, Nishio S, et al. Surgical anatomy of the external branch of the superior laryngeal nerve. Head Neck 1992;14:380. 54. Cernea CR, Nishio S, Hojaij FC. Identification of the external branch of the superior laryngeal nerve (EBSLN) in large goiters. Am J OtolaryngoI1995;16:307. 55. Durham CF, Harrison TS. The surgical anatomy of the superior laryngeal nerve. Surg Gynecol Obstet 1964;118;38. 56. Friedman M, LoSavio P, Ibrahim H. Superior laryngeal nerve identification and preservation in thyroidectomy. Arch Otolaryngol Head Neck Surg 2002;128:296. 57. Kambic V, Kargi M, Radsel Z. Topographic anatomy of the external branch of the superior laryngeal nerve: Its importance in head and neck surgery. J Laryngol Otol 1984;98: 1121. 58. Lennquist S, Cahlin C, Smeds S. The superior laryngeal nerve in thyroid surgery. Surgery 1987;102:999. 59. Lore JM Jr, Kokocharov SI, Kaufman S, et al. Thirty-eight-year evaluation of a surgical technique to protect the external branch of the superior laryngeal nerve during thyroidectomy. Ann Otol Rhinol LaryngoI1998;107:1015. 60. Monfared A, Kim D, Jaikumar S, et al. Microsurgical anatomy of the superior and recurrent laryngeal nerves. Neurosurgery 2001;49:925. 61. Lore JM Jr. Practical anatomical considerations in thyroid tumor surgery. Arch Otolaryngol 1983;109:568.

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69. Schwartz AE, Friedman EW. Preservation of the parathyroid glands in total thyroidectomy. Surg Gynecol Obstet 1987;165:327. 70. Menegaux F, Ruprecht T, Chigot IP. The surgical treatment of Graves' disease. Surg Gynecol Obstet 1993;176:277. 71. Levin KE, Clark AH, Duh QY, et al. Reoperative thyroid surgery. Surgery 1992;111:604. 72. Shaha AR, Jaffe BM. Completion thyroidectomy: A critical appraisal. Surgery 1992;112:1148. 73. Chao TC, Jeng LB, Lin rn, Chen ME Reoperative thyroid surgery. World I Surg 1997;21:644. 74. Lynnerup TH, Wamberg PA, Axelsson CK. [Thyroid gland surgery in a teaching department of parenchymal surgery: Quality control and perspectives based on a IO-year material.] Ugeskr Laeger 1995;157:5971. 75. Martin L, Delbridge L, Martin I, et al. Trainee surgery in teaching hospitals: Is there a cost? Aust N Z I Surg 1989;59:257. 76. Friedrich T, Steinert M, Keitel R, et al. [Incidence of damage to the recurrent laryngeal nerve in surgical therapy of various thyroid gland diseases: A retrospective study.) Zentralbl Chir 1998;123:25.

Thyroid Emergencies: Thyroid Storm and Myxedema Coma Chen-Hsen Lee, MD • Hong-Da Lin, MD

Thyroid storm and myxedema coma are life-threatening medical emergencies resulting from extreme hyperthyroidism or hypothyroidism with multiorgan dysfunction. Although they are rare conditions, when they are not recognized and treated quickly, the outcome may be fatal. Today, these conditions rarely occur after thyroid operations. Nevertheless, it is important that surgeons understand the clinical manifestations, pathophysiology, and effective treatment of these conditions because they may be precipitated by trauma, and patients with untreated or inadequately treated preexisting hyperthyroidism or hypothyroidism may require urgent operations.

Thyroid Storm Thyroid storm is a poorly defined clinical syndrome. The synonyms include thyroid crisis, thyrotoxic storm, and thyrotoxic crisis. Thyroid surgery, once the most common pathogenesis of thyroid storm, has become a rare cause of this disorder. Even senior surgeons have seen only a few such patients. This is attributable to recognition of these patients, to administration of appropriate antithyroid drugs, and to the popularity of radioactive iodine therapy for treating patients with thyrotoxicosis. Nonthyroid surgery, major trauma, infection, and image studies with iodinated contrast medium in patients with unrecognized thyrotoxicosis may act as precipitating factors of thyroid storm. For unequivocal cases of thyroid storm at our medical center, pneumonia, perforation of a peptic ulcer, iodinated contrast medium, and coexistent hyperparathyroidism with extreme hypercalcemia (serum calcium> 15 mg/dL) were considered precipitants. Known precipitants of thyroid storm are listed in Table 24-1.1. 3 Without early clinical recognition and initiation of therapy, thyroid storm carries a 10% to 75% mortality in hospitalized populations."

Clinical Manifestations Thyroid storm is usually abrupt in onset, with clinical features of thyrotoxicosis. Hypermetabolism contributes to the

216

development of fever, with temperatures occasionally exceeding 40° C, and is usually considered a major factor in differentiating thyroid storm from nonstorm thyrotoxicosis.> Without treatment, the fever may progressively increase to lethal levels within 24 to 48 hours. Patients with thyroid storm have warm skin and are flushed, with profuse diaphoresis. A goiter as well as exophthalmos mayor may not be evident. Tachycardia-s-often greater than 140 beats/minand atrial fibrillation are common, and tachypnea is frequently seen. Ventricular dysfunction and acute pulmonary edema or congestive heart failure may develop. Tremor and severe agitation are characteristic. Emotional lability, restlessness, confusion, and delirium are common and may progress to frank psychosis, stupor, and coma. Severe diarrhea is the most common gastrointestinal symptom, but nausea, vomiting, and abdominal pain also occur and may suggest an acute abdominal emergency. Hepatomegaly is often present, and mild jaundice and abnormal liver function tests suggestive of hepatocellular dysfunction are sometimes present. Leukocytosis is present occasionally, especially in patients with coexistent infections.

Diagnosis Early diagnosis and treatment remain the most important determinants in the successful management of patients with thyroid storm. Any delay in establishing this diagnosis and instituting treatment may increase the risk of a fatal outcome. Laboratory examinations for serum triiodothyronine (T 3), thyroxine (T4 ) , and free T 4 are usually nondiagnostic, because these tests are similar in patients with storm and nonstorm thyrotoxicosis." It is important to recognize that this condition is a clinical diagnosis. Characteristic features such as Bayley's symptom complex? of insomnia, anorexia, vomiting, diarrhea, marked sweating, and great emotional instability are reliable in predicting impending storm. A temperature greater than 38° C, marked tachycardia, accentuated symptoms and signs of thyrotoxicosis, and central nervous system (CNS), cardiovascular, or gastrointestinal system dysfunction indicate storm.v" A score of 25 to 44 using the scale of Burch and Wartofsky" is suggestive of

Thyroid Emergencies: Thyroid Storm and Myxedema Coma - - 217

impending storm, and a score of 45 or higher is highly suggestive of storm (Table 24-2). One should be aware that patients rarely have thyroid storm and apathetic thyrotoxicosis, coma, cerebral infarction, status epilepticus, rhabdomyolysis, and acute renal failure."

Pathophysiology The mechanism underlying the pathogenesis of thyroid storm is not completely known. A dramatic increase in serum free T4 level is commonly observed and may precipitate the onset of thyroid storm. Additional factors such as poor nutrition and complicating medical, surgical, and emotional effects on thyroid hormone binding, metabolic clearance, general physiologic reserve, and increased catecholamines are other important contributors." Besides, in our unique experience with thyroid storm combined with primary hyperparathyroidism, a markedly elevated serum calcium level may augment the action of T4 via its role as a second messenger. 10

Treatment It is crucial that treatment be instituted promptly. One should not wait for the results of measurements of serum total and free T4 or T 3 concentrations to begin treatment.' Therapy is directed at blocking thyroid hormone synthesis, secretion, and action on peripheral tissues. Supporting treatment to reverse the ongoing or incipient decompensation of normal homeostatic mechanisms, with elimination of any known precipitating factor or concurrent illness, is imperative. Continuous monitoring and minute to minute titration of therapy in an intensive care unit are mandatory. ANTITHYROID THERAPY

The antithyroid drug propylthiouracil (PTU) is administered by mouth to block new hormone synthesis and to decrease the extrathyroidal conversion of T4 to T3 • The effect of this

treatment begins within an hour of administration. Burch and Wartofsky" advised a loading dose of 600 to 1000 mg PTU followed by 200 to 250 mg every 4 hours. In our experience, a loading dose of 200 mg followed by 200 mg of PTU every 4 hours can be equally effective. Methimazole (20 mg every 4 hours) is not recommended because, even though it decreases thyroid hormone synthesis, unlike PTU it does not affect extrathyroidal conversion of T4 or T3. In patients with severe vomiting or in those who cannot take anything orally, rectal administration can be an alternative. 1I In the stuporous, comatose, or uncooperative patient, gavage is advised via a nasogastric tube. Inorganic iodide is given to inhibit iodine pump, colloid proteolysis, and release of T4 and T3 from the thyroid gland.

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Thyroid Gland

Oral dosages from 0.2 to 2 g/day are recommended. It can be given as Lugol's solution, 8 drops every 6 hours, or a saturated solution of potassium iodide,S drops every 6 hours. Sodium iodide for intravenous use, such as the radiographic contrast medium sodium ipodate, if available, should be infused slowly in a dosage of 0.5 to 1 g every 12 hours.F It is advised that iodine therapy not be started until an effective blockade of new hormone synthesis has been established with antithyroid therapy ('"1 hour), because iodine alone will lead to a further fortification of the thyrotoxic state and increase surgical risk owing to an enrichment of glandular hormone store." Treatment with iodide blocks thyroid gland secretion and, therefore, has a faster onset of effective therapy than PTU, which blocks synthesis in a thyroid gland that has a large store of already formed hormone. ADRENERGIC DEPLETION

The fact that the manifestations of thyrotoxicosis closely resemble those of sympathetic, especially p-adrenergic, overactivity provides the rationale for adrenergic depletion. Reserpine and guanethidine, either alone or in combination with other modes of therapy, have been successful in the treatment of thyroid storm. However, owing to hypotension and other untoward side effects, their use has been replaced by a p-adrenergic receptor blocker as the agent of choice. Propranolol is the most frequently used p blocker, which also inhibits peripheral conversion of T, to T 3 . It is, however, contraindicated in patients with bronchial asthma because of precipitating bronchospasm. Propranolol also blocks the symptoms of hypoglycemia so that patients with insulinrequiring diabetes mellitus may not experience warning signs of this dangerous situation. It should also be used with caution in patients with heart failure unless one is sure that the cardiac embarrassment is not due to intrinsic heart disease. On the other hand, severe bradycardia in response to propranolol may be treated with atropine, and bronchospasm or left ventricular compromise may be treated with isoproterenol. The recommended dosage of propranolol varies from 20 to 80 mg orally, every, 4 to 6 hours. For a more rapid effect, propranolol may be given intravenously by slow push at an initial dose of 0.5 to 1 mg, along with continuous electrocardiographic monitoring. Subsequent intravenous doses of 1 to 2 mg at IS-minute intervals are used to titrate the patient's heart rate. The ultrashort p blocker esmolol has been reported successful in the perioperative management of thyroid storm. 13,14 A loading dose of 250 to 500 ug/kg followed by a continuous infusion rate of 50 to 100 ug/kg/min has been demonstrated. TREATMENT OF SYSTEMIC DECOMPENSATION

Treatment of systemic decompensation includes reversal of hyperthermia, dehydration, congestive heart failure, and dysrhythmia and prevention of adrenal crisis. Hyperthermia should be aggressively treated with antipyretics and peripheral cooling. Acetaminophen is preferred to salicylates for this purpose because aspirin increases free hormone levels by decreasing the binding to T4-binding globulin and potentially could aggravate the thyroid storm." Alcohol sponges, ice packs, and cooling blankets are frequently used for peripheral cooling. It is important to prevent or decrease shivering during the rapid reduction in elevated body temperature with

small doses of chlorpromazine and meperidine; the latter is used so as not to depress the state of mentation.? To replace fluid loss, either gastrointestinal or insensible, a volume of 3 to 5 L/day may be required. A central venous pressure catheter, pulmonary wedge pressure monitoring, or both, is necessary to evaluate fluid replacement carefully. Electrolytes, glucose, and vitamins, especially thiamine, are essential to replace possible deficiency. Cardiovascular complications, including atrial fibrillation and congestive heart failure, are treated conventionally. Larger loading and maintenance doses of digoxin may be required because of the more rapid clearance in patients with marked hyperthyroidism. Serum digoxin levels should be closely monitored, particularly as thyroid storm improves and metabolic rate is lowered, to prevent digitalis intoxication. Intravenous hydrocortisone, 300 mg initially followed by 100 mg every 8 hours, is administered to prevent adrenal crisis because of relative adrenal insufficiency. Steroids also decrease the extrathyroidal conversion of T4 to T 3' TREATMENT OF COEXISTENT ILLNESS AND DEFINITIVE TREATMENT

Because most patients in thyroid storm are febrile, with leukocytosis, an inflammatory or infectious focus should be sought and bacterial cultures obtained. Prophylactic antibiotic treatment is not recommended." Any coexistent hypoglycemia, hypercalcemia, or diabetic ketoacidosis should be corrected, and standard treatment for stroke or pulmonary embolism should be instituted simultaneously with the treatment of thyroid storm. In the stuporous, comatose patient or one with poor communication abilities, a history may be unavailable or inaccurate. As many as 25% to 43% of patients with thyroid storm present with no known precipitating event.4.7 •8 In most patients, clinical improvement is observed within 24 hours, and complete recovery from storm occurs within a few days to a week. These treatment modalities should be withdrawn gradually to prevent recurrent crisis, because the half-life of T, is approximately 1 week. For patients requiring emergency operation and those who have sustained significant trauma, surgical intervention should be performed as soon as the patient is stabilized with such measures as hydration, p blockade, intravenous sodium ipodate, hydrocortisone, PTU, and cooling. For definitive treatment of thyrotoxicosis, a subtotal thyroidectomy or other therapy is performed when the patient is euthyroid and the crisis situation has resolved. Unless contraindicated, p blockade should be continued during the postoperative period. Our patient with thyroid storm and hypercalcemic crisis was successfully treated by urgent removal of a 3-g parathyroid adenoma and simultaneous subtotal thyroidectomy after rapid preoperative treatment of the hypercalcemia and storm were instituted (Fig. 24-1). The mortality rate has fallen from nearly 100% to about 20% with a better understanding of appropriate management of patients with thyroid storm, although the improvement may also be partly attributable to the relaxation of diagnostic criteria.I-?

Prevention Given the significant mortality associated with thyroid storm, it would be beneficial to prevent episodes completely

Thyroid Emergencies: Thyroid Storm and Myxedema Coma - -

219

Hydration, diuretics, and ATD

~

• s ...J

4

E

3

• Serum P

2 Serum creatinine

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a:

-5

0

10

Hospital days

20

FIGURE 24-1. Clinical course of a 47-year-old woman with hyperthyroid and hyperparathyroid crisis. She was found irritable with fever, abdominal pain, and previously unrecognized grade II goiter. The consciousness change progressed to stupor 5 days after disease onset and the patient was therefore referred to this medical center. When myocardial ischemia, shortened QT interval, and hypercalcemia were revealed on electrocardiogram (ECG) and SMAC examinations, radiographs of the hand were taken and showed subperiosteal resorption suggestive of primary hyperparathyroidism. Elevated serum phosphate, amylase, and creatinine levels were also noted. The white blood cell (WBC) count was within the normal limit. Hydration and diuretics were started at the emergency department. On admission to the hospital, 24-hour iodine 131 uptake was 53% and thyroid scan showed diffuse uptake. Antithyroid treatment with propranolol and propylthiouracil were administered before elevated serum triiodothyronine (T3) and thyroxine (T4) levels were available on the third day. At the end of the first week, the vital signs were stabilized and a follow-up ECG showed normal sinus rhythm while the consciousness fluctuated from drowsiness to stupor. A second measurement of T 3 and T 4 levels showed the patient to be euthyroid on the 10th day, and an urgent neck exploration was done. A parathyroid adenoma weighing 3 g was removed, and a simultaneous bilateral subtotal thyroidectomy was performed. The patient was discharged in a euthyroid and fully conscious state 20 days after admission with normal renal function and eucalcemia. P =phosphorus; Ca =calcium; BT = body temperature; PTx = parathyroidectomy; Tx = thyroidectomy; ATD =antithyroid drug; HR = heart rate; CCr =creatine clearance.

or at least recognize impending storm and treat it aggressively before significant decompensation occurs. As noted previously, surgical storm has been virtually eliminated by the preoperative treatment of thyrotoxic patients. Patients with hyperthyroidism should be diagnosed early in their course and treated aggressively to return them to a euthyroid state as quickly as possible. The potential for an intercurrent illness to precipitate storm in a thyrotoxic patient needs to be recognized and communicated to the patient as well. Elective surgery should be postponed. If surgery is urgent, patients should be properly prepared and watched closely for evidence of developing storm. Thionamides should not be withdrawn in preparation for radioiodine until hyperthyroidism is controlled. IS

Myxedema Coma Myxedema coma is another thyroid emergency. It is the extreme clinical manifestation of severe thyroid

hormone deficiency. This syndrome is rare and is usually, but not exclusively, encountered in elderly women during the winter months. Most patients have long-standing untreated hypothyroidism or have arbitrarily discontinued thyroid hormone replacement. Although the prognosis for myxedema coma is markedly improved by the introduction of high-dose intravenous T4 treatment, it is still associated with a mortality rate of about 20%.16

Clinical Manifestations Before the development of myxedema coma, patients usually have some signs of hypothyroidism. In some cases it develops spontaneously as a result of prolonged severe hypothyroidism, but in most situations several factors, such as infection, trauma, surgery, stroke, myocardial infarction, cold exposure, and administration of certain drugs, predispose to its development (see Table 24_1).6.17-19 The pathogenesis of myxedema coma is not completely understood. Major clinical features are progressive deterioration of

220 - - Thyroid Gland consciousness, hypothermia, hypoventilation, hyponatremia, bradycardia, hypotension, and seizure. Because patients often present in coma, it may be difficult to know whether the patient has had a stroke, has myxedema coma, or both. Decreased mental function is an important feature of myxedema coma. Lethargy, stupor, confusion, and psychiatric symptoms may precede the coma. The causes of the altered mental status and CNS decompensation in patients with severe thyroid hormone deficiency include hyponatremia, carbon dioxide (C0 2) narcosis, hypoglycemia, postictal mental disorder, and coexistent sepsis or hypoadrenalism. Administration of sedatives and tranquilizers may further suppress the CNS because the clearance of drugs is markedly retarded in hypothyroid patients. Heat production by brown adipose cells is stimulated by catecholamines through a-adrenergic receptors and modulated by thyroid hormone. Hypothermia is commonly encountered in myxedema coma and may precede the development of coma. The body temperature may be as low as 24° to 34° C and often cannot be recorded by the usual thermometer. Hypothermia is due to severe hypometabolism, adaptive peripheral vasoconstriction, and relatively unopstimulation.'? Underlying hypoglycemia posed ~-adrenergic contributes to, and concurrent infection may impede, the development of hypothermia, Profound hypoventilation is common in patients with myxedema coma and requires mechanical ventilatory assistance to relieve CO 2 retention and hypoxia. Although hypercapnia and loss of hypoxic drive are the cardinal physiologic mechanisms involved, other factors such as macroglossia, edema of vocal cords and pharynx, bradycardia, reduced stroke volume, anemia, pleural effusion, ascites, pericardial effusion, weakness of respiratory muscles, superimposed pulmonary infection, and administration of drugs that cause CNS depression may further suppress or worsen the respiratory function. Hyponatremia is common in severe thyroid hormone deficiency because thyroid hormone has an effect on renal tubule sodium reabsorption and water excretion. In addition, an inappropriate plasma vasopressin level has been demonstrated in some patients with myxedema coma." Other factors such as fluid overload, congestive heart failure, and inadequate use of diuretics further contribute to a low serum sodium concentration. Severe hyponatremia not only leads to deterioration of the patient's consciousness level but is also responsible for most seizures, which occur in about 25% of patients with myxedema coma. Hypoglycemia is an uncommon finding and may indicate coexistent adrenal insufficiency. A low blood glucose concentration, however, may also result from impaired glycogenolysis and gluconeogenesis, increased insulin sensitivity, and malnutrition without hypoadrenalism. Hypoglycemia is also responsible for seizures in some patients with myxedema coma.

Diagnosis The natural course and fatal outcome of myxedema coma can be altered by a timely diagnosis and prompt and appropriate treatment. A high index of suspicion on the basis of history and clinical features is important. Measurement of

serum thyroid-stimulating hormone (TSH) and thyroid hormone concentrations confirms the diagnosis of hypothyroidism. However, just as in thyroid storm, the results of serum thyroid function tests correlate poorly with the clinical severity of myxedema coma, and many patients with hypothyroidism without coma have equally abnormal (high TSH and low T 3 and T4 ) thyroid function tests. In patients with central or secondary hypothyroidism, serum TSH, T 3, and T4 levels are low. Elevation of serum creatine kinase (CK), lactate dehydrogenase, and transaminase levels in severe hypothyroidism may help in the differential diagnosis. The isoenzyme pattern of increased CK is predominantly MM, consistent with skeletal muscle origin. In case of a greatly elevated CK-MB fraction, concomitant myocardial infarction is suggested, which may not be evident clinically." It is important to document these tests and to obtain an electrocardiogram (ECG) before instituting treatment with thyroid hormone in case chest pain develops with treatment. Pituitary adenomas and craniopharyngiomas are the most frequent causes of secondary hypothyroidism. Computed tomography scanning of the head may demonstrate either a pituitary or hypothalamic lesion in most cases of central hypothyroidism. Although the symptoms and signs of myxedema coma usually create a pathognomonic clinical picture, the rarity of this condition sometimes causes the diagnosis to be overlooked. The insidious onset of symptoms further impedes the early recognition of this syndrome. Myxedema coma should be considered in the differential diagnosis of any patient who presents with an altered mental status, profound hypothermia, and unexplained CO 2 retention, either alone or in combination. One should be particularly alert to any hypothyroid patient who has received radioiodine therapy or who has been treated with total or subtotal thyroidectomy for Graves' disease.

Treatment The strategies for the treatment of myxedema coma are (1) maintenance of cardiopulmonary function, (2) institution of thyroid hormone therapy, (3) treatment of metabolic complications, (4) elimination of precipitating factors or concurrent illnesses, and (5) provision of general supportive care. PULMONARY AND CARDIOVASCULAR SYSTEMS

Death in patients with myxedema coma is frequently caused by respiratory failure and cardiovascular collapse. Once the diagnosis is made, prompt and close monitoring of cardiopulmonary function must be instituted. CO2 retention and respiratory acidosis can be confirmed by arterial blood gas analysis and rapidly relieved by intubation and mechanical ventilatory support. These treatments are usually required, especially when hypoventilation is aggravated by the administration of sedatives, tranquilizers, or narcotics. Hypotension in myxedema coma is due to blood volume depletion, intrinsic heart disease, or pericardial effusion. Thyroid hormone therapy, whole-blood transfusion, and administration of hydrocortisone may correct the hypovolemia. Pressor agents are seldom needed. If congestive heart failure develops, the patient should be digitalized and treated with diuretics or afterload-reducing agents. Concomitant myocardial infarction indicates a poor outcome.

Thyroid Emergencies: Thyroid Storm and Myxedema Coma - -

THYROID HORMONE REPLACEMENT

Myxedema coma is due to thyroid hormone deficiency, resulting in organ decompensation. Thyroid hormone replacement is, therefore, essential in its management. The initial dose of levothyroxine is 300 to 500 ug given intravenously. Because the patient with myxedema coma usually has intestinal atony with poor intestinal absorption, thyroid hormone and other medications are administered intravenously rather than orally. After the initial dose, serum T4 and T 3 levels gradually rise, and the patient should be subsequently maintained on 50 to 100 ug/day intravenously. As soon as the patient regains consciousness, orallevothyroxine is instituted. Formerly, low-dose thyroid hormone replacement was recommended because of concern of underlying cardiac disease, but the mortality rate was as high as 80% with low-dose thyroid hormone treatment.Pr" However, there has been considerable progress in supportive medical care in the past decades. Yamamoto and associates suggested that not every patient requires a high dose of thyroid honnone. They also found that a bolus of 500 Ilg of levothyroxine by mouth or via nasogastric tube is effective and can be tolerated by patients younger than 55 years of age." A survey of hospitals in Germany (1993-1995) identified a group of 24 patients with myxedema coma, treated initially with levothyroxine in doses ranging from 25 to 500 ug, that had six deaths (mortality rate, 25%).25 Some authors believe that myxedema coma is partially related to decreased 5'-deiodinase activity with impairment in conversion of T4 to T3 in patients with nonthyroidal illnesses.v-" They recommend using liothyronine (T3) hormone at an initial dosage of 25 ug every 8 hours intravenously for 1 day followed by 12.5 ug every 8 hours the next day. As soon as the patient's consciousness improves, T 3 is changed to orallevothyroxine. Gastrointestinal absorption of T 3 is better than levothyroxine, and because an injectable form is not available, T3 is usually given orally. Careful monitoring of cardiac function is required during T 3 replacement, because treatment with T 3 is associated with more cardiac arrhythmias and a higher mortality rate.23•28 A survey that collected 87 cases of myxedema coma published in English, French, German, and Japanese since 1970 found that the incidence of death was highest after treatment with T3 of 75 ug/day or more with or without levothyroxine." Wartofsky has suggested the combined use of levothyroxine and T 3 for patients with myxedema coma." An initial dose of 200 to 300 ug levothyroxine is given intravenously, followed by a dose of 100 ug 24 hours later. A maintenance dosage of 50 ug/day is started on the third day. T 3 is initially given daily with a dosage of 10 ug every 8 hours and discontinued when the patient can take oral feedings. No matter what type of hormonal replacement is given, continuous ECG monitoring is mandatory, and patients should be continuously monitored in an intensive care unit. In patients with cardiac arrhythmia or myocardial ischemia, thyroid hormone replacement is discontinued or dramatically lowered. TREATMENT OF METABOLIC COMPLICATIONS

Hypothermia usually improves after administration of thyroid hormone. Generally, no specific therapy is needed except

221

blankets to prevent further heat loss. External rewarming should be avoided because it can cause vasodilation, leading to cardiovascular collapse. Because prolonged profound hypothermia suggests a poor prognosis, active rewarming is sometimes recommended, accompanied by whole-blood transfusion in patients with a body temperature below 30° C.6 Mild to moderate hyponatremia is usually corrected by fluid restriction and thyroid hormone therapy. Hypertonic saline and glucose are only occasionally required to alleviate severe hyponatremia (sodium < 110 mEqlL) and hypoglycemia. Seizures are prevented by correcting the hyponatremia, hypoglycemia, hypercapnia, and hypoxia. When seizures occur, they are treated with anticonvulsants. ELIMINATION OF PRECIPITATING FACTORS AND CONCURRENT ILLNESS

Infection is probably the most common precipitating factor of myxedema coma. Any delay in the diagnosis and treatment of bacterial infection is associated with a poor outcome. One should vigorously search for any possible source of infection and aggressively treat it with specific antibiotics, because fever, sweating, tachycardia, and leukocytosis may be totally absent in patients with myxedema coma and concurrent bacterial infection. Nicoloff and LoPresti 19 recommended broad-spectrum intravenous antibiotic coverage for patients until all cultures return to negative. One should also be alert to the presence of other concurrent diseases such as cardiac and cerebrovascular diseases and gastrointestinal bleeding. GENERAL SUPPORTIVE CARE

A plan of general medical care, as applied to comatose patients, such as frequent changes in position, prevention of aspiration, and bowel and bladder care, should be undertaken. Paralytic ileus is frequently found with myxedema coma and should be differentiated from mechanical obstruction, which usually requires surgical intervention. Ileus resulting from myxedema coma improves with thyroid hormone therapy. Both thyroid and adrenocortical failure may occur in patients with panhypopituitarism and polyglandular autoimmune syndrome. Treatment of such patients with thyroid hormone without simultaneous administration of cortisol results in adrenal crisis. Because institution of thyroid hormone therapy in severe hypothyroidism might induce adrenocortical insufficiency, most investigators recommend intravenous hydrocortisone, 100 mg every 8 hours for the first few days, for all myxedema coma patients. 29•3o The dose can be rapidly tapered or discontinued when the random serum cortisol value is 18 ug/dl, or greater."

Summary Thyroid storm and myxedema coma are uncommon important endocrine emergencies. Despite improvement in treatment, patients still die. It is better, therefore, to prevent thyroid storm and myxedema coma than to face their consequences. Rapid diagnosis on the basis of clinical judgment, history, and physical examination and institution of appropriate therapy are important. Since both conditions can be precipitated by trauma and critical illness that brought the

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patients to the emergency department or intensive care unit, physicians in charge should be alert to their occurrence during the management for patients' primary diseases. Usually, these two conditions present with typical findings. Patients with both thyroid storm and myxedema coma should be managed in an intensive care unit with continuous ECG, arterial blood gas, and central venous pressure monitoring. Bacterial infection should be sought both in patients with thyroid storm and with myxedema coma. Delay in instituting therapy and premature weaning from the ventilator are common pitfalls in the management of patients with myxedema coma. In addition, adverse reactions can occur with the administration of vasopressors, sedatives, or tranquilizers and with active rewarming for hypothermia in patients with myxedema coma. Early recognition and proper treatment may avoid the catastrophe. "When in doubt, treat" is an advisable clinical axiom for the successful management of these patients with decompensated hyperthyroidism or hypothyroidism."

REFERENCES I. McDermott MT. Kidd GS, Dodson LE, et al. Radioiodine-induced thyroid storm: Case report and literature review. Am J Med 1983; 75:353. 2. Shimura H, Takazawa K, Endo T, et al. T4 thyroid storm after CT scan with iodinated contrast medium. J Endocrinol Invest 1990;13:73. 3. Thompson NW, Fry WJ. Thyroid crisis. Arch Surg 1964;89:512. 4. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis: Thyroid storm. Endocrinol Metab Clin North Am 1993;22:263. 5. Ingbar SH. Thyroid storm or crisis. In: Werner SC, Ingbar SH (eds), The Thyroid, 4th ed. Hagerstown, MD, Harper & Row, 1978, p 800. 6. Nicoloff JT. Thyroid storm and myxedema coma. Med Clin North Am 1985;69:1005. 7. Bayley RH. Thyroid crisis. Surg Gynecol Obstet 1984;59:41. 8. Waldstein SS, Slodki SL, Kaganiec GI, et al. A clinical study ofthyroid storm. Ann Intern Med 1959;52:626. 9. Mazzaferri EL, Skillman TG. Thyroid storm: A review of 22 episodes with special emphasis on the use of guanethidine. Arch Intern Med 1969;124:684. 10. Bennett WR. Huston DP. Rhabdomyolysis in thyroid storm. Am J Med 1984;77:733.

II. Yeung S, Go R. Balasubramanyam A. Rectal administration of iodide and propylthiouracil in the treatment of thyroid storm. Thyroid 1995;5:403. 12. Wu S-Y, Chopra 11, Solomon DH, et al. The effect of repeated administration of ipodate (Oragrafin) in hyperthyroidism. J Clin Endocrinol Metab 1978;47:1358. 13. Isley L, Dahl S, Gibbs H. Use of esmolol in managing a thyrotoxic patient needing emergency surgery. Am J Med 1990;89:122. 14. Brunette DD, Rothong e. Emergency department management of thyrotoxic crisis with esmolol. Am J Emerg Med 1991;9:232. 15. Tietgens ST, Leinung Me. Thyroid storm. Med Clin North Am 1995;79:169. 16. Jordan RM. Myxedema coma, pathophysiology, therapy and factors affecting prognosis. Med Clin North Am 1995;79:185. 17. Myers L, Hays J. Myxedema coma. Crit Care Clin 1991;7:43. 18. Wartofsky L. Myxedema coma. In: Braverman LE, Utiger RD (eds), The Thyroid. Philadelphia, Lippincott Williams & Wilkins, 2000, p 843. 19. Nicoloff JT, LoPresti JS. Myxedema coma, a form of decompensation hypothyroidism. Endocrinol Metab Clin North Am 1993;22:279. 20. Iwasaki Y, Oisa Y, Yamandin K, et al. Osmoregulation of plasma vasopressin in myxedema. J Clin Endocrinol Metab 1990;70:534. 21. Hickman PE, Silvester W, Musk AA, et al. Cardiac enzyme changes in myxedema coma. Clin Chern 1987;33:622. 22. Nickerson JF, Hill SR, McNeil JH Jr, Barker SB. Fatal myxedema with or without coma. Ann Intern Med 1960;53:475. 23. Forester CF. Coma in myxedema: Report of a case and review of the world literature. Arch Intern Med 1963; 111:100. 24. Yamamoto T, Fukuyama J, Fujiyoshi A. Factors with mortality of myxedema coma: Report of eight cases and literature survey. Thyroid 1999;9:1167. 25. Reinhardt W, Mann K. Incidence, clinical picture, and treatment of hypothyroid coma: Results of a survey. Med Klin 1997;92:521. 26. McCullach W, Price P,Hinds CJ, et al. Effects of low-dose oral triiodothyronine in myxedema coma. Intensive Care Med 1985; II :259. 27. Pereira VG, Haron ES, Lima-Neto N, et al. Management of myxedema coma: Report on three successfully treated cases with nasogastric or intravenous administration of triiodothyronine. J Endocrinol Invest 1982;5:331. 28. Hylander B, Pesenquist U. Treatment of myxedema coma: Factors associated with fatal outcome. Acta EndocrinoI1985;108:65. 29. Ridgway ES, McCammor JA, Benotti J, et al. Acute metabolic responses in myxedema to large doses of intravenous t-thyroxine. Ann Intern Med 1972;77:549. 30. Iranmanesh A, Lizarraldo G, Johnson ML, et al. Dynamics of 24-hour endogenous cortisol secretion and clearance in primary hypothyroidism assessed before and after partial thyroid hormone replacement. J Clin Endocrinol Metab 1990;79:155. 31. Grinspan SR, Riller BMK. Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 1994;79:923.

Pathology of Tumors of the Thyroid Gland Ronald H. Nishiyama, MD

Tumors of the thyroid gland can be problems for endocrinologists, surgeons, and pathologists. Carcinomas of the thyroid gland range from the innocuous occult papillary carcinoma to the extremely lethal anaplastic form. Approximately 12,000 new cases of thyroid cancers are discovered each year in the United States; however, fewer than 1% of deaths caused by cancers are due to thyroid cancers. I Because only 9% of patients affected by the disease die from it, malignant tumors of the thyroid gland are not a significant public health problem. The treatment of carcinoma of the thyroid gland continues to engender controversy. The extent of thyroidectomy in the treatment of papillary and follicular carcinomas is controversial. The role of radioactive iodine in the postoperative treatment of patients is still debated, and histologic criteria for the pathologic diagnoses of certain thyroid tumors are uncertain. This chapter concentrates on the epithelial tumors of the thyroid gland. The discussion centers on the pathology and cytopathology of carcinomas of the thyroid gland. Controversies involving criteria to determine histologic diagnoses and classification of thyroid tumors are described. Descriptions of nonepithelial tumors are included when appropriate. Nodular goiters, thyroiditis, hyperplastic changes in the thyroid gland, and other non-neoplastic changes are discussed in the context of the diagnosis and treatment of thyroid neoplasms.

Adenoma Adenomas are the most common benign tumors of the thyroid gland. They are of follicular cell origin, encapsulated with varying histology. They have been subdivided according to their histology, but no additional information is gained by this practice. Thyroid adenomas are probably common because of the inability of pathologists to separate consistently cellular adenomatous nodules in nodular goiters from adenomas. The majority of "adenomas" are most likely adenomatous nodules.

The atypical adenoma is a troublesome Iesion.? It is a lesion characterized by solid architecture with disorderly arrangements of follicular components and is troublesome when there is moderate or marked cellular atypia, typical of "angioinvasive adenomas" or microangioinvasive welldifferentiated follicular carcinomas. Capsular invasion, invasion of capsular blood vessels, or both identify the malignant lesions. Otherwise, the tumors can be histologically identical. The problem is compounded by the inability of any preoperative procedure to demonstrate consistently evidence of invasive growth. The cytologic smears of these lesions can be problems. Cytologic reports are descriptive and often conclude by suggesting the presence of a follicular neoplasm or follicular neoplasia, the connotation being that a malignant tumor is not totally excluded. It is well recognized that well-differentiated angioinvasive carcinomas cannot usually be distinguished from atypical adenomas and cellular adenomatous nodules by fine-needle aspiration. Such tumors should be surgically removed and evaluated histologically for evidence of invasive growth, and treatment is dictated by the final histologic diagnoses. The extent of thyroidectomies may be determined by protocols developed for the treatment of well-differentiated carcinomas of the thyroid gland at different institutions. The surgical procedure may vary from lobectomy to subtotal or total thyroidectomy. Frozen sections of the offending nodules may be requested when thyroidectomies are preceded by lobectomies. The nodules are sent for frozen sections. However, frozen sections are not useful in follicular and also Htirthle cell neoplasms because capsular or vascular invasion cannot be identified consistently with the small number of sections taken for histologic examination.' An opposing opinion states that frozen sections are cost effective. However, a different procedure is used for frozen sections at that medical center." The histologic criteria to establish the diagnosis of an adenoma are not well defined. Adenomas are solitary nodules that are well encapsulated and histologically distinct from adjacent thyroid parenchyma. Goitrous or adenomatous nodules may satisfy these criteria, and when atypical

223

224 - - Thyroid Gland histologic features are present, they are difficult to separate from minimally invasive follicular carcinomas. The hyalinizing trabecular adenoma may present problems.! These tumors are either single dominant nodules or one nodule in a nodular goiter. They are usually small «2 em) and are encapsulated or circumscribed with pseudofollicles, trabecular or alveolar arrangements of cells, or both. Hyalinization of stroma can be seen, which may be confused with amyloid. Immunohistochemical stains for thyroglobulin are positive and stains for calcitonin are negative. No cytoplasmic secretory granules are seen by electron microscopy. Erroneous diagnoses of medullary carcinoma and papillary carcinoma have been made by mistaking the hyalinized stroma for amyloid and the papillae for those of papillary carcinomas.

Papillary Carcinoma Papillary carcinomas are the most common malignant neoplasms of the thyroid gland." They are rarely composed solely of papillae, with the most common form containing both follicles and papillae. Such tumors were classified as mixed papillary and follicular carcinomas. Follow-up studies have convincingly demonstrated that mixed and purely papillary tumors are associated with similar outcomes, so the separation of mixed papillary and follicular from the purely papillary form is not warranted.' The description of other histologic variants of papillary carcinomas, some allegedly characterized by poorer clinical outcomes than usual papillary carcinomas, has complicated the classification of papillary carcinomas. The present classification of papillary carcinomas may include the following histologic forms: • Usual papillary carcinoma • Microcarcinoma • Follicular variant • Tall cell type • Columnar cell type • Diffuse sclerosing type • Macrofollicular type • Encapsulated type The most common type is the usual papillary carcinoma, identified by a solid, well-circumscribed, unencapsulated tumor arising in the background of a normal thyroid gland. The size is larger than 1 em." Histologically, papillae are present that are formed by fibrovascular cores covered by neoplastic cells. The nuclei are piled on one another, may show "grooves" formed by folds in nuclear membranes, and contain "optically clear" nuclei created by clearing of nuclear chromatin. Cytologically, intranuclear inclusions, formed by inclusions of cytoplasm into the nuclei, can be seen. Psammoma bodies, calcified and laminated structures, support the diagnosis of papillary carcinoma (Figs. 25-1 and 25_2).9.11 Areas of fibrosis and solid and trabecular areas are commonly present. The latter changes are not poorly differentiated areas within papillary carcinomas and do not affect their biologic behavior.l-? The finding of neoplastic papillae is essential to establish the histologic diagnosis of usual papillary carcinoma.

FIGURE 25-1. Papillary carcinoma: fibrovascular papillae, optically clear nuclei (arrowheads), and psammoma body (arrow).

However, non-neoplastic papillae, associated with adenomatous and hyperplastic nodules, can lead to the erroneous diagnosis of papillary carcinoma. These papillae have fibrovascular cores, but the covering cells lack the nuclear changes of cells characteristic of papillary carcinomas. Other important morphologic findings are smaller papillary carcinomas found on the same side of the dominant lesion or in the opposite lobe. The prevalence of bilateral lesions has been reported to be as high as 78%.13 The smaller foci were considered to be additional primary tumors; however, morphologic evidence indicates that these are intraglandular metastases.P The evidence consists of the location of the neoplasms in interstitial tissue and within lymphatic channels, the close relationship of the number of lymph nodal metastases to the incidence of small neoplastic foci in the parenchyma of the gland, and the more common

FIGURE 25-2. Papillary carcinoma, fine-needle aspirate: cells with intranuclear inclusion (arrow) and nuclear groove (arrowhead).

Pathology of Tumors of the Thyroid Gland - - 225

occurrence of psammoma bodies, thought to originate from intralymphatic tumor thrombi, in the primary tumors. However, contrary evidence, the finding of different types of RET/PTC rearrangements in the multiple foci of cancers, favors the conclusion that they are additional primary tumors." Papillary microcarcinoma, also known as occult carcinoma, occult sclerosing carcinoma, minimal carcinoma, and encapsulated sclerosing carcinoma, is a common variant. The World Health Organization (WHO) definition of a microcarcinoma limits its size to 1 em or less." Clinicians object to this definition because microcarcinomas can sometimes be palpated in the thyroid gland and can arise as palpable lymph nodes, containing metastases, in the neck. The ubiquitous nature of microcarcinomas is a unique feature of these small cancers. 13 The rates of occurrence of microcarcinomas in normal individuals vary with the geographic location, with the highest occurring in Japanese in Japan and Hawaii and Finns in Finland. The rates in the United States are relatively low, with the highest recorded at 13%.15 Papillary microcarcinomas are incidental findings under two conditions: • Thyroid glands removed for other thyroid diseases such as Graves' disease, hyperthyroidism, nodular goiters and, rarely, autoimmune thyroiditis • Thyroid glands, included in radical neck operations for malignancies, other than thyroid cancers. They occur multifocally and bilaterally in such glands and in those removed for treatment of primary thyroidal cancers. This may argue for total removal of the thyroid gland in the treatment of papillary carcinomas. However, there is no convincing proof that microcarcinomas consistently develop into clinically significant neoplasms. The histology of microcarcinomas includes the classic lesion, formed by a central core of neoplastic cells with papillae with the pertinent nuclear changes, which are not encapsulated but show radiating strands of fibrous tissue that contain neoplasm. Other tumors can consist of neoplastic cells arranged as follicles with no encapsulation, with the cells showing nuclear changes characteristic of papillary carcinomas. One clinical circumstance in which microcarcinomas become significant is that of the patient who presents with a palpable mass or masses in the neck, usually enlarged lymph nodes. A biopsy reveals metastatic papillary carcinoma, but there are no palpable abnormalities in the thyroid gland. This usually results in a lobectomy on the side of the positive lymph nodes. The problem, then, is to find the primary thyroid carcinoma. When the metastatic deposits are very well differentiated, the problem of "lateral aberrant thyroid" may arise when the primary lesion is not discovered." However, the primary carcinoma is inevitably demonstrated in all cases. A report of 535 patients with papillary microcarcinomas, treated surgically during a 50-year period, revealed the following!": • Mean tumor size, 8 mm • Intrathyroidallocation, 98% • Nodal metastases, 32% • Tumor, nodes, and metastasis (TNM) stages I (91%), III (9%), IV (one patient) • Bilateral lobar resection (91%)

• Incomplete resection of tumor (three patients) • Postoperative radioiodine ablation (l 0%) • 20-year recurrence rate (6%) in patients with positive lymph nodes or unilateral lobectomy • Death from tumors (two patients) Primary diagnoses were established at the time of thyroidectomies in 69% of patients. In 20%, the diagnosis was confirmed by biopsies of cervical lymph nodes. Thirteen percent of cases were considered to be incidental findings at operations. The conclusions were that • Patients with microcarcinomas have excellent outcomes when initially treated by bilateral lobar resection. • Postoperative radioiodine ablation is not indicated. Microcarcinomas are not entirely innocuous. A few cases have been associated with distant metastases and a rare death.l":" The follicular variant of papillary carcinoma is a pathologic paradox.'? A histologic diagnosis of papillary carcinoma is made in the absence of demonstrable papillae. The statement has been made that in everyone of these lesions, papillae can be demonstrated by careful examination of the thyroid gland. Nonetheless, within the limitations of the techniques employed, there are papillary tumors that are identified purely from the nuclear changes seen in the neoplastic cells. They are composed of follicles usually containing darkly eosinophilic colloid with serrated edges, which mimic the changes in Graves' disease and in neoplastic cells with nuclear changes peculiar to papillary carcinomas. The follicular variant warrants recognition because of the difference in biologic behavior between papillary and follicular carcinomas. This lesion was first recognized in 1960, so it is not a new entity.'? Undue emphasis on this variant of papillary carcinoma may lead to erroneous designations of follicular lesions as carcinomas. On the other hand, diagnosing some lesions as follicular carcinomas may not be as grievous an error as the erroneous diagnosis of a benign lesion. Tall cell variants of papillary carcinomas are defined as papillary carcinomas composed of cells that are twice as tall as they are wide." The definition now includes the requirement that at least 30% of the neoplasm be composed of tall cells.F The criteria to establish a diagnosis now encompass two parameters that are highly subjective and vulnerable to significant interobserver errors. The current consensus on the prognosis for patients with tall cell cancers is that more suffer from poor outcomes than those with usual papillary carcinomas.P:" Additional data now indicate that tall cell cancers are histologically unique forms of papillary carcinomas but are not more aggressive than usual papillary carcinomas. 26 A comparison of a group of patients with tall cell cancers with a large group of patients with usual papillary carcinomas showed the following: • Tall cell cancers were larger. • Tall cell cancers had a higher rate of metastases. • Tall cell cancers had a higher rate of extrathyroidal invasion. • Patients older than 50 years had poorer outcomes. The only factor that affected prognoses in patients with tall cell cancers was age. The effect of age on prognosis in patients with usual papillary carcinomas is well established, with the age of 50 years recognized as a clinical benchmark."

226 - - Thyroid Gland Paradoxically, two phenomena, allegedly identifying more aggressive thyroid neoplasms, are associated with tall cell cancers: the overexpression of p53 and the more efficient delivery of mitogenic signals by papillary carcinomas with RET/PTC3 rearrangements.P'" Overexpression of p53 has been demonstrated in tall cell cancers. One conclusion is that localization of p53 immunohistochemically is a useful prognostic index of clinical behavior in differentiated carcinomas of follicular derivation. All of the cancers in that study showed extrathyroidal invasion. Because the tumors were not staged further, it is difficult to determine whether positivity for p53 was the sole indicator of aggressive behavior. Another study demonstrated that clinical stages of the tumors at time of presentation were more significant in determining outcomes than the percentage of tumors staining positively for p53. The RET tyrosine kinase rearrangements that recombine RET with heterologous genes to generate RET/PTC oncogenes are the most frequent genetic alterations in papillary thyroid cancers." The most prevalent oncogenes that result are RET/PTC] and RET/PTC3. RET rearrangements were found in 36% of tall cell thyroid cancers and were all of the RET/PTC3 type." The cells derived from these neoplasms delivered mitogenic signals more efficiently to thyroid cells of rats, and this phenomenon is proposed to account for the alleged aggressive behavior of tall cell cancers in humans. In contrast, the conclusion has been drawn that all thyroid carcinomas harboring RET rearrangements show a welldifferentiated phenotype and are not more aggressive than less differentiated tumors." However, RET/PTC3 oncogenes are more common in cancers that develop in irradiated thyroid glands and in children. Columnar cell thyroid carcinomas differ from tall cell cancers because of the stratification of nuclei within the tall cells." The initial cases behaved aggressively and were followed by other reports concurring with the conclusion that these cancers were more virulent forms of papillary cancer.P Indolent encapsulated forms have been reported in addition to tumors composed of tall cells and columnar cells, suggesting that the two neoplasms are expressions of one form of papillary carcinoma." The conclusion that columnar cell carcinomas are more aggressive than usual papillary thyroid carcinomas (PTCs) is challenged by a report of a group of patients whose outcomes were determined by the clinical stages at the time of presentation, rather than the unusual histology of the neoplasms." These tumors did not differ in their behavior from usual papillary carcinomas when gender, age, tumor size, and histology were considered. The most important prognostic factor was extrathyroidal invasion. Biologic behavior of columnar cell papillary carcinomas of thyroid gland appears to be determined by the same factors that affect the behavior of usual forms of papillary carcinomas. The unusual histology of these tumors does not identify tumors that are clinically more aggressive. The diffuse sclerosing variant is recognized by diffuse, bilateral involvement of the thyroid gland. 36-39 Microscopically, clusters of neoplastic cells with numerous psammoma bodies are found in well-defined spaces, presumably lymphatic channels, all in a background resembling autoimmune thyroiditis.

The patients are young, predominantly female, and commonly present with metastases to lymph nodes in the neck and lungs. In spite of the extensive involvement of the thyroid gland, the propensity to metastasize early to lymph nodes and lungs, and a high rate of persistent disease postoperatively, the prognosis appears to be good. 36•38 However, this conclusion is disputed. Others report that the prognosis associated with these neoplasms may be poor. 12.39 The youth of the patients may be the ultimate determining factor of clinical outcomes. It is well recognized that among young patients, papillary carcinomas with metastases to regional lymph nodes and lungs are more common but, with proper treatment, the outcomes are excellent. The rare macrofollicular variant is of greater interest to pathologists than surgeons because its morphology is such that it can easily be misdiagnosed as an adenomatous nodule. 40A 1 The prognoses for patients are no different from those for usual papillary carcinomas. The encapsulated form of papillary carcinoma is a slowgrowing tumor with excellent clinical outcomes. Twentyfive patients with tumors with an average size of 3.1 cm showed no metastases or recurrences after long periods of follow-up." In summary, the histology of papillary carcinomas does not appear to be a significant prognostic factor. Others concur with this conclusion." Prognostic factors for causespecific deaths caused by papillary carcinomas in a group of 685 patients were determined to be age, extrathyroidal invasion. and the differentiation of the neoplasm-that is, the grade of the neoplasm.f Grading of neoplasm was initially included in the AGES (age of a patient, grade of neoplasm, extrathyroidal invasion, size of tumor) system for predicting prognoses in patients with papillary carcinomas at the Mayo Clinic." However, with use, it became apparent that the grading of papillary carcinomas was subject to significant interobserver variation. The system was modified to include distant metastasis and completeness of excision and discarded the grading of tumors, the only histologic variable of the system." With the group of patients described previously, histology of the tumors (differentiation) was defined as the level of differentiation within the nonpapillary areas. Tall cell, columnar cell, or insular changes were not described. The tumors were divided into well-differentiated, moderately differentiated, and poorly differentiated types, with the latter two types being worse. Three factors predictive of local, nodal, or systemic recurrences were age, nodal involvement, and the size of the tumors. Patients younger than 40 years had a much better rate of survival than patients older than 50 years. Extrathyroidal invasion was defined as extension of neoplasm into perithyroidal tissue.

Follicular Carcinomas Follicular carcinomas are more common in iodine-deficient areas and less prevalent in countries that are iodine sufficient.v-" Unlike papillary carcinomas, follicular carcinomas have no histologic landmarks, such as papillae, psammoma bodies, or distinctive nuclear changes (Fig. 25-3).

Pathology of Tumors of the Thyroid Gland - - 227

FIGURE 25-3. Minimally invasive follicular carcinoma with invasion of capsular vein (arrow).

Follicular carcinomas can be divided into minimally and extensively invasive forms, encapsulated and invasive types, or microangioinvasive and macroangioinvasive tumors. 7,47-53 Well-differentiated, minimally invasive carcinomas are difficult to identify. For tumors formed of follicles lined by well-differentiated cells and enclosed within well-formed capsules, invasion through the capsule, into capsular blood vessels, or both, must be identified before a diagnosis of malignancy is made.5 1.54 Capsular invasion is defined by complete penetration of the capsule by neoplasm with extension into adjacent parenchyma. The significance of capsular invasion alone as a marker for malignancy has been questioned. 55 Tumors with only capsular invasion did not develop regional or distant metastases or cause cancer-related deaths among such patients. The conclusion was that vascular invasion is the most important criterion to establish the histologic diagnosis of well-differentiated follicular carcinomas. The significance of invasion of the capsules of follicular neoplasms was previously questioned. 56 Vascular invasion is defined as growth of neoplasm into a blood vessel, usually a vein, within the capsule of the tumors. Neoplastic thrombi are found within capsular blood vessels and covered by a thin layer of endothelium, visible only microscopically. Because of this requirement, follicular tumors with such changes have been designated as encapsulated, microangioinvasive, well-differentiated follicular carcinomas.f'>'

Encapsulated, angioinvasive, follicular carcinomas (angioinvasive adenomas) have atypical histologic features with increased numbers of mitotic figures, and follow-up of such tumors showed recurrences and metastases within 5 years after excision of the tumors. The histology of the tumors was not as reliable an indicator of malignancy as the finding of vascular invasion. Eighteen percent of patients died as a result of the tumors, and 68% developed metastases or local recurrences in one report.> Vascular invasion is difficult to detect, and much controversy exists over the changes that characterize invasion of a blood vessel." The extensively invasive or macroangioinvasive follicular carcinomas are easier to identify. Experienced surgeons, at times, can identify neoplasm within larger blood vessels and satellite nodules within parenchyma adjacent to the tumor at the time of thyroidectomy. Grossly, minimally invasive follicular carcinomas are wellencapsulated nodules, usually in a background of nodular goiters. The extensively invasive carcinomas have visible nodules outside the tumor capsule and are relatively easy to recognize. Metastases to lymph nodes are uncommon, and distant metastases are usually found in the lungs, bone, or both. Patients with minimally invasive follicular carcinomas have good prognoses, whereas those with extensively invasive forms have graver outcomes. Factors that determined cancer-specific deaths in a group of 253 patients with follicular cancers included extrathyroidal invasion, metastases, size, and nodal involvement.f Extrathyroidal invasion was a potent predictor of cause-specific deaths, and distant metastasis was, predictably, another important factor. The sizes of the tumor and nodal metastases, supposedly an uncommon event in follicular carcinomas, were other significant variables. Distant metastases, age, postoperative status, nodal involvement, and the size of the primary tumors were predictive of recurrences. The postoperative status of the patients indicates the completeness of excision of the primary tumor, as judged by the surgeons and pathologists. The prevalence of follicular carcinomas in this country has markedly decreased.F-" One major medical center recorded only two cases of follicular carcinomas in I year, a relative incidence of I %, during a 5-year period. 57 During the same period, not a single case of follicular carcinoma was identified by fine-needle aspiration biopsy. The two cases of anatomically documented follicular carcinomas did not have fine-needle aspirates. Perusal of reports of follicular carcinomas from large medical centers appears to confirm the lowered incidence of follicular carcinomas in iodine-sufficient countries. 48-52.59 Eighteen cases were recorded during 10 years (1.8 cases a year) at the MD Anderson Hospital, 100 patients in 24 years (4 cases a year) at the Mayo Clinic, 37 cases in 20 years (1.8 cases a year) at the University of Michigan, 65 patients in 35 years (1.8 cases a year) at the University of California at San Francisco, and 9 tumors in 6 years (1.5 cases a year) at the Karolinska Hospital. The incidence of follicular carcinomas is low. This phenomenon appears to be predominantly due to the introduction of iodine prophylaxis in the United States. It lowered the incidence of nodular goiters, which in tum lowered the

228 - - Thyroid Gland number of follicular carcinomas. The association of follicular carcinomas with nodular goiters in iodine-deficient areas has been well documented." Is it significant to have so few follicular carcinomas in the United States? One untoward result may be an increase in the number of unnecessary thyroidectomies. Well-differentiated follicular carcinomas cannot be consistently separated from adenomas or cellular goitrous nodules.s? Because of this problem, clinicians have become accustomed to the "risky" cytologic report, identified by reference to the presence of follicular neoplasia or a follicular neoplasm.57 Such reports usually result in thyroidectomies. The histologic diagnoses in the overwhelming majority in such cases are of benign disorders, either follicular adenomas or cellular adenomatous nodules. At times, follicular variants of papillary carcinomas are removed, but the number of "true" follicular carcinomas is low. A large portion of our medical resources is then being used to detect and treat a rare neoplasm, the well-differentiated follicular carcinoma. The solution to this dilemma may be either improved interpretations of fine-needle aspirates or modifications in the clinical approach to patients with such nodules. This may require the resurrection of methods used to evaluate thyroid nodules before the availability of fine-needle aspiration. The age and sex of a patient and palpatory findings, including sizes of the nodules, may need to be considered before embarking on thyroidectomies. Another alternative may be to inform patients regarding the risk of thyroid carcinomas associated with risky cytologic reports.V Follicular carcinomas are more likely to metastasize hematogenously to the lungs and bone than to regional lymph nodes, representing one of the major differences between the biologic behavior of follicular carcinoma and that of papillary carcinoma. Perhaps any "follicular carcinoma" metastatic to lymph nodes should be re-evaluated for a "follicular-like carcinoma," possibly a follicular variant of papillary carcinoma. Follicular carcinomas are considered as biologically distinct from papillary carcinomas because of their propensity to metastasize hematogenously to lungs and bone as well as lacking metastases to regional lymph nodes. The separation of papillary thyroid carcinomas from follicular carcinomas is advocated to emphasize these differences, especially because it may affect treatment. Another point of view is that the observed differences between papillary and follicular carcinomas may be purely academic, because differences in survival rates are more closely related to factors other than the papillary and follicular histology of the tumors.43•6 1 Perhaps it is appropriate to refer to these follicular cell neoplasms generically as welldifferentiated carcinomas of the thyroid gland.

Hurthle Cell (Oncocytic) Tumors Hiirthle cell tumors are neoplasms composed of oncocytes or Hiirthle cells. These cells contain numerous mitochondria and have a distinctive granular microscopic appearance with routine hematoxylin and eosin stains. Oncocytes are not peculiar to the thyroid gland but can occur in salivary glands, upper respiratory glands, and the kidneys.

Considerable controversy is associated with Hiirthle cell neoplasms. The criteria for histologic diagnosis, their biologic behavior and treatment, are subjects for debate. Oncocytic papillary carcinomas occur, but contrary conclusions concerning their aggressiveness and treatment have been stated. 62-64 Some behave like their usual counterparts, whereas others result in poorer outcomes. The suggestion has been made that oxyphilic variants of papillary carcinomas are more akin to follicular carcinomas than usual papillary carcinomas in their aggressiveness. Hiirthle cell neoplasms can be divided into adenomas and carcinomas by the same criteria used to distinguish follicular adenomas from carcinomas. Similarly, there are minimally invasive and extensively invasive forms, and prognosis is determined by the extent of invasive growth. A controversy concerning Hiirthle cell neoplasms is whether benign lesions can be consistently differentiated from malignant ones. A report, the center of this controversy, concluded that all Hiirthle cell tumors are potentially malignant and should be treated as such.65 The impetus for the statement was that benign tumors could not be consistently separated from the malignant ones in that analysis. This may have been a catalyst for other institutions to report their experiences with Hiirthle cell tumors. 66-73 The present consensus is that Hiirthle cell adenomas can be reliably differentiated from carcinomas, using the criteria applied to follicular carcinomas. However, some doubt still remains, demonstrated by a statement that Hiirthle cell tumors larger than 4 cm are malignant." In addition, one institution reported two patients with the histologic diagnoses of indeterminate for malignancy (i.e., the neoplasms invaded into but not through the capsule) who developed recurrences.s'' One carcinoma was found in 40 patients with benign diagnoses. The percentage of patients included in this and the original controversial report who ultimately developed carcinomas when the histologic diagnoses were indeterminate or benign is 12.9%,65.66 a small but not insignificant number. However, in another report, the percentage was 1%.69 Does the problem still persist? Is a cellular Hiirthle cell nodule, composed entirely of a uniform population of oncocytes with no cytologic atypia and no evidence of invasive growth, benign or malignant? Are all Hiirthle cell tumors larger than 4 em malignant? A group of poorly differentiated oxyphilic tumors have been described that may account for most of the problems associated with Hiirthle cell tumors." These tumors had capsular or vascular invasion, or both, and were divided into two groups: large cell and small cell types. Solid or trabecular histologic patterns predominated, with little development of follicles. However, there were problems with the descriptions of these tumors. Vascular invasion was described as minimal in 10 cases. However, minimal invasion of blood vessels was not defined. Capsular invasion was present in 15 of 20 cases. No details of the degree of invasive growth were given. The small cell tumors were more aggressive, with a rate of recurrences of 37%, and 30% of the patients were either alive with residual neoplasm or had died of their tumors. In contrast, only I of 40 patients with the large cell type died of neoplasm.

Pathology of Tumors of the Thyroid Gland - - 229

The small cell type is most likely the type of Hiirthle cell carcinoma that causes difficulties. However, large cellular neoplasms, composed only of large Hiirthle cells, may also present problems for the pathologists. The treatment of Hiirthle cell carcinomas is modified from that of follicular carcinomas because not all Hiirthle cell carcinomas take up radioactive iodine, and so the use of radioactive iodine is less effective. Under such circumstances, total surgical removal of the neoplasm is indicated and external beam radiation may be considered for invasive and incompletely resected neoplasms. Chemotherapy has been ineffective. A confounding factor is the presence of Hiirthle cell nodules in benign diseases of the thyroid gland, notably in nodular goiters and Hashimoto thyroiditis. Hurthle cell metaplasia of follicular cells is common in nodular goiters and is an integral part of autoimmune thyroiditis. Histologically, such nodules are usually not problematic. However, extensive Hiirthle cell changes in a goitrous nodule can suggest a Hiirthle cell neoplasm. A more troublesome lesion is the solid nodule composed entirely of Hiirthle cells in autoimmune thyroiditis. It may be encapsulated, and a Hiirthle cell neoplasm becomes a serious consideration. To determine definitively which of such lesions is malignant can be pathologically difficult. The aggressiveness of Hiirthle carcinoma is between that of papillary carcinoma and that of anaplastic carcinoma. They are tumors of moderate malignancy." A description of polymerase chain reaction-based microsatellite polymorphism analysis of Hiirthle cell tumors suggests that the oncocytes of Hiirthle cell tumors differ significantly from cells of follicular tumors." Could this account for the aggressiveness of these tumors when compared with ordinary follicular carcinomas?

Medullary Carcinoma The C cell is the cell of origin for medullary carcinoma and is at the basal portion of follicular epithelium adjacent to the basement membrane. C cells are best demonstrated by immunohistochemical stains for calcitonin and markers for neuroendocrine cells, such as neuron-specific enolase, chromogranin, and synaptophysin. The clinical syndromes encountered with C cells include • C-cell hyperplasia • C-cell adenomas • Familial medullary carcinoma • Nonfamilial or sporadic medullary carcinoma Seventy-fivepercent of medullary carcinomas are sporadic and the remaining 25% are familial. The familial forms are77 • Medullary thyroid carcinoma alone (familial MTC or FMTC). • Multiple endocrine neoplasia type 2A (MEN 2A), characterized by medullary carcinoma of the thyroid gland, bilateral adrenal medullary hyperplasias or pheochromocytomas, primary hyperparathyroidism with parathyroid glandular hyperplasia, and congenital colonic aganglionosis (Hirschsprung disease).

• Multiple endocrine neoplasia type 2B (MEN 2B), defined by medullary carcinoma, pheochromocytomas, a marfanoid habitus with distinct facies, hyperextensibility of joints, hypertrophic corneal nerves, submucosal neuromas of the conjunctiva and tongue, and submucosal colonic ganglioneuromatosis. C-cell hyperplasia is recognized as the precursor for MTCs in the familial forms." There are two types of hyperplasia, one associated with familial medullary carcinomas (neoplasm associated) and the second (physiologic hyperplasia) found with conditions such as autoimmune thyroiditis, occasionally with hypothyroidism, non-Hodgkin thyroidal lymphomas, and nodular and diffuse goiters with or without hyperthyroidism. Primary and secondary hyperparathyroidism has been associated with C-cell hyperplasia. The pathogenetic mechanisms for physiologic hyperplasia may be thyroid-stimulating hormone stimulation and hypercalcemia. C-cell hyperplasia has also been described adjacent to thyroid tumors of follicular cell origin." No explanation for this phenomenon is available. In a few cases, mild increases in serum calcitonin have been demonstrated, and preoperative diagnoses of C-cell carcinomas have been considered. In contrast to the familial forms of C-cell hyperplasia, physiologic hyperplasia appears to have extremely low potential for malignant change. Rare cases of small medullary carcinomas, existing with C-cell hyperplasia, have been reported in thyroid glands of patients with longstanding primary or secondary hyperparathyroidism and rarely when medullary carcinomas are found in glands affected by autoimmune thyroiditis. Medullary carcinomas form discrete masses that are usually solid and well demarcated. They vary in size from a few millimeters to large masses that occupy an entire thyroid lobe. The neoplasms can be associated with massive metastases to regional lymph nodes. Microscopically, the neoplasms are composed of oval and spindle cells, separated into organoid nodules by thin bands of collagen, similar to the pattern seen in carcinoids and paragangliomas (Fig. 25-4). Amyloid is present in 75% to 80% of the tumors." Amyloid stains pink with hematoxylin-eosin stain, and its presence is confirmed by the green birefringence

FIGURE 25-4. Medullary carcinoma: nests of ovoid cells surrounded by dense matrix (amyloid by Congo red stain) (arrow).

230 - - Thyroid Gland seen when examined by polarized light. The most dependable method for identifying C-cell carcinomas is an immunohistochemical stain for calcitonin. The tumors are unilateral in the sporadic forms, whereas the familial tumors are usually bilateral and, when found unilaterally, are also multifocal. Only 6% of familial tumors occur unilaterally.F'" Spread to lymph nodes is usually to the central and lateral compartments. In patients who present with no palpable tumors in the neck, metastases to lymph nodes are uncommon (10%). In contrast, patients with palpable neck masses have high rates of involvement of lymph nodes by metastases.F"? Medullary carcinomas of all types represent approximately 7% of all thyroid carcinomas and, of these, 75% are sporadic. In sporadic cases, patients are usually in their fourth decade and present with unilateral lesions without associated endocrinopathy. The remainder occur as familial forms, inherited as autosomal dominant traits. The most indolent and most difficult to detect is FMTC. MEN 2A may not be clinically expressed in 30% of patients by 70 years of age. Pheochromocytomas, usually bilateral, occur in approximately 50% of patients and hyperparathyroidism in approximately 20%. In MEN 2A, the thyroid carcinoma develops before the pheochromocytomas or parathyroid hyperplasia. MEN 2A can be associated with cutaneous lichen amyloidosis, Hirschsprung disease, or both. Patients with MEN 2B have a marfanoid habitus, mucosal and intestinal neuromas, and medullary carcinoma. The patients have distinctive facies, with thick lips showing neuromas that also occur in the conjunctiva and tongue. Pheochromocytomas develop in 50% of patients, but unlike the situation in MEN 2A, parathyroid glandular hyperplasia does not. Hirschsprung disease, primarily a sporadic disease, has been described in patients with FMTC and MEN 2A with heterogeneous germline mutations of RET in some of the families. Surgery, total thyroidectomy, is the preferred method of treatment for all medullary carcinomas, with resection of all affected lymph nodes in the central compartment. If the primary tumor is larger than 1.5 ern, the dissection is extended to include the lateral neck with removal of all affected lymph nodes. These tumors do not take up radioactive iodine, and there are no effective chemotherapeutic agents. Preventive surgery in patients with MEN 2A and MEN 2B has become routine because of the ready availability of screening methods for the RET protooncogene.I''?? In patients with MEN 2A and FMTC, prophylactic surgery at 6 years of age is favored, and in patients with MEN 2B, thyroidectomies are recommended during infancy. The earlier operations in patients with MEN 2B are recommended because of the early development and aggressiveness of the carcinomas in these patients. The clinical outcomes associated with the different forms of medullary carcinoma are • All forms, 5-year survival rate, 78% to 91%; lO-year rate, 61 % to 75% • Sporadic MTC, corrected for stage, similar to MEN 2A • FMTC, best survival rate • MEN 2A, midway between sporadic MTC and 2B • MEN 2B, worst survival rate Tumors of C cells with cells in papillary and follicular patterns have been reported, and metastases with similar

histologic patterns have been described. 80-82 The cell of origin for such tumors has not been established. Their clinical behavior is similar to that of the usual medullary carcinomas. C-cell adenomas have been described but have not been accepted as recognizable clinical entities.P

Poorly Differentiated, Small Cell, and Anaplastic Carcinomas Poorly differentiated carcinomas purportedly are carcinomas that have clinical outcomes midway between those of welldifferentiated and anaplastic carcinomas.tv" Insular carcinomas and poorly differentiated carcinomas, as they occur in papillary and follicular carcinomas, are the two major forms. The category of poorly differentiated carcinomas is compromised by the inclusion of tall cell, columnar cell, and mixed tall and columnar carcinoma variants of papillary carcinomas. 33,87,88 As noted previously, these tumors can be recognized as follicular cell tumors and so, in the traditional sense, are not poorly differentiated. Insular carcinomas are characterized by solid masses of round and oval cells separated into islands by thin bands of fibrous connective tissue. 84 ,89 Mitotic figures, areas of necrosis, and invasive growth are common and some show papillary or follicular differentiation. A review of a large number of cases in the literature showed that insular carcinomas were very aggressive, but another study resulted in a contrary conclusion.i-'" Insular carcinomas within papillary and follicular carcinomas do not appear to affect the prognosis adversely. Insular carcinomas, in the initial report of such cases, were described as aggressive tumors that caused early deaths in patients. However, a second observer, after examining a series of slides included in the initial report, commented that an array of histologic changes were represented in the slides and only two cases possessed the histology described by the authors." Another histologic type of poorly differentiated carcinoma is described in "high-risk" groups of patients with papillary and follicular carcinomas.s" The tumors consist of poorly differentiated carcinoma characterized by solid, trabecular, or scirrhous patterns of neoplastic follicular cells within well-differentiated papillary and follicular carcinomas, The conclusion was that the poorly differentiated areas in papillary and follicular carcinomas are associated with poorer clinical outcomes than with well-differentiated carcinomas but better than with anaplastic carcinomas. Poorly differentiated carcinoma, as defined before, is difficult to recognize because solid, trabecular, and desmoplastic histologic patterns are also found in well-differentiated papillary and follicular carcinomas and do not portend aggressiveness.V:'? Alternatively, tumors with areas of poor differentiation could be designated as high-grade papillary or follicular carcinomas instead of poorly differentiated carcinornas.?' Another report of patients with papillary and follicular carcinomas with areas of poorly differentiated carcinomas, as defined before, included two cases with insular changes and one with columnar cells. The overwhelming number of cases had well-differentiated thyroid carcinomas associated

Pathology of Tumors of the Thyroid Gland - -

with poorly differentiated carcinoma, so the analysis essentially recapitulates the previous data." Age, distant metastases at diagnosis, differentiation, and extrathyroidal invasion were the prognostic factors. Except for the omission of size, the variables in the AGES system are duplicated. The results highlighted a group of tumors (diffuse, poorly differentiated carcinomas) that were associated with local invasion, large tumor size, and lymph nodal and distant metastases that caused more frequent relapses and poorer outcomes. The conclusion was that diffuse, poorly differentiated carcinoma is an important clinicopathologic entity, with "diffuse" identifying differentiated carcinomas with poorly differentiated areas forming greater than 10% of the neoplasm. A flaw in the study was the selection of 10% as the cutoff point between focal and diffuse, poorly differentiated carcinomas. Ten percent is a small number and subject to significant interobserver variations. The most important finding was that, as with all well-differentiated carcinomas, the stage of the neoplasm at the time of diagnosis appears to be the most significant prognostic factor. Solid-trabecular forms of PTCs in adults have been reported as separate pathologic entities. 93,94 One study considers the possibility that the cells in the solid-trabecular areas were reminiscent of fetal thyroid cells (primordial cells). Tumors were divided into two groups: those with "insular" components and those with predominantly solidtrabecular areas with minor insular components. The conclusions were as follows: • No fatalities within 6 months • No differences in survival rates • More frequent recurrences and distant metastases with the insular group • Tumors are aggressive but show slow clinical courses with good response to therapy The data do not show that the tumors with the solidtrabecular patterns of growth are more aggressive. Descriptions to stage the neoplasms are absent except for sizes of the tumors, the presence of metastases, and infiltration of the mediastinum. A second study concluded that solid variants of PTC are associated with a higher risk of distant metastases and slightly lower long-term survival.P The results are such that separation of this histologic type of papillary carcinoma from usual papillary carcinomas is probably not warranted. In summary, a thyroid neoplasm that can be classified as a poorly differentiated carcinoma has not been definitively described. There is no denying that papillary and follicular carcinomas with less differentiated areas occasionally cause deaths. However, the best prognostic factors are those that have been long identified: age, extrathyroidal invasion, completeness of excision, size, and distant metastases at the time of diagnosis. Anaplastic thyroid carcinomas constitute approximately 1.5% of all cases of thyroid carcinomas in the United States, an extremely small number of approximately 300 cases per year." The rarity of the tumors accounts for the lack of adequate data and expertise to assess the clinical behavior and treatment of these tumors. They occur more frequently in iodine-deficient geographic areas with a high prevalence of nodular goiters and follicular carcinornas.v-" Iodine sufficiency, attributed to iodine

231

prophylaxis, may account for the low prevalence in the United States of nodular goiters and follicular carcinomas. It may also have increased the number of papillary carcinomas. Follicular carcinomas occur more commonly in nodular goiters, and the rarity of follicular carcinomas in the United States may account for the very low rate of anaplastic carcinomas. Anaplastic carcinomas are typically found in women, in older patients (mean age, 57 to 67 years), and in patients who present with rapidly enlarging masses in the neck. Hoarseness and dyspnea are common. Nearly 80% of patients have tumors greater than 5 ern in diameter. Cervical lymphadenopathy (40%), metastases to regional lymph nodes (50%), and distant metastases (50%) are common. Distant metastases commonly involve the lung, followed by metastases to bone and brain. Microscopically, these tumors consist predominantly of spindle and giant cells (Fig. 25-5). It has been convincingly demonstrated that many, if not all, anaplastic tumors are accompanied by papillary and follicular carcinomas.v-" They are also associated with medullary carcinoma, although this phenomenon is problematic.v-" Some consider all anaplastic tumors as originating from preexisting medullary carcinomas. However, this is not the prevailing opinion, although anaplastic carcinomas do occur simultaneously with medullary carcinomas. The anaplastic areas can resemble soft tissue sarcomas histologically." Histologic patterns that replicate osteogenic sarcomas, chondrosarcomas, giant cell tumors of bone, and fibrosarcomas have been documented. This phenomenon makes the diagnosis of primary soft tissue malignancies of the thyroid gland difficult to establish. An exception may be the hemangioendothelioma, a soft tissue sarcoma in the thyroid gland that has been reported nearly exclusively in

Europe.?? Immunohistochemical methods play an important role in establishing the diagnosis of anaplastic thyroid cancer.95,97 The most consistent procedure is an immunohistochemical stain for keratin, positive in a great number of these tumors, Stains for thyroglobulin are inconsistent and unreliable.

FIGURE 25-5. Anaplastic carcinoma: spindle cells, giant cells, and neoplastic follicle (follicular carcinoma).

232 - - Thyroid Gland There are two viewpoints concerning the genesis of these tumors. 95.97 The prevailing consensus is that the association with well-differentiated carcinomas is consistent; the contrary opinion contends that anaplastic carcinomas arise de novo. The evidence for the de novo origin of anaplastic carcinomas is based on cytophotometric analysis of anaplastic tumors." Only a portion of the differentiated cancers associated with anaplastic cancers shared the aneuploidy of the anaplastic components, demonstrating that anaplastic tumors do originate de novo. However, a contrasting study showed that both elements can be aneuploid, and aneuploidy in differentiated tumors was predictive of anaplastic transformation. Aneuploidy is common in anaplastic cancers but is not a reliable prognostic factor. Coexistent papillary and follicular thyroid cancers in anaplastic carcinomas have similar cytogenetic patterns by comparative genomic hybridization, which suggests that anaplastic cancers may have arisen from the differentiated thyroid cancers." The genes and oncogenes associated with anaplastic cancers include p53, c-myc, NM23, and Ras. 95 Activation of ras results in the expression of human H-ras, a rare phenomenon. Mutations of p53 have been found in most anaplastic cancers as well as in well-differentiated tumors, so the implication of their presence in thyroid tumors is uncertain. The clinical course of these patients is alarmingly short, a mean survival of approximately 4 months. It is the rare patient who survives beyond a year. Comments have been made that the tumors of patients who survive for a long period should be re-examined for small cell tumors. Anaplastic cancers occur most commonly in elderly people, but cases in patients younger than 40 years have been described.P''" The youngest patient was 22 years of age. The results of treatment of these tumors have been discouraging. The treatment modalities include surgery, external radiation, and chemotherapy. Varying combinations have been attempted, with poor results. Appropriate therapy for these tumors is yet to be developed. One drastic change in the second WHO classification of thyroid tumors was the exclusion of anaplastic small cell carcinomas of the thyroid gland," The rationale was that tumors previously classified as small cell carcinomas had been identified as malignant lymphomas.95-97.100.101 Small cell carcinomas of epithelial origin in the thyroid gland are either medullary carcinomas or neoplasms that resemble oat cell carcinomas of lung. 102 The latter stain immunohistochemically like neuroendocrine tumors but do not contain calcitonin. These tumors were clinically aggressive and caused the deaths of the patients in a short time. These may be carcinomas similar to those that occur in other organs that are tumors of neuroendocrine cells, but are not medullary carcinomas of the thyroid gland.

Malignant Lymphoma Malignant lymphomas are rare in the thyroid gland. Approximately 5% of thyroid malignancies are non-Hodgkin lymphomas of large diffuse B-cell type.l'" Lymphomas of the thyroid gland are lymphomas of mucosa-associated lymphoid tissue (MALToma or MALT-type lymphoma) and have been

classified as extranodal marginal zone B-celllymphoma (lowgrade B-celllymphoma of MALT type). 103-106 For uniformity, lymphomas of mucosa-associated lymphoid and extranodal lymphomas are referred to as marginal zone lymphomas. Isaacson and Wright introduced the concept of extranodal lymphomas of MALT. 107 Central to their idea was that the morphologic characteristics and the behavior of lymphocytes in the marginal zones found in the spleen and Peyer's patch of terminal ileum were duplicated by lymphomas derived from them. A marginal zone is not found in normal lymph nodes except in mesenteric lymph nodes, but analogous areas are found in lymph nodes involved in inflammatory processes. Marginal zone lymphocytes possess distinctive morphologic characteristics, and so do the cells of marginal zone lymphomas. The cells of marginal zone lymphomas characteristically invade epithelial structures to form lymphoepitheliallesions, which, when present, support the histologic diagnosis of malignant lymphoma. Marginal zone lymphomas can involve the stomach, salivary gland, thyroid gland, dura, lung, skin, ocular regions, and breast. 108 The stomach and thyroid gland are normally devoid of lymphoid tissue but acquire lymphoid tissue in response to chronic antigenic stimulation by chronic infections or autoimmunity-that is, the stomach in response to infections with Helicobacter pylori and the thyroid gland to autoimmune thyroiditis. Another characteristic of marginal zone lymphomas is their "homing" property.I07.l08 The lymphocytes in MALT are postulated to be cells from the marginal zone of normal lymph nodes. These cells are thought to have tissue-specific homing properties that may well be determined from whence they came. Cells originating in lymph nodes "home" to lymph nodes, and cells from mucosal follicles migrate to the gut or other mucosa-lined organ. However, considering that marginal zone lymphomas also arise in kidneys, urinary bladder, and prostate gland, all organs lined by epithelial cells, usually columnar in type, may home to epithelium rather than mucosa. The cells can be distinguished from other cells only by morphologic and immunophenotypic features because there is no single immunologic marker that identifies these cells. Because there are similarities in morphology and other characteristics among lymphomas that arise in extranodal sites, the spleen, and lymph nodes, the term marginal zone lymphoma identifies these lymphomas.P''?' Marginal zone lymphomas of the thyroid gland are most common in older women with autoimmune thyroiditis. 109, 110 The relative risk of lymphomas arising in patients with autoimmune thyroiditis was 67 times greater than anticipated.l'" In Japan, the risk was determined to be 80 times greater than expected. Most malignant lymphomas of the thyroid gland are diffuse large B-cell types that probably evolved from marginal zone lymphomas, suggesting a morphologic progression from autoimmune thyroiditis to low-grade marginal zone lymphoma to high-grade diffuse B-celllymphoma (Fig. 25-6).108 Because only a few cases of marginal zone lymphoma of the thyroid gland have been reported, meaningful clinical and pathologic data are not available. The clinical presentation probably mimics that of autoimmune thyroiditis-namely, female preponderance, goiter

Pathology of Tumors of the Thyroid Gland - - 233

FIGURE 25-6. Malignant lymphoma: large lymphoid cells of diffuse B-celllymphoma, residual follicle (star).

with hypothyroidism, and perhaps symptoms related to the enlarged gland.l'" They remain localized for some time and therefore may be curable by localized therapy. In addition, when relapses occur, they develop in epithelium-lined organs and are associated with prolonged disease-free intervals. There are no meaningful data for low-grade marginal zone lymphomas of the thyroid gland on treatment and the outcomes of treatment. However, because thyroid lymphomas are nearly all marginal zone lymphomas, which may then develop into diffuse large B-cell lymphomas, the tumors, diagnosed in the early stages, should respond well to conservative, localized treatment, with good outcomes. The reports of lymphomas of the thyroid gland, prior to the introduction of the concept of low-grade lymphomas of the MALT type, dealt with an array of malignant lymphomas such as diffuse histiocytic (large cell), plasmacytoma, lymphoma with plasmacytoid features, germinal center cell (follicular and follicular and diffuse), immunoblastic, and follicular center cell lymphomas. 103·1 12 The adoption of the MALT concept and the designation of such lymphomas as marginal zone lymphomas unify malignant lymphomas of the thyroid gland into one diagnostic category and facilitate diagnosis and treatment.

Childhood Thyroid Carcinoma The nuclear accident at Chernobyl in 1986 refocused interest on radiation as a factor in the development of thyroid carcinorna.T'<" Prior to 1950, irradiation was frequently used to treat acne, enlarged tonsils and adenoids, chronic sinusitis, and other benign conditions.I" External radiation was commonly used to irradiate enlarged thymuses in infants and young children. The latent period, the interval from exposure to the appearance of thyroid cancer, was assumed to be 1 years and increased for at least 3 decades. Childhood thyroid cancer appeared within 4 years after the Chernobyl accident. Thyroid carcinomas in children and adolescents are rare and differ from adult carcinomas of the thyroid gland in the

°

following ways 113-118: • More advanced disease in children: a high rate of extrathyroidal invasion, more frequent metastases to regional lymph nodes and lungs, larger tumors but a lower rate of nondiploid tumors • Low mortality rates in spite of what may be more advanced disease; higher rates of recurrences in lymph nodes and lungs The histologic categories for the thyroid tumors found in irradiated patients include I 13-121: • Papillary carcinoma, including diffuse sclerosing and oxyphilic types • Follicular carcinoma • Medullary carcinoma • Solid-follicular type The papillary and follicular carcinomas are identical to those described in adults. Medullary carcinomas constituted a significant part (17%) of one report.!" However, the frequency of these tumors increased with the passage of time, with the highest number recorded in the last segment of one survey; hence, the increase is attributed to the development of screening programs. The results of investigations of thyroid cancers occurring after the Chernobyl accident led to the consideration of these questions concerning postradiation cancers in children: • Does the age of a patient affect the development of thyroid carcinomas after exposure? • Is there a unique histologic variant of thyroid cancer in this group of children? • Do such thyroid carcinomas behave more aggressively? Studies related to thyroid carcinomas associated with the Chernobyl accident have demonstrated that the thyroid glands of very young children are much more sensitive to the carcinogenic effect of radiation from fallout than the thyroid glands in older children. 121 The relative risk of developing thyroid carcinomas in irradiated children younger than I year was 44 times more than the relative risk in nonirradiated patients (237:6). The histology of the tumors was identical to that in postirradiated adults with the exception of a unique thyroid carcinoma, the solid-follicular type. A previous analysis of such tumors indicated that they may well be more aggressive than other histologic forms found in children. 122 Microscopic examination of the tumors found in children exposed at Chemobyl showed a significant number of solidfollicular carcinomas, most prevalent in patients in whom the tumors developed earliest after exposure. However, can one conclude that these tumors are more aggressive than other forms of well-differentiatedcarcinomas? One probably cannot, and longer follow-up is necessary to answer this question.

Genes, Protooncogenes, and Thyroid Cancers This • • •

section is limited to: RET protooncogene and MTC RET protooncogene and PTC Thyroid carcinomas and familial adenomatous polyposis (FAP) • Thyroid carcinoma and Cowden's disease

234 - - Thyroid Gland RET protooncogene encodes a transmembrane receptor that is a member of the receptors of the tyrosine kinase family and is found on chromosome 10 (lOql1.2).31,123 The gene is expressed normally in thyroid gland, adrenal gland, nerve tissue, and developing kidney and pathologically in neuroendocrine tumors (MTC, pheochromocytomas) and hyperplasia and neoplasia of parathyroid glands. The RET gene derived its name from an experiment in which it induced classic NIH 3T3 transformation, NIH 3T being an NIH assay (rearranged during rransfection).!" The gene encodes a transmembrane receptor, tyrosine kinase, that acts as a link between the extracytoplasm and plasma membrane and the nucleus of the cell by the transduction of signals. The RET receptor is part of a complex of proteins that serve as coreceptors on the cell membrane. The coreceptors increase the affinity of RET receptors for three ligands, of which glial cell line-derived neurotrophic factor (GDNF) is the most prominent. GDNF is associated in the pathogenesis of Hirschsprung disease.31.123 The RET protooncogene has been conclusively identified in the MEN 2A and 2B syndromes and FMTC The characteristics associated with medullary carcinoma and the MEN syndromes can be summarized as followS31,123:

• Germline mutations may be associated with specific areas of the gene. • 95% of patients with MEN 2A have mutations in exons 10 and l l on chromosome 10. • 90% of patients with MEN 2B have changes in exon 16, codon 918. • FMTC is associated with mutations in exons 10, 11, and 13, codons 768, 609, 611, 620, and 634. • Patients with MEN 2A who have changes in codon 63 with Cys 634 to Arg are at a greater risk for the development of parathyroid disease. The mutations that occur in RET are": • Missense germline mutations, found in 97% of patients with MEN 2A and 86% of patients with FMTC (codon 609,611,620, or 634) • Mutations involving the tyrosine kinase domain, nearly exclusively in FMTC (codon 768, 790, 804, 844, or 891) • Unique mutations in exon 13 or 14 • Mutations involving the tk domain, codon 883 or 918, in virtually all patients with MEN 2B The data for sporadic MTC are • Missense mutations in exon 16, substitution of methionine for threonine in codon 918. • Other mutations at codon 768, exon 13; codon 883, exon 15. • Mutations at exons 10 and 11 may not lead to development of MTC but may prime the C cells before transformation occurs. About 23% of patients with sporadic MTC have mutations affecting exon 16 and codon 918. Because identical mutations are found in MEN 2B, familial and sporadic MTCs may result from similar changes in the gene. One report concluded that a mutation in codon 918 in the RET protooncogene in sporadic MTC is associated with a poor prognosis, with frequent distant metastases and recurrences.

The characteristics of pheochromocytomas with or without MEN changes are: • Sporadic pheochromocytomas have mutations in codon 768. • There are mutations in codon 634 (cysteine to arginine) in MEN 2A families (with at least one member with pheochromocytoma and parathyroid hyperplasia). • Mutations involve codon 609, 611, 618, or 620 in families with parathyroid hyperplasia and FMTC without pheochromocytoma. • There is a significant association of hyperparathyroidism and pheochromocytoma with mutation at codon 634. • No specific mutation correlates with familial pheochromocytoma. Parathyroid hyperplasia in MEN 2A, pheochromocytomas in MEN 2A and 2B, and the other somatic lesions, such as marfanoid habitus, intestinal ganglioneuromatosis, skeletal abnormalities and, rarely, parathyroid hyperplasia, reflect the presence of the RET protooncogene in their respective normal counterparts. RET mutations, missense and nonsense, in exons 2, 3, 5, and 6 have been found in patients with Hirschsprung disease. The mutations lead to inactivation of RET rather than the activation found with medullary thyroid cancer. The normal activity of RET, in reference to the nervous system, is to develop the enteric autonomic nervous system. Its absence leads to the neural defect of Hirschsprung disease (absence of ganglion cells in colonic enteric plexuses)." The clinical significance of mutations of the RET gene in sporadic MTC is controversial. Such tumors appear to be aggressive and result in poor outcomes because of frequent development of distant metastases and recurrences. However, these findings have not been firmly established. The rate of de novo mutations in MEN 2A and FMTC is approximately 10%, whereas the rate in MEN 2B is approximately 50%. The finding of RET protooncogene in familial forms of medullary carcinoma syndromes has altered the screening procedures for medullary carcinoma (MTC). Before the discovery of the association of MTC with RET protooncogene, screening was accomplished using intravenous pentagastrin and calcium, a procedure fraught with discomfort for the patient and a small but significant number (approximately 15%) of false-negative and false-positive results. Biochemical screening has now been largely replaced by genetic screening. Blood levels of calcitonin, either basal or after provocation, are now primarily used to observe patients for recurrent or persistent MTC after thyroidectomies." The associations of the RET gene with PTC are I4,31,123,124: • RET/PTC rearrangements are unique to human PTC • The rearrangements are oncogenes, formed by translocation of three different genes of the tyrosine domain of the RET protooncogene. • Four forms are recognized, RET/PTC] to RET/PTC4. • There is loss of differentiated functions of the thyroid gland: thyroglobulin, thyroperoxidase, and thyrotropin receptor gene expression. • Thyrotropin-independent cell growth is promoted. • Frequency of RET/PTC activation in PTCs varies from 2% to 60% but is significantly higher in the

Pathology of Tumors of the Thyroid Gland - -

4- to 30-year-old age group; this may account for the contribution of age to the clinical features of PTe. • No connection of RET/PTC rearrangements to the aggressiveness of papillary carcinomas has yet been demonstrated. • All thyroid carcinomas with RET rearrangements show a well-differentiated phenotype and do not progress to aggressive, poorly differentiated forms. • RET/PTC] is dominant in sporadic tumors and both RET/PTC] and RET/PTC3 are common in radiationinduced tumors. • RET/PTC arrangements are common in papillary microcarcinomas, so they are early developments in thyroid neoplasia. The incidence of RET/PTC rearrangements in clinically significant papillary carcinomas is not known, although a frequency of 2.5% to 50% has been reported. 14 Immunohistochemical staining for RET/PTC rearrangements can now be employed to identify definitively papillary carcinomas that mimic follicular lesions. Follicular variants of papillary carcinomas can now be more precisely identified. Eighty percent of papillary microcarcinomas have the rearrangements, as well as 50% of clinically significant tumors." Using RET/PTC rearrangements as markers for papillary differentiation, Htirthle cell tumors can now be more accurately subdivided into Htirthle cell adenomas, Htirthle cell carcinomas, and Htirthle cell papillary carcinomas. The association of FAP with thyroid carcinoma has been well documented.F'v-? The extracolonic manifestations of the syndrome include upper gastrointestinal adenomas, congenital hypertrophic retinal pigment epithelial lesions, desmoids, osteomas, epidermoid cysts of skin, and dental abnormalities. Relevant data concerning FAP-associated thyroid carcinomas can be summarized as follows: • Age: younger patients, mean age 25 to 34 years. • Sex: predominantly female (12:1). • Histopathology: unique papillary carcinoma with papillary pattern plus cribriform and solid areas with spindle cells, squamoid cells, and whorled spindle cells; numerous multifocal and bilateral microcarcinomas; Hashimoto-like parenchymal changes.!" • Genetics: autosomal dominant; adenomatous polyposis coli (APC) germline mutations on chromosome 5q21. • Coexisting RET/PTC rearrangements: RET/PTC] and RET/PTC3 in 80% of PTCs. • Treatment: total thyroidectomy because of unilateral and bilateral multifocallesions. • Prognosis: presumably good; carcinomas appear to be variants of papillary carcinoma, and no genetic or other findings suggest poor clinical outcomes. The APC gene is a tumor suppressor gene and does not participate in the progression of sporadic thyroid cancer. Interactions between the RET/PTC] activation and APC mutations are postulated in the development of FAP-associated thyroid carcinomas. The age and sex in FAP-associated carcinomas are in keeping with usual papillary carcinomas. Bilateral and multicentric tumors are analogous to pathologic findings in PTCs.

235

The cribriform and solid histology in these tumors may be sufficiently distinctive for pathologists to suggest the presence of the APC gene in patients in whom thyroid cancers are the initial manifestations (Fig. 25_7).126 However, the same histopathologic pattern allegedly occurs in sporadic cases.P" Thyroid cancers are not common in patients with APe. Only 1% to 2% of patients develop thyroid carcinomas. Cowden's syndrome, the multiple hamartoma syndrome, is an autosomal dominant disorder characterized by multiple benign and malignant neoplastic lesions found in many organs, including the thyroid gland and breast. 131-134 The thyroidal lesions are multinodular goiters, follicular adenomas, or carcinomas. The specific change in the follicular neoplasms is loss of heterozygosity on chromosome arm 10q. A novel tumor suppressor gene, PTEN, mapped to lOq23.3 is the susceptibility gene for Cowden's syndrome. The thyroid lesions are the major extracutaneous manifestations of the syndrome and are papillary carcinomas in adenomatous goiters, multicentric follicular adenomas, adenomatous nodules, and follicular carcinomas. As with

B FIGURE 25-7. Familial adenomatous polyposis (FAP)-associated thyroid carcinoma.

236 - - Thyroid Gland FAP-associated tumors, it is postulated that the histologic findings in the thyroid gland may be unique to Cowden's disease and its presence can be suggested by the changes in the thyroid gland. 133,134 The finding of multiple adenomatous goiters or multiple follicular adenomas, particularly in children and adolescents, should alert physicians to the possibility of an inherited trait, such as Cowden's disease. Because the tumors can be multicentric and can progress, total thyroidectomy is recommended, even though the tumors are usually benign. Progression of an adenoma to carcinoma is not inevitable because there are studies that suggest that adenomas and carcinomas can develop along separate, nonserial pathways.

Cytopathology Fine-needle aspiration of thyroid lesions has made interpretation of the aspirates one of the more important diagnostic steps in the treatment of benign and malignant diseases of the thyroid gland. However, every clinician who treats thyroid diseases should be aware of the limitations of the method. The difficulty encountered in differentiating benign from malignant follicular tumors, as well as the separation of benign Hiirthle cell lesions from their malignant counterparts, has been described. There is liberal use of descriptive terminology, such as "follicular neoplasia cannot be excluded," with the connotation that a well-differentiated follicular carcinoma may very well be present. Such cytologic reports may have resulted in the excess expenditure of resources in pursuit of uncommon follicular carcinomas. Suggestions have been made to rectify this situation. The same comments apply to Hiirthle cell lesions. The interpretations of fine-needle aspirates are nearly indispensable in the diagnosis and treatment of papillary and medullary carcinomas of the thyroid gland. Cytologic smears of papillary carcinomas are easily recognized by the syncytia of large follicular cells with nuclear membrane folds (grooves), intranuclear inclusions, and prominent nuclei. The clear nuclei seen on histologic slides are absent, being artifacts of formalin fixation. Medullary carcinomas are usually easily recognized. In addition, stains for calcitonin and carcinoembryonic antigen can aid in the diagnosis. The cytopathologic appearances of tall cell and columnar cell carcinomas have been described. However, these lesions are rare, and the recognition of a malignant tumor should suffice without specifying the cell type. Cytopathologic smears are extremely helpful in establishing the diagnosis of malignant lymphomas of the thyroid gland. Marginal zone lymphomas, per se, have rarely been reported in the thyroid gland. The usual lymphoma of the thyroid gland is a diffuse, large B-cell lymphoma. These lymphomas are characterized by large cells with cleaved or noncleaved nuclei and prominent nucleoli. Flow cytometry, immunohistochemicalstaining, and gene rearrangement studies on fresh tissue specimens are extremely helpful in establishing the proper diagnosis. The association of autoimmune thyroiditis with lymphomas of the thyroid gland may make the diagnosis difficult. The ancillary studies suggested are very helpful in establishing the proper diagnosis.

Cytopathologic smears can also establish the diagnosis of benign lesions, such as nodular goiters and autoimmune thyroiditis. The nodules of a nodular goiter are often associated with syncytia of cells, as seen in papillary carcinomas; however, none of the nuclear changes of papillary carcinoma are seen, and the nuclei appear bland and benign. Collections of macrophages, some laden with hemosiderin, can be numerous. Typically, sheets of cells, most often Hiirthle cells, are surrounded by benign-appearing lymphocytes in autoimmune thyroiditis.

Summary Thyroid carcinomas are basically separated into the four familiar forms: papillary, follicular, medullary, and anaplastic carcinomas. Hiirthle cell carcinoma may be separated as a special type, with distinctive morphologic changes and somewhat more aggressive behavior than the other welldifferentiated carcinomas. The subdivision of papillary carcinomas into tall cell and columnar cell types, considered to be more aggressive than the usual papillary carcinoma by some experts, has not been clinically relevant, nor has the addition of the category of poorly differentiated carcinoma as an intermediate form between well-differentiated carcinoma and anaplastic carcinoma, with outcomes intermediate between the two forms. Malignant lymphomas of thyroid gland are MALT lymphomas that probably evolve into diffuse, large B-celllymphoma, currently the most common malignant lymphoma of the thyroid gland. Marginal zone lymphomas tend to remain localized and spread according to their homing properties. They are low-grade lymphomas that can be treated locally, with long periods of remission. Autoimmune thyroiditis is commonly associated with them. The association of point mutations in the RET protooncogene with medullary carcinoma and gene rearrangements with papillary carcinoma has been firmly established. The Chemobyl accident has reemphasized the association of radiation with thyroid cancer, especially in younger children. RET/PTC3 and RET/PTC] are the primary gene rearrangements that have been identified in these cancers. The finding of a unique, solid-trabecular variant of papillary carcinoma in these children suggests that the solid variant and the presence of RET/PTC3 oncogene may be associated with a more aggressive form of papillary carcinoma. Specimens for cytologic examination, acquired by fineneedle aspiration, are extremely useful in establishing the diagnoses of thyroid diseases. However, their interpretations are not without hazard. Papillary carcinomas are easily recognized, but follicular and Hiirthle cell carcinomas are difficult to differentiate from their respective benign lesions.

REFERENCES I. Robbins J, Merino MJ, Boice JD, et al. Thyroid cancer: A lethal endocrine neoplasm. Ann Intern Med I991;1I5:133. 2. Hazard 18, Kenyon R. Atypical adenoma of the thyroid. Arch Pathol 1954;58:554. 3. Chen H, Nicol TL, Udelsman R. Follicular lesions of the thyroid: Does frozen section evaluation alter operative management? Ann Surg 1995;222:!OI.

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238 - - Thyroid Gland 60. Blum M, Feiner HD, Worth MH, et al. Clinical implications of the rare thyroid carcinoma which is indistinguishable from a follicular adenoma. Am J Med Sci 1978;276:99. 61. Mazzaferri EL. Treating differentiated thyroid carcinoma: Where do we draw the line? Mayo C1in Proc 1991;66:105. 62. Beckner ME, Heffess CS, Oertel JE. Oxyphilic papillary thyroid carcinomas. Am J Clin PathoI1995;103:280. 63. Berho M, Suster S. The oncocytic variant of papillary carcinoma of the thyroid: A clinicopathologic study of 15 cases. Hum Pathol 1997;28:47. 64. Herrera MF, Hay ro, Wu PS, et al. Hiirthle cell (oxyphilic) papillary thyroid carcinoma: A variant with more aggressive behavior. World J Surg 1992;16:669. 65. Thompson NW, Dunn EL, Batsakis JG, et al. Hiirthle cell lesions of the thyroid gland. Surg Gynecol Obstet 1974; 139:555. 66. Arganini MA, Bebar R, Wu TC, et al. Hiirthle cell tumors: A twentyfive year experience. Surgery 1986;100:1108. 67. Carcangiu ML, Bianchi S, Savino D, et al. Follicular Hiirthle cell tumors of the thyroid gland. Cancer 1991;68: 1944. 68. Gosain AK, Clark O. Hiirthle cell neoplasms: Malignant potential. Arch Surg 1984;119:515. 69. Grant CS, Barr D, Goellner JR, et al. Benign Hiirthle cell tumors of the thyroid: A diagnosis to be trusted? World J Surg 1988;12:488. 70. Har-EI G, Hadar T, Segal K, et al. Hiirthle cell carcinoma of the thyroid gland: A tumor of moderate malignancy. Cancer 1986;57: 1613. 71. Stojadinovic A, Ghossein RA, Hoos A, et al. Hiirthle cell carcinoma: A critical histopathologic appraisal. J Clin OncoI2001;19:2616. 72. Tallini G, Carcangiu ML, Rosai J. Oncocytic neoplasms of the thyroid gland. Acta Pathol Jpn 1992;42:305. 73. Watson R, Brennan MD, Goellner JR, et al. Invasive Hiirthle cell carcinoma of the thyroid: Natural history and management. Mayo Clin Proc 1984;59:851. 74. Chen H, Nicol TL, Zeiger MS, et al. HiirthIe cell neoplasms of the thyroid: Are there factors predictive of malignancy? Ann Surg 1998;227:542. 75. Papotti M, Torchio B, Favero A, et al. Poorly differentiated oxyphilic (Hiirthle cell) carcinomas of the thyroid. Am J Surg Pathol 1996; 20:686. 76. Segev D, Seiji M, Phillips GS, et al. Polymerase chain reaction-based microsatellite polymorphism analysis of follicular and Hiirthle cell neoplasms of the thyroid. J Clin Endocrinol Metab 1998;83:2036. 77. Phay JE, Moley JF, Lairmore TC. Multiple endocrine neoplasia. Semin Surg OncoI2000;18:324. 78. Albores-Saaverdra J, Kreuger JE. C-cell hyperplasia and medullary thyroid microcarcinoma. Endocr PathoI2001;12:365. 79. Randolph GW, Maniar D. Medullary carcinoma of the thyroid. Cancer Control 2000;7:253. 80. Apel RL, Alpert LC, Rizzo A, et aI. A metastasizing composite carcinoma of the thyroid with distinct medullary and papillary components. Arch Pathol Lab Med 1994;118: 1143. 81. Papotti M, Volante M, Komminoth P, et al. Thyroid carcinoma with mixed follicular and C-cell differentiation patterns. Semin Diagn PathoI2000;17:109. 82. Volante M, Papotti M, Roth J, et al. Mixed medullary-follicular thyroid carcinoma: Molecular evidence for a dual origin of tumor components. Am J PathoI1999;155:1499. 83. Kodama T, Okamoto T, Fujimoto Y, et al. C cell adenoma of the thyroid: A rare but distinct clinical entity. Surgery 1988;104:997. 84. Carcangiu ML, Zampi G, Rosai J. Poorly differentiated ("insular") thyroid carcinoma: A reinterpretation of Langhans' "wuchernde Struma." Am J Surg PathoI1984;8:655. 85. Rosai J, Saxen EA, Woolner LW. Undifferentiated and poorly differentiated carcinoma. Semin Diagn PathoI1985;2:123. 86. Sakamoto A, Kasai N, Sugano H. Poorly differentiated carcinoma of the thyroid: A clinicopathologic entity for a high-risk group of papillary and follicular carcinomas. Cancer 1983;52:1849. 87. Nishida T, Katayama S, Tsujimoto M, et al. Clinicopathological significance of poorly differentiated thyroid carcinoma. Am J Surg PathoI1999;2:205. 88. Pilotti S, Collini P, Manzari A, et al. Poorly differentiated forms of papillary thyroid carcinoma: Distinctive entities or morphologic patterns? Semin Diagn Pathol 1995;12:249. 89. Flynn SD, Forman BH, Stewart AF, et al. Poorly differentiated ("insular") carcinoma of thyroid. An aggressive subset of differentiated thyroid neoplasms. Surgery 1988;104:970.

90. Ashfaq R, Vuvitch F, Delgado R, et al. Papillary and follicular thyroid carcinomas with an insular component. Cancer 1994;73:416. 91. Carney JA Comment on: Flynn SD, Forman BH, Stewart AF, et al. Poorly differentiated ("insular") carcinoma of the thyroid: An aggressive subset of differentiated thyroid neoplasms. Surgery 1988;104:970. 92. Sobrinho-Simoes M. Poorly differentiated carcinomas of the thyroid. Endocr PathoI1996;7:99. 93. Nikiforov YE, Erickson LA, Nikiforova MN, et al. Solid variant of papillary thyroid carcinoma: Incidence, clinical-pathological characteristics, molecular analysis and biologic behavior. Am J Surg Pathol 2001;25:1478. 94. Papotti M, Botto Micca F, Favero A, et al. Poorly differentiated thyroid carcinomas with primordial cell component: A group of aggressive lesions sharing insular, trabecular and solid patterns. Am J Surg PathoI1993;17:291. 95. Ain KB. Anaplastic thyroid carcinoma: Behavior, biology, and therapeutic approaches. Thyroid 1998;8:715. 96. Nishiyama RH, Dunn EL, Thompson NW. Anaplastic spindle-cell and giant-cell tumors of the thyroid gland. Cancer 1972;30:113. 97. Carcangiu ML, Steeper T, Zampi G, et aI. Anaplastic thyroid carcinoma. A study of 70 cases. Am J Clin PathoI1985;83: 135. 98. Swamy Venkatesh YS, Ordonez NG, Schultz PN, et al. Anaplastic carcinoma of the thyroid: A clinicopathologic study of 121 cases. Cancer 1990;66:321. 99. Miura D, Wada N, Chin K, et al. Anaplastic thyroid cancer: Cytogenetic patterns by comparative genomic hybridization. Thyroid 2003; 13:283. 100. Rayfield EJ, Nishiyama RH, Sisson JC. Small cell tumors of the thyroid: A clinicopathologic study. Cancer 1971;28:1023. 101. WolfBC, Sheahan K, DeCoste D, et al. Immunohistochemical analysis of small cell tumors of the thyroid gland: An Eastern Cooperative Oncology Group study. Hum PathoI1992;23:1252. 102. Eusebi V, Damiani S, Riva C, et al. Calcitonin free oat-cell carcinoma of the thyroid gland. Virchows Arch A Pathol Anat Histopathol 1990;417:267. 103. Butler JS, Brady LW, Amendola BE. Lymphoma of the thyroid: Report of five cases and review. Am J Clin Oncol 1990;13:64. 104. Kossev P, Livolsi V. Lymphoid lesions of the thyroid: Review in light of the revised European-American lymphoma classification and upcoming World Health Organization classification. Thyroid 1999;9:1273. 105. Harris NL. Low-grade B-cell lymphoma of mucosa-associated lymphoid tissue and monocytoid B-celllymphoma. Arch Pathol Lab Med 1993;117:771. 106. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 1994;84: 1361. 107. Isaacson PG. Mucosa-associated lymphoid tissue lymphoma. Semin HematoI1999;36:139. 108. Burke JS. Are there site-specific differences among the MALT lymphomas-Morphologic, clinical? Am J Clin Pathol 1999; III (Suppl 1):SI33. 109. Anscombe AM, Wright DH. Primary malignant lymphoma of the thyroid-A tumour of mucosa-associated lymphoid tissue: A review of76 cases. Histopathology 1985;9:81. 110. Hyjek E, Isaacson PG. Primary B cell lymphoma of the thyroid and its relationship to Hashimoto's thyroiditis. Hum Pathol 1988; 19:1315. Ill. Aozasa K, Inoue A, Tajima K, et al. Malignant lymphomas of the thyroid gland: Analysis of 79 patients with emphasis on histologic prognostic factors. Cancer 1986;58: I00. 112. Oertel JE, Heffess CS. Lymphoma of the thyroid and related disorders. Semin OncoI1987;14:333. 113. Feinmesser R, Lubin EL, Segal K, et al. Carcinoma of the thyroid in children: A review. J Pediatr Endocrinol Metab 1997;10:561. 114. Harness JK, Thompson NW, Nishiyama RH. Childhood thyroid carcinoma. Arch Surg 1971;102:278. 115. Nishiyama RH, Schmidt RW, Batsakis JB. Carcinoma of the thyroid gland in children and adolescents. JAMA 1962;181 :94. 116. Viswanathan K, Gierlowski TC, Schneider AB. Childhood thyroid cancer: Characteristics and long-term outcome in children irradiated for benign conditions of the head and neck. Arch Pediatr Adolesc Med 1994;148:260. 117. Wiersinga WM. Thyroid cancer in children and adolescents: Consequences in later life. J Pediatr Endocrinol Metab 2001; 14(SuppI5):1289.

Pathology of Tumors of the Thyroid Gland - - 239 118. Zimmerman D, Hay ill, Gough I, et al. Papillary thyroid carcinoma in children and adults: Long term follow-up of 1039 patients conservatively treated at one institution during three decades. Surgery 1988;104:1157. 119. Schwenn MR, Brill AB. Childhood cancer 10 years after the Chernobyl accident. CUffOpin Pediatr 1997;9:51. 120. Tuttle RM, Becker DY. The Chernobyl accident and its consequences: Update at the millennium. Semin Nucl Med 2000;30:133. 121. Williams D. Cancer after nuclear fallout: Lessons from the Chernobyl accident. Nat Rev Cancer 2002;2:543. 122. Harach HR, Williams ED. Childhood thyroid cancer in England and Wales. Br J Cancer 1995;72:777. 123. Lloyd RY. RET proto-oncogene mutations and rearrangements in endocrine diseases. Am J PathoI1995;147:1539. 124. Nikiforov YE, Rowland JM, Bove KE, et al. Distinct pattern of ret oncogene rearrangements in morphological variants of radiationinduced and sporadic thyroid papillary carcinomas in children. Cancer Res 1997;57:1690. 125. Giardello FM, Offerhaus GJA, Lee DH, et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut 1993;34:1394. 126. Harach HR, Williams GT, Williams ED. Familial adenomatous polyposis associated thyroid carcinoma. A distinct type of follicular cell neoplasm. Histopathology 1994;25:549.

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Factors That Predispose to Thyroid Neoplasia Rachel R. Kelz, MD • Douglas L. Fraker, MD

Radiation exposure of the thyroid gland is the only welldocumented risk factor that increases the incidence of welldifferentiated thyroid cancer. 1.2 Thyroid exposure to radiation can result from external sources or from internal exposure by ingestion of radioisotopes of iodine, which concentrate in the thyroid gland. External exposure to the thyroid is primarily from medically administered radiation but can also occur with environmental exposures related to nuclear weapons or, more recently, nuclear power plant accidents. This association of radiation exposure and thyroid cancer is well established and well characterized but accounts for only a small portion of the total annual cases of well-differentiated thyroid cancer. 3 Other potential contributing etiologic factors, including diet, effects of steroid hormones, and other occupational exposures, have been evaluated.l-"

Radiation Exposure Historical Aspects The association between radiation exposure and increased risk of thyroid cancer was first recognized by investigators studying the increasing clinical problem of childhood thyroid cancer in the mid-20th century.V The number of cases of thyroid cancer diagnosed and treated in children or adolescents was quite low; only 18 cases of childhood thyroid cancer were reported in the medical literature before 1930 (Fig. 26-1).7 Duffy and Fitzgerald recognized an increased incidence of this disease and reported 28 cases between 1932 and 1948 at Memorial Sloan Kettering in New York City.' They evaluated this population with the stated goals of highlighting this increasingly important clinical condition, defining the disease and natural history of childhood thyroid cancer, and discovering "possible etiologic factors ... from analysis of environmental, familial, and other biologic factors." In addition to analyzing the sex distribution of the patients, age at diagnosis in relation to puberty, and regional dietary factors for these children, Duffy and Fitzgerald noted that 9 of the 28 patients received radiation in infancy for an enlarged thymus. Because 19 of these patients were

240

not known to have prior radiation, Duffy and Fitzgerald believed that no definite association between radiation exposure and thyroid cancer could be concluded from their data. Five years later, Clark adopted a similar strategy in evaluating in detail 13 cases of thyroid cancer diagnosed and treated in patients younger than 15 years at the University of Chicago." Contrary to Duffy and Fitzgerald, Clark found that all of his patients had received some type of childhood radiation, although only 3 of the 13 were treated for an enlarged thymus; others received radiation therapy for acne, tonsillitis, or cervical adenitis. Winship and Rosvoll further documented the relationship between radiation and childhood thyroid cancer by compiling a national registry to track the incidence of this disease." The peak number of cases in the United States was reported from 1950 to 1960 (see Fig. 26-1). The subsequent drop in incidence reflects the elimination of widespread use of radiation treatments for benign conditions of infancy and early childhood, which occurred during the end of the 1950s. Detailed analysis of subjects treated with radiation in early childhood documenting the development of thyroid disease over a long period of time, as well as case-control studies looking at the same factor, defined the true risk of radiation exposure. The impact of other variables such as the age at exposure, the doseresponse effect, and the greater problem of thyroid cancer diagnosed in adults who were exposed to radiation therapy as children has been characterized."

Childhood Radiation Exposure 1\\'0 case-control studies with extensive follow-up of large populations of patients irradiated in childhood have been published.v'? Shore and colleagues studied 2650 children irradiated between 1926 and 1957 in Rochester, New York, for an enlarged thymus compared with 4800 sibling control subjects." Thirty cancers and 59 benign thyroid nodules were detected in the treated group compared with 1 thyroid cancer and 8 benign nodules in the control group. The relative risk for this entire population was 45 for cancer and 15 for benign neoplasms.

Factors That Predispose to Thyroid Neoplasia - -

300

~

200

'0

!E ::I

Z

100

1900

1910

1920

1930

1940

1950

1960

1970

Year

FIGURE 26-1. The incidence of pediatric thyroid cancer in the UnitedStatesfrom 1900to 1970from a nationalregistrydeveloped by Winship showing the peak incidence occurring during the 1950s. (Adapted from Winship T, Rosvoll RV. Thyroid carcinoma in childhood: Final reporton a 20 year study. Clin Proc Child Hosp 1970;26:327.)

Ron and coworkers studied 10,834 patients treated for tinea capitis with radiation therapy before age 16 years between the years 1948 and 1960. 10 A nonirradiated control population consisted of 5392 siblings and 10,834 subjects from the same area in Israel. In this study, there were 43 malignant thyroid tumors and 55 benign tumors in the irradiated subjects compared with 16 cancers and 41 benign lesions in the control subjects. The relative risk from radiation in this large study was 4 for malignant disease and 2 for benign thyroid disease. The difference in the degree of risk in these two studies is explained by the characteristics of the radiation exposure and the age of the patients at exposure. The relative risk of thyroid cancer after childhood radiation is inversely related to age at exposure and directly proportional to exposure dose in lower dose ranges." The ages of subjects in the tinea capitis study by Ron and coworkers ranged from infancy to 15 years (mean age, 7.4 years),'? whereas in the study by Shore and colleagues, radiation treatment for an enlarged thymus was given only to infants." The effect of having much younger subjects in the study by Shore and colleagues is to increase the relative risk, and this relationship is further documented by analysis of the treated subjects in the study by Ron and colleagues, in which the relative risk is less for patients irradiated at age 7 years and older. The mean dose of radiation to the thyroid in the Shore study? was more than lO-fold higher (120 rad) than the mean dose in the Ron study of scalp irradiation (9 rad).'? For a given population, a roughly linear relationship exists between exposure dose and estimated increased risk such that Ron and coworkers could calculate an excess relative risk (ERR) of thyroid cancer of 0.3 per rad of childhood radiation exposure.!?

241

In a series of reports, Schneider and coworkers at the University of Chicago extensively studied their institution's population of more than 3000 patients who underwent childhood radiation between 1939 and 1962. 11- 13 Of 3042 patients, 1145 had thyroid nodules and 318 were confirmed to have thyroid cancer. II The natural history of almost 300 thyroid cancers related to childhood radiation was reported in 1986. Almost 75% were identified as lesions smaller than 1.5 em in maximal diameter, but more than 50% of the patients had multifocal disease. Eighty-eight percent of cases were papillary or mixed histology, and approximately 33% had lymph node involvement." A 1993 analysis of the age at exposure and dose of radiation confirms the relationship between these factors in terms of degree of relative risk defined by the case-control studies. 12 The ERR was 0.030 per rad for thyroid cancer and followed a linear relationship for the benign and malignant nodules over an exposure dose range of 0 to 150 rad. The ERRs at various ages at exposure are shown in Figure 26-2, demonstrating an increased relative risk with radiation at a younger age. Although females have a higher overall incidence of thyroid cancer, the ERR tended to be greater in the irradiated male population, although this variable was not significant. Other undefined genetic or environmental factors may contribute to radiation-induced thyroid neoplasia. Perkel and colleagues identified 286 radiated sib pairs (i.e., two children from the same family, both of whom had childhood radiation exposure ).13 There was a significant familial concordance for all thyroid neoplasms (P = .05) but only a trend for the subgroup of patients in whom thyroid cancer developed (P = .18), indicating that for a given age and dose of exposure there are other factors that tend to make children from certain families more susceptible than others to eventual thyroid cancer. There are two explanations for the relatively high proportion of irradiated subjects documented to have thyroid cancer in the Schneider population (10.5% of the total subjects observed). I 1 First, the length of follow-up in this population

0.04 0.03

a:a:~ 0.02 w

0.01 0.00

< 1 year

1-4 years

5-15 years

Age

FIGURE 26-2. The effect of age at the time of radiation exposure on the development of thyroid cancer. The excess relative risk (ERR) per rad of thyroid exposure is shown over different age ranges. (Adaptedfrom SchneiderAB, Ron E, Lubin J, et al. Doseresponse relationships for radiation-induced thyroid cancer and thyroid nodules. J Clin Endocrinol Metab 1993;77:362. © The EndocrineSociety.)

242 - - Thyroid Gland was very long; the majority of patients were monitored for more than 30 to 40 years after receiving radiation. In the subgroup of patients observed for at least 40 years after exposure, 60% had thyroid nodules and 15% had thyroid cancer.12 The data of Schneider and coworkers indicate that the annual incidence for thyroid cancer after childhood irradiation does not reach a plateau even after a long period of time from exposure, suggesting that subjects irradiated between 1930 and 1950 who are now in their sixth and seventh decades of life continue to have an increased ERR.12 Second, there is possible selection bias because this is a non-case-control study. The potential for overestimation of thyroid disease was demonstrated in a study comparing the impact of childhood irradiation using two methods of analysis: a questionnaire versus clinical evaluation. The degree of increased relative risk was sixfold higher when the same population was studied by questionnaire as opposed to clinical examination." This difference was believed to be due to the increased attention paid to the potential development of thyroid nodules by patients who had received childhood radiation exposure and by the physicians who took care of them because of this well-defined risk factor. Although the data characterizing relationship to dose of exposure and age of exposure are unaffected in single institutional reviews, the most accurate analyses of true estimates of increased risk come from the case-control studies, in which all patients undergo a clinical evaluation by the same team of investigators.

Radiation Exposure from Medical Therapy and Diagnosis Recognition of the potential for causing eventual thyroid cancer by administration of radiation treatments in childhood essentially eliminated this practice for treatment of benign diseases of the thymus, scalp, cervical lymph nodes, tonsils, and skin more than 30 years ago." Although administration of external beam radiation treatments for malignant conditions affects a smaller number of patients-particularly those in the lower age ranges-patients receiving therapeutic and diagnostic radiation therapy currently represent the largest population in which the thyroid is exposed to potentially carcinogenic doses of radiation. Because younger age of exposure and higher radiation doses increase the relative risk, patients receiving significant radiation therapy

in early childhood are the subgroup with the greatest likelihood of developing thyroid cancer. A 1991 study by Tucker and associates of 9570 pediatric subjects who received radiation therapy for a variety of malignant diagnoses, predominantly Wilms' tumor, Hodgkin's disease, neuroblastoma, and non-Hodgkin's lymphoma, demonstrated a significant risk in this group of survivors of childhood malignancies. IS Patients with neuroblastoma were irradiated at a mean age of 2 years with an estimated thyroid exposure of 600 rad-significantly greater than the usual exposures for the benign childhood conditions-and had an increased relative risk of thyroid cancer of 350. A similar highly significant increased risk in patients with Wilms' tumor of 132 indicates that a high therapeutic radiation dose at a young age (younger than 4 years) places the long-term survivors of this disease at a very high risk for developing a secondary thyroid cancer. IS In this study, patients with lymphoma had a significantly greater radiation exposure (dose range, 2000 to 3500 rad), but it was administered at an older age, and the relative risk was 81 and 67 for non-Hodgkin's lymphoma and Hodgkin's disease, respectively. IS Another large study of Hodgkin's disease not restricted to pediatric patients reported an increased relative risk in a group of subjects treated at a mean age of 29 years. 16 Hancock and colleagues identified six thyroid cancers in 1677 patients treated with radiation alone or radiation plus chemotherapy for Hodgkin's disease, which was 15.6 times the expected risk. The population of patients with Hodgkin's disease makes up a significant proportion of currently treated patients at risk for second thyroid neoplasms, because there is a high cure rate with this disease compared with other solid pediatric malignancies in which radiation treatment is administered. The impact of age at exposure and dose of exposure on relative risk can be seen from data extracted from several case-control studies in which these variables were defined (Table 26-1). Other medical radiation exposures may occur in smaller amounts in older patients but still may significantly alter the risk of thyroid neoplasia. A large study of more than 150,000 women treated with radiation therapy for cervical cancer reported a relative risk of 2.35 for thyroid cancer with an estimated exposure of only II rad.!? Finally, patients who receive minimal exposure from diagnostic or medical x-ray examinations with an estimated thyroid dose of less than 1 rad still showed a modest increase in relative risk, particularly female patients younger than 50 years. 18

Factors That Predispose to Thyroid Neoplasia - - 243

Another type of medical exposure is that to radioactive iodine, particularly iodine 131, for diagnostic or therapeutic purposes. A significant amount of ingested iodine is taken up and remains within the thyroid, and this gamma ray emitter over time exposes the thyroid tissue to a significant radiation dose. Therapeutic use of 131 1 for ablation of the thyroid in Graves' disease exposes the thyroid to a dose equivalent of between 6000 and 10,000 rad of external beam exposure. 19,20 Despite this high dose, there is minimal apparent increased risk of thyroid cancer. A study of more than 3000 patients treated with high-dose UII identified only 4 cases of thyroid cancer compared with 3.2 predicted cases." An update from the same investigatorsof a larger population of 10,552 patients evaluating all types of secondary malignancies after highdose 131 1 showed a 10-year standardized incidence ratio (SIR) of 1.32 for thyroid cancer." This mildly increased risk in this population was similar to the increased risk of stomach cancer in the same patients (SIR = 1.33) but was lower than the increased risk of brain and renal cancers (SIRs = 1.63 and 1.51, respectivelyj." Although this high-exposure dose is similar to that from external beam treatments administered for Hodgkin's disease, in which there is a much more significant risk, the lower increased risk with 131 1 treatment may reflect the ability of this type of exposure to ablate or destroy the thyroid parenchyma. A second more widely used dose range of 131 1 is that administered for diagnostic thyroid scans, which corresponds to approximately 50 rad of external beam exposure. A study of more than 35,000 diagnostic 131 1 scans administered between 1951 and 1969 showed a slight increase in thyroid cancer, with 50 actual cases versus 39.4 cases predicted (SIR = 1.27).22 Subgroup analysis showed that the risk was more significantlyelevated in males (SIR =2.70) than females (SIR = 1.12) receiving UII diagnostic scans (Fig. 26-3). One deficiency in this case-control study is the reason why the treated population ended up in the group that received a thyroid scan. That is, by definition, patients who undergo

3

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Thyroid Functional Nodules Disease

FIGURE 26-3. The risk of thyroid cancer after diagnostic iodine 131 thyroid scans giving an estimated dose of 50 rad. The standardized incremental risk is shown for the total population, for subgroups based on sex, and for subgroups based on the category of thyroid disease for which they were being studied. (Adapted from Holm LE, Wiklund KE, Lundell GE, et al. Thyroid cancer after diagnostic doses of iodine 131: A retrospective cohort study. J Nat! Cancer Inst 1988;80:1132.)

a thyroid scan must have some clinical indications for having this test ordered and, therefore, may be predisposed to the development of thyroid neoplasms on those grounds as opposed to any increased risk from the administered radioisotope. Subgroup analysis of the patients who had a diagnostic scan for nodular thyroid disease compared with functional thyroid disease confirms this selection bias. Patients who underwent a thyroid scan for nodular disease had a significantly higher risk for acquiring an eventual thyroid cancer (SIR = 2.77) compared with patients scanned for functional reasons (SIR = 0.62).22 The overall analysis of these large studies indicates that exposure doses of 131 1 in a low range (diagnostic scans) or a high range (therapeutic ablation) do not have the same relative risk as an equivalent dose of external beam radiation, as delineated previously. The reason for this difference is probably the energy levels and time course of a radiation exposure from ingested UII as opposed to a clearly defined acute delivery of fractionated external beam radiation. Other factors such as the impact of the iodine dose as well as the ablative effects of 131 1 directly on the thyroid gland may contribute to the fact that radiation from ingested medically used isotopes is not as carcinogenic as the external beam radiation therapy.P

Environmental Radiation Exposure As with the medical radiation exposure just described, environmental radiation exposure of the thyroid can be from external sources as well as internal ingestion of radioisotopes of iodine. The populations exposed are geographically related to discrete regional events involving either nuclear weapons or nuclear power plant accidents. The largest, best studied population exposed to acute external radiation from an environmental source includes survivors of the atomic bombs detonated at Hiroshima and Nagasaki.P>' A cohort of more than 100,000 residents of these cities with a variable exposure dose on the basis of proximity to the sites of explosion has been identified and monitored. Relative risk of thyroid cancer clearly increased in this population on the basis of age at exposure and dose of radiation received. Younger people and, in particular, females younger than 30 years at the time of the blasts had the most increased relative risk. The dose response is particularly well documented in Nagasaki, and the estimated relative risks are 1.28, 1.61,2.36, and 3.82 for estimated exposure doses of 25, 50, 100, and 200 rad, respectively.-' This increased risk is pertinent only to gamma ray exposure but does not correlate with neutron radiation exposure. Within this population, studied after the atomic bomb explosions, there have been 112 total cases of thyroid cancer: 62 from Hiroshima and 50 from Nagasaki." Histologically, the vast majority of this radiation-associated thyroid cancer has been papillary. The long-term survival for radiation-associated papillary thyroid cancer in Hiroshima is 82% compared with 85% for comparable cases not associated with radiation exposure from that area." These equivalent survival data suggest that radiation-induced thyroid cancer does not have an altered or more aggressive natural history.

244 - - Thyroid Gland

Although, on the basis of the Japanese studies, acute gamma radiation exposure from a single event such as an atomic explosion clearly increases the risk of thyroid cancer, chronic gamma radiation exposure does not have the same effect. 25 A long-term study of subjects in southern China, where a high level of background radiation is present as a result of radioactive sand, showed an increase in chromosome abnormalities of the thyroid gland but no increased incidence of thyroid neoplasia. The estimated exposure over 40 years in this population was a total of 14 rad, which as an acute exposure would increase the risk of thyroid cancer, and the relative risk was 1.02 compared with control subjects after this chronic exposure.P Nuclear weapon explosions also produce radioisotopes of iodine in fallout that can contaminate water and food supplies, leading to ingestion by patients. Like medically administered iodine, these isotopes concentrate in the thyroid gland and can deliver focal radiation to the gland. Whereas 1311 is used medically, nuclear fallout contains a mixture of 1311 with short-lived radioisotopes such as 1291, 1321, 1331, 1341, and l351.26.27 The best data concerning nuclear weapon fallout exposure come from testing sites in the Marshall Islands and Nevada. On March I, 1954, a 15-megaton bomb was detonated in the atmosphere over a test site on the uninhabited Bikini atoll in the northern Marshall Islands." Unfortunately, high-activity radiation fallout from this blast exposed 253 residents of the neighboring two islands, causing acute radiation sickness. Among the 86 subjects most exposed on the closest atoll, thyroid nodules developed in 32% of the total population and in 63% of children younger than 10 years at exposure." One report demonstrated that 12 other Marshall Island atolls thought initially to be unexposed to fallout had an increased incidence of thyroid nodules inversely proportional to the distance from the test site. The estimated doseresponse relationship defined in this study is II excess cases per rad per year per I million population." A second study of nuclear fallout involved Nevada test sites. The U.S. Atomic Energy Commission conducted more than 100 aboveground nuclear detonations between 1951 and 1958 at these sites.F This exposure was not as precisely defined in time and amount as the Marshall Islands incident, but dosimetry of surrounding areas including soil, vegetation, and milk from cattle showed that areas of Utah, Nevada, and Arizona were exposed. A cohort was identified including 4818 children who ranged in age from 0 to 7 years in 1953, the estimated time of peak exposure from fallout. An increased relative risk of 3.4 for the development of thyroid nodules was shown in the group of children with an estimated thyroid exposure greater than 40 rad? Again, the short-lived radioisotopes of iodine were believed to be a major factor in this exposure. All of the environmental exposures described previously occurred more than 40 years ago and have in large part been studied retrospectively to provide a long-term database for acute gamma radiation and nuclear fallout exposure. In April 1986, the Chernobyl nuclear power plant explosion released an estimated 50 million Ci of radioactive materials into the atmosphere and exposed an estimated 1.5 million people in southern Belarus and the northern Ukraine." The fallout early in the disaster consisted of a large amount of 1311 together with short-lived isotopes 1291, 1321, l331, 1341, and 1351. 29

An early study completed 4.5 years after the event using clinical examination and ultrasonographic studies showed no significant increased incidence of thyroid nodules in exposed populations versus control subjects." However, this study was completed just as the latent period after this exposure was ending. Cases of pediatric thyroid cancer in Belarus increased sequentially from 1986 through 199328,29 (Fig. 26-4). By 1996, more than 500 cases had been diagnosed in children younger than 15 years." The disease in the exposed children initially showed an equal sex distribution; 83 of 84 cases involved papillary thyroid cancer and 1 involved medullary thyroid cancer." Histologically, lesions that occurred soon after exposure were aggressive, with capsular invasion in 89% and lymph node metastases in 88%. Later, in 1998, Farahati and colleagues examined the agespecific effects of radiation on disease severity in 483 children living in Belarus and younger than 8 years of age at the time ofthe accident." They found that the frequency of thyroid carcinoma was highest among infants and children younger than 3 years and decreased rapidly with the advancing age at the time of exposure. There was a higher incidence of differentiated thyroid cancer among females compared with males (1.6). Follicular cancer represented only 3.6% of the cases, which may be explained by a longer latency period for this variant. Age at exposure was inversely related to disease severity. The study confirmed that younger patients had more extrathyroid disease, lymph node involvement, and distant metastasis. The latency period, however, did not differ by age group. The inverse relationship between disease severity and age at the time of exposure is postulated to be due to the small volume of thyroid tissue in children

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FIGURE 26-4. The number of cases of pediatric thyroid cancer in Belarus from 1986 to 1993 showing increased incidence since the April 1986 Chemobyl disaster. (Adapted from Nikiforov Y, Gnepp DR. Pediatric thyroid cancer after the Chemobyl disaster. Cancer 1994;74:748. Copyright © 1994, American Cancer Society. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

Factors That Predispose to Thyroid Neoplasia - - 245

younger than 2. The small volume of tissue would lead to a proportionately larger radiation dose at the same level of exposure. Data for the radioactive exposure by ingestion from the Marshall Islands, Nevada test sites, and Chernobyl show a clear increased risk of thyroid cancer; the important variables of age at exposure and dose of exposure contribute to the risk. This increase in incidence contrasts with the data presented previously regarding medically administered 1311, which even at high doses has minimal effect. 20•22 One difference is that, contrary to 1311, radioactive fallout has shortlived high-energy beta isotopes, which may cause more injury over a short period of time to the thyroid parenchyma than an equivalent exposure dose of only 13IJ.26 However, Baverstock pointed out that the negative data concerning medical 131 1 use and thyroid cancer come almost exclusively from an adult population of patients.P Little information is available regarding medical exposure in children, who are rarely treated or scanned with 1311. As the data from Chernobyl continue to mature, the characteristics of increased risk in both younger and older populations exposed to this high dose of fallout will become clearer. Some investigators have suggested that the increased incidence of pediatric thyroid cancer in and around Chernobyl is due to increased surveillance.F A French study of a population near a long-term nuclear power plant at Chooz showed no increased incidence in terms of proximity to this plant and the exposure from normal operations near a nuclear plant." However, the situation at Chernobyl with early, very aggressive lesions documented in exposed children is incontrovertible and argues that this acute intense exposure has significantly increased thyroid cancer incidence, which will probably continue over the next several decades.

Molecular Carcinogenesis The pathogenesis of radiation-induced thyroid cancer has not yet been elucidated. Gene rearrangements may play an important role in the process. Nikiforova and associates found that radiation-induced tumors had a 4% prevalence of BRAF point mutations and a 58% prevalence of RET/PTC rearrangements, and sporadic papillary thyroid cancers demonstrated a 37% prevalence of BRAF point mutations and only a 20% prevalence of RET/PTC rearrangements.r' Similarly, RET/PTC3 rearrangement was found in aggressive tumors that occurred less than 10 years after the Chernobyl accident. 35 Elisei and coauthors also found a prevalence of 38% of RET/PTC rearrangements in adenomas found within radiation-exposed glands, implying that this rearrangement is not restricted to the malignant phenotype but may be a step in the development of malignant transformation of radiationinduced thyroid tumors. 36

Other Factors A summary of the characteristics of radiation exposure and thyroid cancer is given in Table 26-2. Although a sizable body of data clearly defines this risk factor, most patients currently with thyroid cancer have no history of radiation exposure.'

A study from the Connecticut tumor registry showed that only 9% of thyroid cancers could be related in any way to radiation exposure. Other risk factors include dietary intake, sex hormones, other environmental exposures, lifestyle factors, and increased genetic susceptibility. The epidemiologic data on well-differentiated thyroid cancer may offer some clues to other etiologic factors. First, females are affected more frequently than males. Second, certain geographic regions have a significantly higher incidence, particularly Iceland, Switzerland, coastal Norway, and Hawaii." Unfortunately, studies of these populations in regard to dietary, hormonal, and environmental factors yielded very inconsistent results. Some studies reported opposite results, with some showing that certain factors increased the incidence of thyroid cancer, whereas other investigators showed a decrease risk from the same factors (Table 26-3). Dietary influences contributing to thyroid cancer have been extensively studied, focusing particularly on goitrogens and iodine-deficient or iodine-excessive diets. Animal models document that increased thyroid-stimulating hormone (TSH) levels result in thyroid neoplasia, and dietary factors may exert their effects by increasing TSH in one of three ways." Iodine deficiency leads to compensatory higher TSH levels; high-goitrogen diets (e.g., vegetables from the cruciferous family) may block iodine uptake and incorporation and lead to thyroid hypertrophy under the influence of TSH or to direct anterior pituitary effects that release TSH. Although theoretically these dietary influences can increase the risk of thyroid cancer, in reality the data are mixed. Both low-iodine diets and high-iodine diets have been reported to increase risk." Large intake of shellfish and other seafoods that are quite high in iodine content occurs in areas of the highest incidence of thyroid cancer such as Iceland, Norway, and Hawaii. 39,40 However, studies from northern Italy show that high intake of fish exerts a protective effect; increased risk is associated with starchy foods such as potatoes, rice, pasta, and bread." except in one study in which pasta was shown to have a protective effect." Lifestyle factors have been studied with regard to the development of thyroid neoplasms. Although consumption of alcohol can cause TSH release directly, it does not appear to be associated with increased risk." In fact, one study actually found a reduced risk among women who consumed

246 - - Thyroid Gland

at least 12 drinks per year," Cigarette smoking has also been evaluated as a potential carcinogen; however, the association between cigarette smoking and thyroid cancer has either been nonexistent or found to be protective against the development of thyroid neoplasia. 42-45 The mechanisms of this finding have not yet been elucidated. Caffeine-containing beverages have also been examined without evidence for any association with thyroid neoplasia. Finally, working in the wood-processing, pulp, and paper-making industry has been shown to be associated with an elevated risk of thyroid cancer." Hydrocarbons have been suggested to be the causative agent in this setting, but this has not been adequately studied. A second area of associated risk factors specific for females is the influence of sex hormone status. Different factors such as parity, early "artificial" menopause, oral contraceptive use, abortions, and late age at first birth have been reported to be associated with an increased risk of thyroid cancer.47,48 However, not all studies have come to the same conclusions (see Table 26-3). For example, two large studies from Norway showed different results in terms of parity.49.50 One study showed a proportional increased risk between zero and four children born, whereas a second study showed no association with parity. One consistent finding in several studies related to hormonal status is body weight. 1\\10 investigators have reported that obese patients in both younger and older age groups, and particularly females, have an increased risk for thyroid neoplasia.v-" The precise mechanism of this effect, whether dietary or hormonal, is unclear. Finally, the presence of benign nodular thyroid disease is clearly associated with thyroid cancer. I This finding may be related to a screening or selection bias or may be related to common factors that lead to both nontoxic nodular goiter and thyroid cancer. If only this subgroup of goiter patients is analyzed (nontoxic nodular), there is a reported incidence of thyroid cancer as high as 17% in one study; others report the development of thyroid cancer in 9% to 11% of this population. 52Associations between thyroid cancer and other malignancies suggest possible genetic influences. An association with familial polyposis of the colon, as well as melanoma and testicular and bladder cancers, has been reported.

Summary The only clearly documented risk factor for thyroid neoplasia is radiation exposure; a majority of patients acquiring this disease have no known risk factors. Major questions for the future include the definition of other genetic or environmental risk factors. Progress in this epidemiologic area will go hand in hand with increased understanding of the molecular biology of thyroid cancer (see Chapters 30 and 31). In patients with radiation-related thyroid cancer, investigators must determine whether the large population exposed as infants or children who are now in their sixth or seventh decade of life will continue to have a higher incidence of thyroid cancer 40 to 60 years after exposure and, if so, whether these radiation-induced thyroid cancers will have the same more aggressive natural history as non-radiation-induced cancers occurring in the elderly population of patients.

REFERENCES I. Franceschi S, Boyle P, Maisonneuve P, et al. The epidemiology of thyroid carcinoma. Crit Rev Oncog 1993;4:25. 2. Shore RE. Issues and epidemiological evidence regarding radiationinduced thyroid cancer. Radiat Res 1992;131:98. 3. Ron E, Kleinerman RA, Boice lD lr, et al. A population-based case-control study of thyroid cancer. 1 Natl Cancer Inst 1987;79:1. 4. Langsteger W, Koltringer P, Wolf G, et al. The impact of geographical, clinical, dietary and radiation-induced features in epidemiology of thyroid cancer. Eur 1 Cancer 1993;29A: 1547. 5. Duffy Bl lr, Fitzgerald Pl. Cancer of the thyroid in children: A report of 28 cases. 1 Clin Endocrinol Metab 1950;10:1296. 6. Clark DE. Association of irradiation with cancer of the thyroid in children and adolescents. lAMA 1955;159:1007. 7. Winship T, Rosvoll RY. Thyroid carcinoma in childhood: Final report on a 20 year study. Clin Proc Child Hosp 1970;26:327. 8. Schneider AB. Radiation-induced thyroid tumors. Endocrinol Metab ClinNorthAm 1990;19:495. 9. Shore RE, Woodard E, Hildreth N, et al. Thyroid tumors following thymus irradiation. 1 Natl Cancer Inst 1985;74:1177. 10. Ron E, Modan B, Preston D, et al. Thyroid neoplasia following low-dose radiation in childhood. Radiat Res 1989;120:516. 11. Schneider AB, Recant W, Pincky SM, et al. Radiation-induced thyroid carcinoma: Clinical course and results of therapy in 296 patients. Ann Intern Med 1986;105:405.

Factors That Predispose to Thyroid Neoplasia - - 247 12. Schneider AB, Ron E, Lubin J, et al. Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: Evidence for the prolonged effects of radiation on the thyroid. J Clin Endocrinol Metab 1993;77:362. 13. Perkel VS, Gail MH, Lubin J, et al. Radiation-induced thyroid neoplasms: Evidence for familial susceptibility factors. J Clin Endocrinol Metab 1988;66:1316. 14. Pottern LM, Kaplan MM, Larsen PR, et al. Thyroid nodularity after childhood irradiation for lymphoid hyperplasia: A comparison of questionnaire and clinical findings. J Clin EpidemioI1990;43:449. 15. Tucker MA, Jones PHM, Boice JD Jr, et al. Therapeutic radiation at a young age is linked to secondary thyroid cancer. Cancer Res 1991; 51 :2885. 16. Hancock SL, Cox RS, McDougall IR. Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 1991;325:599. 17. Boice JD Jr, Engholm G, Kleinerman RA, et al. Radiation dose and second cancer risk in patients treated for cancer of the cervix. Radiat Res 1988;116:3. 18. Hallquist A, Hardell L, Degerman A, et al. Medical diagnostic and therapeutic ionizing radiation and the risk for thyroid cancer: A casecontrol study. Eur J Cancer Prev 1994;3:259. 19. Dobyns BM, Sheline GE, Workman 18, et al. Malignant and benign neoplasms of the thyroid in patients treated for hyperthyroidism: A report of the cooperative thyrotoxicosis therapy follow-up study. J Clin Endocrinol Metab 1974;38:976. 20. Holm LE, Dahlqvist I. Israellson A, Lundell G. Malignant thyroid tumors after iodine-13I therapy. N Engl J Med 1980;303:188. 21. Holm LE, Hall P, Wiklund K, et al. Cancer risk after iodine-131 therapy for hyperthyroidism. J Natl Cancer Inst 1991;83: 1072. 22. Holm LE, Wiklund KE, Lundell GE, et al. Thyroid cancer after diagnostic doses of iodine-131: A retrospective cohort study. J Natl Cancer Inst 1988;80:1132. 23. Prentice RL, Kato H, Yoshimoto K, Mason M. Radiation exposure and thyroid cancer incidence among Hiroshima and Nagasaki residents. Natl Cancer Inst Monogr 1982;62:207. 24. Takeichi N, Ezaki H, Dohi K. A review of forty-five years study of Hiroshima and Nagasaki atomic bomb survivors. Thyroid cancer: Reports up to date and a review. J Radiat Res (Tokyo) 1991;32(Suppl):180. 25. Wang Z, Boice JD Jr, Wei L, et al. Thyroid nodularity and chromosome aberrations among women in areas of high background radiation in China. J Natl Cancer Inst 1990;82:478. 26. Hamilton TE, van Belle G, LoGerfo JP. Thyroid neoplasia in Marshall Islanders exposed to nuclear fallout. JAMA 1987;258:629. 27. Kerber RA, Till JE, Simon SL, et al. A cohort study of thyroid disease in relation to fallout from nuclear weapons testing. JAMA 1993;270:2076. 28. Nikiforov Y, Gnepp DR. Pediatric thyroid cancer after the Chernobyl disaster. Cancer 1994;74:748. 29. Baverstock KF. Thyroid cancer in children in Belarus after Chernobyl. World Health Stat Q 1993;46:204. 30. Mettler FA Jr, Williamson MR, Royal HD, et al. Thyroid nodules in the population living around Chernobyl. JAMA 1992;268:616. 31. Farahati J, Demidchik EP, Biko J, Reiners C. Inverse association between age at the time of radiation exposure and extent of disease in cases of radiation-induced childhood thyroid carcinoma in Belarus. Cancer 2000;88: 1470. 32. Furmanchuk AW, Roussak N, Ruchti C. Occult thyroid carcinomas in the region of Minsk, Belarus: An autopsy study of 215 patients. Histopathology 1993;23:319. 33. Rekacewicz C, de Vathair F, Delise MJ. Differentiated thyroid carcinoma incidence around the French nuclear power plant in Chooz. Lancet 1993;341:493.

34. Nikiforova, A, Ciampi R, Salvatore G, et al. Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Cancer Lett 2004;209: 1. 35. Rubino C, Cailleux F, et al. Thyroid cancer after radiation exposure. Eur J Cancer 2002;38:645. 36. Elisei R, Romei C, Vorontsova T, et al. RETIPTC rearrangements in thyroid nodules: Studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. J Clin Endocrinol Metab 2001;86:3211. 37. Franceschi S, Talamini R, Fassina A, Bidoli E. Diet and epithelial cancer of the thyroid gland. Tumori 1990;76:331. 38. Franceschi S, Levi F, Negri E, et al. Diet and thyroid cancer: A pooled analysis of four European case-control studies. Int J Cancer 1991;48:395. 39. Glattre E, Haldorsen T, Berg JP, et al. Norwegian case-control study testing the hypothesis that seafood increases the risk of thyroid cancer. Cancer Causes Control 1993;4: 11. 40. Kolonel LN, Hankin JH, Wilkens LR, et al. An epidemiologic study of thyroid cancer in Hawaii. Cancer Causes Control 1990;1:223. 41. Markaki I, Linos D, Linos A. The int1uence of dietary patterns on the development of thyroid cancer. Eur J Cancer 2003;39: 1912. 42. Rossing MA, Cushing KL, Voigt LF, et al. Risk of papillary thyroid cancer in women in relation to smoking and alcohol consumption. Epidemiology 2000; 11:49. 43. Hallquist A, Hardell L, Degerman A, Boquist L. Occupational exposures and thyroid cancer: Results of a case-control study. Eur J Cancer Prev 1993;2:345. 44. Mack WJ, Preston-Martin S, Dal Maso L, et al. A pooled analysis of case-control studies of thyroid cancer: Cigarette smoking, and consumption of alcohol, coffee and tea. Cancer Causes Control. 2003;14:787. 45. Kreiger N, Parkes R. Cigarette smoking and risk of thyroid cancer. Eur J Cancer 2000;36:1969. 46. Fincham SM, Ugnat AM, Hill GB, et al. Is occupation a risk factor for thyroid cancer? J Occup Environ Med 2000;42:318. 47. Levi F, Franceschi S, Gulie C, et al. Female thyroid cancer: The role of reproductive and hormonal factors in Switzerland. Oncology 1993;50:309. 48. Preston-Martin S, Jin F, Duda MJ, Mack WJ. A case-control study of thyroid cancer in women under age 55 in Shanghai (People's Republic of China). Cancer Causes Control 1993;4:431. 49. Kravdal 0, Glattre E, Haldorsen T. Positive correlation between parity and incidence of thyroid cancer: New evidence based on complete Norwegian birth cohorts. Int J Cancer 1991;49:831. 50. Akslen LA, Nilssen S, Kvale G. Reproductive factors and risk of thyroid cancer: A prospective study of 63,090 women from Norway. Br J Cancer 1992;65:772. 51. Goodman MT, Kolonel LN, Wilkens LR. The association of body size, reproductive factors and thyroid cancer. Br J Cancer 1992;66: 1180. 52. Cole WHo Incidence of carcinoma of the thyroid in nodular goiter. Semin Surg Oncol 1991;7:61. 53. Zivaljevic V, Vlajinac H, Marinkovic J, et al. Cigarette smoking as a risk factor for cancer of the thyroid in women. Tumori. 2004;90:273. 54. Zivaljevic V, Vlajinac H, Jankovic R, et al. Case-control study of female thyroid cancer-Menstrual, reproductive and hormonal factors. Eur J Cancer Prev 2003;12:63. 55. Memon A, Varghese A, Suresh A. Benign thyroid disease and dietary factors in thyroid cancer: A case-control study in Kuwait. Br J Cancer 2002;86: 1745. 56. Bosetti C, Kolonel L, Negri E, et al. A pooled analysis of case-control studies of thyroid cancer. VI. Fish and shellfish consumption. Cancer Causes Control 2001;12:375.

Predictors of Thyroid Tumor Aggressiveness Blake Cady, MD

The antecedents of attempts to predict thyroid cancer behavior date back to the 1930s, when the concept of "lateral aberrant thyroid'v-' was established, because thyroid tissue appearing in lymph nodes in the neck was known to be associated with an innocent clinical behavior pattern in a vast majority of cases. As a result, these cases were considered to be not cancer but an arrested embryonic migration phenomenon, until Crile convincingly demonstrated small primary papillary cancers in such cases.' That was also an era when 15% to 20% of all thyroid cancers were of an anaplastic variety that was almost uniformly and rapidly fatal"; median survival associated with anaplastic cancers was only 3 or 4 months, and all but a few patients were dead within 6 months. This wide range of clinical behavior from cancers arising from the same thyroid follicular cell was noteworthy, even then, in displaying the extremes of tumor biologic behavior. Currently, of course, we have several well worked-out and easily clinically applicable indicators of risk group assignment to predict accurately the biologic behavior of cancers of the thyroid gland.>!" Arriving at these unique, clinically discernible risk estimations is a simple process in thyroid cancer, whereas clinical predictors of outcome are much less accurate and effective in other human cancers, particularly in defining a preponderance of patients at very low risk. It is important for surgeons to recognize the striking differences in behavior of thyroid cancers originating from an identical cell so that appropriate surgical techniques can be applied to patients to minimize morbidity and to restore and maintain normal life in the vast majority of patients currently being treated for differentiated thyroid carcinoma.

Epidemiology A number of epidemiologic features in thyroid carcinoma may have implications regarding thyroid cancer behavior. Beginning in the 1950s, it became well established that there was an increased incidence of differentiated thyroid carcinoma in patients who had received therapeutic radiation as infants and children. IS Such therapeutic radiation in the

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1930s and the 1940s was frequently given for thymic, adenoid, and tonsillar enlargement, facial acne, and even tinea capitis. As many as 30% to 40% of such patients later operated on for thyroid nodules were discovered to have differentiated thyroid carcinoma, usually papillary and often only microscopic." When this etiologic association became apparent, such low-dose radiation therapy disappeared from clinical practice, and as a result few patients today are seen with a history of radiation treatment. Thyroid gland abnormalities in survivors of the nuclear bomb explosions in Japan and the Pacific atolls are well described. I? These nodules were both benign and malignant, but in almost half of the cases of cancer, the lesion was a microscopic or small focus in thyroid tissue adjacent to a benign nodule. In the geographic area downwind of the Chernobyl nuclear accident, an appreciable number of children exposed to radioactive fallout have acquired thyroid carcinoma. 18 It is now evident that these cases represent a real increase in thyroid cancer (Fig. 27-1). A peculiar aspect of the Chernobyl reports has been the very short latency period of only a few years to the appearance of these cancers'? and iodine deficiency.20.21 The median time to appearance of thyroid carcinoma associated with childhood radiation therapy in previous reports has been about 20 years, and it appears to increase for at least 3 decades after exposure. No cases of thyroid carcinoma have been reported from the Three Mile Island nuclear accident in Pennsylvania. Although there are vast differences in background cosmic radiation between sea level and mountain communities and between house construction of brick or stone compared with wood frame, there have never been adequate data indicating that increased background cosmic radiation has been associated with an increased incidence of human thyroid carcinoma. Although widespread childhood radiation is no longer an issue in the United States, childhood Hodgkin's disease is frequently treated with a mantle radiation port that includes the thyroid gland; these patients have an increased risk for the development of differentiated thyroid cancer." Radiation-associated thyroid cancers appear to exhibit biologic behavior similar to that found in patients with thyroid cancer who have not received radiation.

Predictors of Thyroid Tumor Aggressiveness - - 249

radiation-induced thyroid cancer, has received much attention28-33 and continues to elicit genetic analysis and definitions.

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Year FIGURE 27-1. Sharp increase. Childhood thyroid cancer is rising in three republics most affected by Chemobyl. (Redrawn with permission from Balter M. Chemobyl's thyroid cancer toll. Science 1995;270:1758. Copyright 1995, American Association for the Advancement of Science.)

The basic iodine content in the diet has been linked to varying patterns and incidences of thyroid carcinoma. 20 ,23-25 In regions with low dietary iodine, there is an increased proportion of follicular carcinoma and a high incidence of anaplastic carcinoma compared with areas with adequate dietary iodine, where papillary carcinoma predominates and anaplastic carcinoma is uncommon. There seem to be other subtle differences in the pattern of both differentiated and undifferentiated thyroid carcinoma in iodine-rich areas compared with iodine-poor areas. Historically, because of the presence of large "goiter belts" in the United States, an experiment was carried out in Akron, Ohio, in the 1920s in which schoolgirls were given iodine supplements, which produced a marked reduction in endemic goiter incidence. By the mid-1930s, the United States had established routine iodinization of household salt to control endemic goiter. As a result, 70 years later we have had two generations of our population growing up with adequate iodine in their diet. During this time there has been an increasing preponderance of papillary carcinoma of the thyroid in the United States and the virtual disappearance of anaplastic carcinoma.v? Conversion of long-standing or recurrent papillary carcinoma to anaplastic cancer of the thyroid with resultant death was a well-recognized phenomenon in the 1930s and 1940s but is now uncommon in patients born and raised in this country with adequate dietary iodine. This phenomenon of ensuring adequate dietary iodine represents a major public health accomplishment in preventing goiter and is undoubtedly a major cause of the changes in presentation of thyroid carcinoma since 1930. Many immigrants to the United States come from iodine-poor regions, however, and may display a pattern of disease that mimics the American experience of the 1930s. Other subtle environmental factors in the epidemiology of differentiated thyroid carcinoma may exist and have effects on outcome but have not been defined adequately to be recognized as a problem.P-" The role of genetic abnormalities in thyroid cancer, particularly

Pathology Understanding the pathology of thyroid carcinoma is critical to appreciating the biologic behavior of the various neoplasms arising from the thyroid follicle cell and allowing predictions of aggressiveness. Papillary and follicular thyroid carcinomas are the most common thyroid cancers worldwide. Differentiated thyroid carcinomas that have both papillary and follicular thyroid elements are classified as papillary carcinomas because they have the same biologic behavior as that of papillary carcinoma.v' In our series," whether the carcinomas were pure papillary or mixed papillary and follicular with varying proportions of follicular components, including follicular predominant forms, the clinical behavior was identical. In contradistinction, follicular carcinoma should describe thyroid cancers of a pure follicular pattern. Follicular carcinoma of poor differentiation has a poor prognosis but must be separated from anaplastic carcinomas consisting of giant and spindle cells. Undifferentiated thyroid carcinoma is a uniquely aggressive form of carcinoma consisting of spindle and giant cell anaplastic lesions, as well as some cases of small cell carcinomas.' Although the diagnosis of small cell undifferentiated carcinoma was used frequently in the 1930s, 1940s, and 1950 in contemporary studies using histochemical staining, many of these were either medullary carcinomas (first described in 1957) or lymphomas of the thyroid. Thus, the proportion of undifferentiated thyroid cancers that are of the small cell variety is quite small. Lymphoma of the thyroid is a recognized presentation of extranodal non-Hodgkin's lymphoma.P-" Patients with such lesions should have extensive diagnostic evaluation to rule out disseminated lymphoma with thyroid involvement. Thyroid lymphomas arise more often in patients with Hashimoto's thyroiditis and lymphoid hyperplasia. Histologic differentiation between these entities may be difficult, may cause diagnostic confusion, and may require sophisticated histochemical staining and electromicroscopy for accurate diagnosis. Patients with thyroid lymphoma can be treated for cure using surgical resection, if possible, but primarily through chemotherapy and radiation therapy." Rare types of thyroid carcinoma, such as sarcoma and squamous cell carcinoma, also occur. Melanoma and cancers of the lung, breast, and kidney are the tumors that most often metastasize to the thyroid gland. At present, in the United States, differentiated thyroid cancers make up about 95% of cases of thyroid malignancy, of which at least 80% are papillary; anaplastic carcinoma makes up less than 2%, and thyroid lymphoma makes up about 1%. Medullary carcinoma of the thyroid arises from parafollicular C cells, rather than thyroid follicle cells, and makes up less than 4% of all thyroid cancers.v'? Many reports in the literature indicate higher proportions of medullary carcinoma in a particular institution, but this represents the phenomenon of selection by diagnosis of familial clusters in the inherited form of the disease. Overall, medullary carcinoma represents less than 4% of all thyroid gland carcinomas.

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Thyroid Gland

Differentiated Thyroid Carcinoma Follicular Carcinoma Pure follicular carcinoma appears to be decreasing in frequency and now makes up about 10% of differentiated thyroid cancers. This proportion may be different in geographic areas with insufficient dietary iodine or with different pathologic definitions.P'" Follicular cancers are diagnosed by the invasion of the follicular cells into or through the veins or tumor pseudocapsule or into metastatic sites. Minor tumor pseudocapsular involvement or only minor vessel involvement within the tumor itself may define follicular carcinoma, but such technically defined follicular adenocarcinomas have little, if any, risk of recurrence, metastases, or death from disease, regardless of age or risk group. Such a follicular cancer with minor capsular involvement may be found in retrospect in a patient presenting with distant metastases, but this is rare. Extensive data from the Mayo Clinic" and Lahey Clinic 9,34 confirm the essential absence of risk of recurrence or death in such patients. In the 1930s and 1940s, the phenomenon of "benign metastasizing follicular adenoma" was described but represented inadequate sampling of the primary thyroid tumor pseudocapsule to discern completely the extent of capsular involvement in such metastatic cancers. However, major tumor pseudocapsular involvement represents a far more aggressive type of follicular thyroid cancer.34 Thus, gross breaching of the thyroid tumor pseudocapsule, particularly with extension outside the thyroid gland itself into surrounding structures (strap muscle, esophagus, soft tissues, laryngeal or tracheal wall), clearly represents a type of follicular adenocarcinoma with a worse prognosis. Such pathologic extension through the tumor pseudocapsule is a phenomenon that is somewhat linked with size, so that large follicular adenocarcinomas frequently have extension outside the thyroid gland and into surrounding structures, and minor tumor pseudocapsular involvement usually occurs in smaller lesions that are intraglandular. However, on occasion, even small follicular adenocarcinomas demonstrate gross involvement of the thyroid gland capsule and invasion of surrounding tissues. Such follicular adenocarcinomas, with major tumor pseudocapsular involvement and extraglandular extension, have a poor prognosis regardless of size. This poor prognostic implication of extensive tumor pseudocapsular involvement by follicular carcinoma applies across all age ranges, including a few patients who otherwise might be considered at low risk, but in older patients is particularly ominous. Thus, the mortality rate in the few younger patients is about 25%, but in older patients, who are more frequently affected, it may be as high as 75%. Overall, patients with follicular carcinoma have the same prognosis as patients with papillary carcinoma. 9,34042 We do not separate Htirthle cell cancer from other follicular cancers." Whether patients with Hiirthle cell cancer have a unique risk of recurrence or death is debatable."

Papillary Carcinoma Mention was previously made of the concept of lateral aberrant thyroid, which represented a phenomenon with such an

innocent long-term outlook that for many years it was considered an embryonic abnormality rather than a cancer.' This history represents one aspect of the difficulty of prognostication in thyroid cancer. It is important to realize that occult papillary cancers are extremely common in autopsy studies and in apparently normal thyroid tissue and have no impact or risk of clinical cancer or death from cancer. These occult lesions are seen in between 6% and 18% of American patients and are even more common in other countries.r' Now, of course, with rare exceptions, we recognize the presence of even benign-appearing thyroid tissue in lymph nodes of the neck as metastatic disease, frequently with an occult primary in the thyroid gland. More than 75% of young patients with papillary thyroid cancer have lymph node metastases when node dissections are performed. Twenty-five percent of young patients present because of a palpable lymph node in the neck rather than because of a tumor in the thyroid gland. 34045 Although the initial presentation with a palpable lymph node metastasis in all other head and neck carcinomas represents a poor prognosis and the presence of lymph node metastases in all other human cancers indicates a worse prognosis than cases that have negative nodes, the implication of nodal metastases is uniquely different in young patients with low-risk papillary carcinoma of the thyroid. Indeed, with some exceptions,704M7 reports of multifactorial analysis of differentiated thyroid carcinoma prognosis and risk groups fail to find lymph node metastases as a significant factor, and none of the risk group scoring systems include lymph node metastases. Many surgeons, endocrinologists, and physicians, however, still have difficulty in accepting such a uniquely different implication of nodal metastases.v"

Risk Groups in Differentiated Thyroid Cancer The phenomenon of a relationship between age and outcome in differentiated thyroid carcinoma dates back to reports from the 1940s and earlier," Clinically, it became obvious that the outcome of patients younger than 45 years was distinctly different from that of patients in older age groups. It is now apparent that there is a strong relationship between increasing age and worsening prognosis with age greater than 40, 45, or 50 years, variously defined in different reports.lv" Thus, in our reports,"!' all patients older than 70 years had an extremely high risk of recurrence and death (67%) from disease regardless of the individual features of the cancer, such as size, extent of disease, pathologic type, and extent of surgery. In all the multifactorial risk group designations published over the past 20 years, age has been one of the major prognosticating features, if not the major one. When other primary tumor features, such as extent of disease, size, grade, completeness of surgery, and flow cytometry," are included with age, uniquely effective separations of the benign-behaving preponderance of low-risk cases from higher risk groups, which represent a minority of cases, can be established. Early attempts at such prognostication by clinical phenomena were represented by the International Union Against Cancer tumor, nodes, and metastases (TNM) staging system" and the European Oncology Research for the Treatment of Cancer staging system published in the 1970s. 7

Predictors of Thyroid Tumor Aggressiveness - -

In the late 1970s and early 1980s, two other systems of clinical assessment of risk were published-AGES (age, grade, extent, and size) by the Mayo Clinic 8 and AMES (age, metastases, extent, and size) by the Lahey Clinicf--; that illustrated uniquely simple and effective postoperative prognostic scoring systems. The latter two systems demonstrated that the basic risk group assessment superseded the prognostic effect of type of surgery, use of radioactive iodine, use of external radiation therapy, presentation of primary disease, presentation of recurrent or metastatic disease, and perhaps even use of thyroid-stimulating hormone (TSH) suppression by thyroid hormone administration. The addition of flow cytometry to the AMES category (DAMES) I I was proposed as yet another sophisticated prognostication in individual cases but was not routinely clinically applicable at the time of surgery because of the need for a postoperative tumor analysis by flow cytometry. A major report by Shah and colleagues'? at Memorial Hospital in New York again confirmed all the basic features of the previously published multifactorial risk groups (age, metastases, extent, size). Finally, a Mayo Clinic study published by Hay and coauthors 14 has incorporated completeness of surgical removal of the primary thyroid cancer in the most recent iteration of their multifactorial analysis: MACIS (metastases, age, completeness of surgery, invasion of cancer, and size). Of all their MACIS patients with papillary cancer, 84% fall into a low-risk group, which has only a 3% 10-year recurrence rate and a 1% 20-year death rate. Such a low death rate is identical to that for an age-adjusted similar population without thyroid carcinoma. Three further levels of risk group assignment in this MACIS system have progressively worse prognoses, culminating in the highest scoring patients, who have a 75% risk of cause-specific mortality. The MACIS system is the only one that includes surgical resection, but it is important to understand that the operative features relate only to completeness of cancer removal and do not in any way demonstrate a difference in survival when total thyroidectomy and lesser procedures are compared. The outcome after incomplete surgical resection is heavily dependent on age. We have noted that only 11% of young or low-risk patients who had incomplete removal of the primary cancer died of disease when monitored for a minimum of 15 years, whereas high-risk or older patients had a risk of death of greater than 90% if the cancer was not grossly completely resected." Thus, even the results after incomplete surgical removal are heavily dependent on basic biologic phenomena, principally age and basic risk group.

Surgical Therapy of the Primary Cancer and Lymph Node Metastases Most multifactorial studies.>!" as well as many other reports,50-61 document that the extent of thyroid gland resection, the extent of lymph node resection, and the number of lymph node metastases involved had no bearing on patients' survival. There may be a higher risk of local recurrence in patients treated by thyroid lobectomy," but a recurrence in the remnant thyroid tissue never caused a death in the Mayo Clinic report. 57 No other human cancer represents such a lack of relationship between survival and lymph node metastases

251

or the presence of residual cancer at the conclusion of the surgical procedure as in young, low-risk patients with thyroid carcinoma. Indeed, even distant metastatic disease in differentiated carcinoma is not uniformly fatal in children or young adults 49,61 and can be treated for cure in a high proportion (>50%) of low-risk patients with radioactive iodine therapy.62-64 To have effective treatment in these patients, the remnant thyroid tissue must be removed or ablated. It should be noted that, regarding outcome and prognosis, medullary carcinoma of the parafollicular C cells does not display this unique lack of relationship between lymph node metastases and outcome. Medullary carcinoma of the thyroid does display some age association with prognosis but has the usual relationship between increasing lymph node involvement and poorer long-term survival." Thus, even cancers arising from different cells within the same gland display uniquely different biologic phenomena. This merely reemphasizes the fact that lymph node metastases in almost all human cancers are "indicators but not governors'P" of poor outcome. In patients with differentiated thyroid carcinoma, the indicator function is less precise, and the prognosis either is not affected by or, in one report, is even better in cases with lymph node metastases." Lymph node metastases are extremely common in papillary cancer, and two thirds of recurrences in the low-risk cancer are lymph node metastases." None of these presentations of lymph node metastases (occult, palpable, multiple, or recurrent) have deleterious effects on the prognosis of low-risk patients with differentiated thyroid carcinoma. In high-risk thyroid cancer patients, however, there may well be an association between lymph node metastases and a worse prognosis.f the usual relationship, again displaying the unique features of lowrisk patients.

Radioactive Iodine Clearly, in the presence of unresectable local disease, recurrent local disease, and distant metastases to the lungs, bones, or other sites, the potential curability of patients is almost totally dependent on the success of radioactive iodine (RAI) therapy.67.68 Not all differentiated carcinomas of the thyroid take up RAI, but when they do, the nuclear dose of radiation therapy is extraordinarily high (20,000 to 30,000 cGy) and, therefore, highly successful in ablating metastatic deposits. When tumors cannot be induced to take up RAI, however, therapeutic effectiveness is absent. In younger patients (low risk) and in children with distant metastases, metastases frequently take up RAI in therapeutically significant amounts,63.64 and long-term disease-free life can be achieved. This represents the unique phenomenon of a "homing" compound (iodine) carrying a lethal cellular poison (radiation-emitting isotope) that can seek out and destroy cancer cells throughout the body, even in disseminated metastases. Such an idealized cancer treatment remains the model and the elusive goal of cancer therapy and, to date, has seldom been duplicated in any other human cancer on a regular basis. Because the avidity of the normal thyroid gland for iodine and its radioactive isotopes is many magnitudes higher than that of even the most efficient iodine metabolism

252 - - Thyroid Gland of differentiated thyroid cancer, all normal thyroid tissue has to be eliminated to attempt therapeutic utilization of RAI. In patients with metastases or unresectable local disease, the need for total thyroidectomy, either surgical or radiotherapeutic, is unquestioned. After total thyroidectomy, with avoidance of removal or devascularization of the parathyroid glands, diagnostic RAI scans are used to detect residual normal thyroid tissue, which can be eliminated with small therapeutic doses of RAI (-30 mCi). After ablation of normal remnant thyroid tissue, iodine 131 can be used in hypothyroid patients with high serum TSH levels to ablate metastatic deposits. The curability of patients with metastatic thyroid carcinoma is related to their basic risk group,49.63.64 but all patients with distant metastases should receive treatment with RAI. In low-risk or young patients, the curability of pulmonary metastases is extremely high after appropriate RAI use, but in older or high-risk patients successful and effective treatment of distant metastases by RAI seldom results in a long-term disease-free state because other metastases develop or the original metastases regrow. Despite the acknowledged value of RAI for treatment in advanced, high-risk, recurrent, or metastatic cases of differentiated thyroid carcinoma, there is little evidence that routine adjuvant use of RAI in low-risk patients is of any benefit. 67.68 Hay and colleagues'" have questioned the routine adjuvant use of RAI in low-risk patients and found no evidence of improved cause-specific survival with RAI.

Changing Presentation of Thyroid Cancer The clinical presentation of thyroid carcinoma has changed dramatically over the years. The median size of all differentiated thyroid carcinomas has declined progressively, so that by 1980 and continuing currently only 10% of older and 6% of younger patients presented with lesions larger than 3 em in diameter, and almost 66% of the younger patients and 60% of the older patients presented with primary cancers smaller than 2 em in diameter." Clearly, such earlier disease presentation has improved the overall prognosis. Several authors have reported a better overall prognosis beginning about 195034 or 1960 5 1.62 for reasons that may be related to earlier diagnosis and, therefore, better risk group definition but are primarily related to the declining incidence of conversion of papillary to anaplastic carcinoma and the presence of less aggressive cancers that occur in populations with adequate dietary iodine. Thus, patients seen in the 1990s had a far better prognosis overall but, when separately defined by a multifactorial risk group, were seen to have a clinical behavior similar to that in previous decades." The better overall prognosis, then, is related to a higher proportion of cancers that can be completely resected, the smaller cancers diagnosed, the decreased frequency of extension outside the thyroid gland, and a lower proportion of patients presenting initially with distant metastases. In the 1930s, as many as 6% of patients initially presented with distant metastases, usually pulmonary, but the proportion is currently less than 1%. A multifactorial risk group assessment is also applicable to patients with large or advanced cancers from third-world countries (R. S. Rao, personal communication, 1994). Lowrisk patients by the AMES multifactorial classification still have an excellent prognosis.

Children Although frequently presenting with relatively advanced local, nodal, or metastatic disease, young children and teenagers have an extremely good prognosis.sl'" In some reports, more children die of pulmonary fibrosis secondary to RAJ treatment of the pulmonary metastases than die of thyroid carcinoma. Children younger than 7 years may have a poorer prognosis. Pulmonary metastases in children usually take up RAI, and these children can usually be cured with appropriate treatment.

Recurrence The term recurrent thyroid carcinoma is expected to imply some decrement in outcome and prognosis. However, if the "recurrence" is actually a new primary tumor in residual contralateral thyroid tissue.? the prognosis is no different from that for a primary carcinoma in any other presentation and risk group assignment. True recurrent carcinoma in the bed of the previously resected thyroid gland may be a difficult pattern of disease to treat; most such true local recurrences are not readily surgically resectable, but resection should be attempted. If RAI in therapeutic doses was not used initially, its potential use should be investigated by diagnostic scans and elimination of all residual normal thyroid. Reoperation for the completion of a total thyroidectomy at this time in the few patients who display such local tumor bed recurrence should be performed or the residual thyroid gland ablated by RAI. Occasionally, persistent disease in the wall of a trachea or larynx, with progressive growth, may cause airway encroachment and require surgical therapy."? Resection of a small segment of trachea is sometimes required and can be accomplished successfully. On rare occasions, laryngectomy for recurrent disease with airway obstruction may be required. Such extensive surgery should rarely be performed initially because of the excellent therapeutic outcome achieved with RAI, which can result in a good disease-free, long-term survival in low-risk or young patients." Thus, although recurrence is a poor prognostic sign in high-risk patients, it is not invariably an indication of fatal outcome, and indeed low-risk patients may do quite well." In our study, 80% of low-risk patients with recurrent disease survived, whereas 80% of older high-risk patients died. This is a further example of the risk group assuming more importance than the particular presentation of disease, type of recurrence, or type of therapy. Shaha has given a contemporary summary of risk group relationship to outcome."

Metastases Distant metastatic disease usually appears after treatment of a patient with an advanced primary cancer; it is rarely the presenting complaint of patients with a small or an obscure primary thyroid carcinoma, particularly older or high-risk patients. Low-risk patients with pulmonary metastases have better than 50% long-term disease-free survival after treatment with 131 1 and TSH suppression.49.63.64.72.73 As mentioned earlier, pulmonary metastases are far less common todayy·34.49 Whether earlier detection and treatment in a preclinical

Predictors of Thyroid TumorAggressiveness - - 253 stage by diagnostic scanning (which requires total thyroid ablation) and treatment when detected later by chest radiography are equivalent in outcome after RAI therapy is a matter of some debate." Patients with distant metastases other than to the lung tend to have a very poor outcome over the long term, although aggressive resection of isolated bone metastases with postresection RAI therapy is sometimes effective. Long-term outcome in these patients is also influenced by age and basic risk group.49,63.64,72,73 High-risk patients may have prolonged disease courses, but eventually almost all older patients with distant metastases die of disease.

Clinical Application of Indicators of Thyroid Tumor Aggressiveness The ready application of a variety of risk group definitions (AMES, AGES, MACIS) indicates that all patients should be so characterized before initial surgery and again at completion of surgery. Age and tumor size can be determined preoperatively, whereas local invasion, distant metastases, resectability, and tumor histology or grade are usually determined postoperatively. By characterizing the risk group, the surgeon can make an initial preoperative estimate of the need for and extent of thyroid and regional lymph node resection and, postoperatively, the need for RAI treatment. When the risk of recurrence is only 3% and the risk of death only I % in the low-risk MACIS, AMES, or AGES risk definition categories, it is impossible to prove the advantage of total thyroidectomy with RAI in contrast to a more limited or unilateral operation. Although no randomized trial has been conducted because of the infrequency of thyroid carcinoma even in young patients, studies addressing the issue of extent of surgical resection in low-risk patients find no consistent evidence of improved prognosis in patients undergoing total thyroid removal.P''" The critical need in patients who are young and have little or no risk of death is to have an operation that avoids, as much as possible, the chances of morbidity.57.75,76 In low-risk patients, the use of RAI scanning in surgical follow-up appears to be unnecessary because it contributes nothing to improvement in the near-perfect outcome. 66,68 Indeed, even the value of thyroid hormone administration in such patients is now questioned,68,77 except, of course, in patients who initially undergo total or near-total thyroidectomy. Because all studies of long-term medication indicate poor compliance by patients after many years, one needs either to monitor such patients closely throughout the rest of their lives by repeated TSH testing to prevent subtle hypothyroidism or iatrogenic hyperthyroidism or to leave enough thyroid tissue so that the patient is euthyroid in the absence of thyroid hormone administration. In older or high-risk patients and in low-risk patients with extensive or bilateral disease, strong consideration should be given to performing a total thyroidectomy initially because postoperative RAI therapy almost certainly should be attempted and TSH suppression therapy used. Total thyroidectomy in these situations is used primarily to facilitate the use of RAI.

Because lymph node metastases do not appear to influence patients' outcomes adversely and their cells do not implant in surgical wounds, it seems illogical to focus too greatly on maximizing the extent of lymph node resections, and selected nodal removal is adequate. Good functional and cosmetic results should be the principal goals. Reports from Sweden documenting prolonged microscopic surgical dissection of extensive regional lymph node areas in patients with medullary thyroid cancers seem illogical. No biologic rationale for such an endeavor in differentiated thyroid carcinoma exists, and the results of such reports should be critically evaluated. A convenient clinical approach to regional lymph node metastases in low-risk patients indicates that, for preoperatively palpable lymph node metastases in the neck, a function-preserving modified neck dissection is adequate. Such a functional neck dissection would include, at the very least, preservation of the spinal accessory nerve and the submandibular area with the ramus mandibularis. In addition, preservation of the sternocleidomastoid muscle and jugular vein should be attempted because limited selective dissection of the lymph nodes themselves is adequate, The phenomenon of wound implantation with differentiated thyroid carcinoma is rare. If lymph node metastases are not felt preoperatively but are observed or are palpable at the time of thyroid surgery, these nodes and the central compartment containing fat and nodes should be removed without extending the thyroid incision. Limited lateral neck dissection should be done to include palpable node metastases. Such central compartment or restricted node removal can be accomplished with minimal to no morbidity. As a corollary to the generally good prognosis and lack of relationship of lymph nodes to outcome, it should be noted that any functioning recurrent laryngeal nerve should be preserved at all costs, even if it has to be carefully dissected out from surrounding conglomerate lymph node metastases. Finally, if no obvious lymph node metastases are noted either before or at surgery, no formal lymph node removal needs to be performed. It is worth commenting on the fact that any young person presenting with a palpable lymph node in the neck should have as the first diagnostic maneuver a needle aspiration, not an excision, of the lymph node that is palpable. Well-trained cytopathologists can uniformly make the diagnosis of thyroid carcinoma using needle aspiration cytology of lymph node metastases. If the diagnosis is made by aspiration, even though the primary thyroid cancer is not palpable, operative strategy and treatment can be planned effectively with avoidance of a separate node biopsy. When an appropriate neck dissection has been performed, recurrence of cervical node metastases is very uncommon. Overall, most recurrences (two thirds) in low-risk patients are in the form of palpable lymph node metastases in the absence of previous neck dissection. Because lymph node metastases have little bearing on prognosis, the surgical or therapeutic RAI treatment of node metastases is associated with an excellent outcome, in keeping with the basic risk group definition. Although either surgical approaches or RAI may be suitable, there are advantages in performing a cosmetically acceptable and function-preserving neck dissection because (1) not all of these tumors take up RAI,

254 - - Thyroid Gland (2) treatment with RAI is prolonged and complicated and may require hospitalization and a previous total thyroidectomy, and (3) the results are not as good as with surgical removal. The use of serum thyroglobulin determination as a tumor marker has been encouraged as a component of the postoperative management of thyroid carcinoma. It seems illogical to perform expensive technologic tests for careful follow-up in the low-risk patients because the 20-year mortality is only I % and total thyroid ablation is required for the utilization of thyroglobulin determinations. Repeated RAI diagnostic scans require a hypothyroid state each time and should be avoided in low-risk patients, in whom such repeated periods of hypothyroidism are disabling. Thus, a simplified followup approach would avoid any kind of intensive technical follow-up in the 85% to 90% of patients at low risk, as judged by the MACIS or AMES scoring systems. In highrisk patients in whom more extensive surgery was used, the use of thyroglobulin determination and RAI scanning postoperatively appears to be justified in an attempt to increase long-term disease-free survival, but almost all distant metastases eventually prove fatal. Finally, several attempts78-80 to define differentiated thyroid cancer aggressiveness further are too recent to evaluate their feasibility for clinical use, particularly when such efficient practical clinical risk groups exist.

Summary Most patients with papillary and follicular thyroid cancer can be classified into low-risk groups by the AGES, AMES, TNM, or MACIS classifications. These low-risk patients have an excellent prognosis, so that total thyroidectomy is not required for patients with cancers confined to one lobe. Lymph node metastases should be removed by a functional neck dissection preserving the spinal accessory nerve, the internal jugular vein, and the sternocleidomastoid muscle. High-risk patients may benefit from total or near-total thyroidectomy as well as postoperative use of RAI adjuvant treatment, serum thyroglobulin determination, and TSH suppression therapy.

REFERENCES 1. SchragerVL. Lateral aberrant thyroids. Am J Surg 1966;163:665. 2. Dunhill TP. Carcinoma of the thyroid gland. Br J Surg 1931;19:83. 3. Crile G Jr. Papillary carcinoma of the thyroid and lateral cervical legion: So-called "lateral aberrant thyroid." Surg Gynecol Obstet 1947;85:757. 4. Rossi R, Cady B, Meissner WA, et al. Prognosis of undifferentiated carcinoma and lymphoma ofthe thyroid. Am J Surg 1978;135:589. 5. Hermanek P, Sobin LH. TNM classification of malignant tumors. In: UICC, International Union Against Cancer. Manual of Clinical Oncology, 4th ed. Berlin, Springer-Verlag, 1987, p 79. 6. Kukkonen ST, Haapiainen RK, Franssila KO, et al. Papillary thyroid carcinoma: The new, age-related TNM classification system in a retrospective analysis of 199 patients. World J Surg 1990;14:837. 7. Byar D, Green S, Dor P, et al. A prognostic index for thyroid carcinoma: A study of the EORTC Thyroid Cancer Cooperative Group. Eur J Cancer 1979;15:1033. 8. Hay 10, Grant CS, Taylor WF, et al. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: A retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 1987;102: 1088.

9. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988;104:947. 10. Cady B. Hayes Martin Lecture. Our AMES is true: How an old concept still hits the mark: Or, risk group assignment points the arrow to rational therapy selection in differentiated thyroid cancer. Am J Surg 1997;174:462. II. Sanders LE, Cady B. Differentiated thyroid cancer: Reexamination of risk groups and outcome of treatment. Arch Surg 1998;133:419. 12. Shah JP, Loree TR, Dharker D, et al. Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg 1992;164:658. 13. Pasieka JL, Zedenius J, Auer G, et al. Addition of nuclear DNA content to the AMES risk-group classification for papillary thyroid cancer. Surgery 1992;112:154. 14. Hay 10, Bergstralh EJ, Goellner JR, et al. Predicting outcome in papillary thyroid carcinoma: Development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993;114:1050. 15. Foster RS. Thyroid irradiation and carcinogenesis: Review with assessment of clinical implications. Am J Surg 1975;130:608. 16. Cerletty JM, Guansing AR, Engbring NH, et al. Radiation related thyroid carcinoma. Arch Surg 1978;113:1072. 17. Nagataki S, Shibata Y, luoue S, et al. Thyroid diseases among atomic bomb survivors in Nagasaki. JAMA 1994;272:364. 18. Rahu M. Health Effects of the Chernobyl accident: Fears, rumours and the truth. Eur J Cancer 2003;39:295. 19. Lohrer HD, Braselmann H, Richter HE, et al. Instability of microsatellites in radiation-associated thyroid tumours with short latency periods. Int J Radiat BioI 2001;77:891. 20. Jackson RJ, DeLozier DM, Gerasimov G, et al. Chernobyl and iodine deficiency in the Russian Federation: An environmental disaster leading to a public health opportunity. J Public Health Policy 2002;23:453. 21. Williams D. Cancer after nuclear fallout: Lessons from the Chernobyl accident. Nat Rev Cancer 2002;2:543. 22. McHenry C, Jarosz H, Calandra D, et al. Thyroid neoplasia following radiation therapy for Hodgkin's lymphoma. Arch Surg 1987;122:684. 23. Williams ED, Doniach I, Bjarnason 0, et al. Thyroid cancer in iodide rich area: A histopathologic study. Cancer 1977;39:215. 24. Belfiore A, LaRosa GL, Padova G, et al. The frequency of cold thyroid nodules and thyroid malignancies in patients from an iodine-deficient area. Cancer 1987;60:3096. 25. Harach HR, Escalante DA, Day ES. Thyroid cancer and thyroiditis in Salta, Argentina: A 40-yr study in relation to iodine prophylaxis. Endocr PathoI2002;13:175. 26. Goodman MT, Yoshizawa CN, Kolonel LN. Descriptive epidemiology of thyroid cancer in Hawaii. Cancer 1988;61: 1272. 27. Ozaki 0, Ito K, Kobayashi K, et al. Familial occurrence of differentiated, nonmedullary thyroid carcinoma. World J Surg 1988;12:565. 28. Cady B. Presidential address: Beyond risk groups-A new look at differentiated thyroid cancer. Surgery 1998;124:947. 29. Ito M, Nakashima M, Nakayama T, et al. Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in pediatric thyroid carcinomas around Chernobyl. Thyroid 2002; 12:971. 30. Burgess JR, Skabo S, McArdle K, Tucker P. Temporal trends and clinical correlates for the retJPTCI mutation in papillary thyroid carcinoma. Aust N Z J Surg 2003;73:31. 31. Nikiforova MN, Ciampi R, Salvatore G, et al. Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Cancer Lett 2004;209: I. 32. Soares P, Trovisco V, Rocha AS, et al. BRAF mutations and RETIPTC rearrangements are alternative events in the etiopathogenesis of PTe. Oncogene 2003;22:4578. 33. DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds). Pathology and Genetics: Tumors of Endocrine Organs. World Health Organization Classification of Tumors. Lyon, France, International Agency for Research on Cancer (IARC Press), 2004. 34. Cady B, Sedgwick CE, Meissner WA, et al. Changing clinical, pathologic, therapeutic, and survival patterns in differentiated thyroid carcinoma. Ann Surg 1976;184:541. 35. Pasieka JL. Hashimoto's disease and thyroid lymphoma: Role of the surgeon. World J Surg 2000;24:966. 36. DiBiase SJ, Grigsby PW, Guo C, et al. Outcome analysis for stage IE and lIE thyroid lymphoma. Am J Clin OncoI2004;27:178. 37. Rossi RL, Cady B. Nonfamilial medullary thyroid carcinoma. Am J Surg 1980;138:554.

Predictors of Thyroid Tumor Aggressiveness - - 255 38. Hundahl SA, Cady B, Cunningham MP, et al. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study. Cancer 2000;89:202. 39. Samaan NA, Schultz PN, Hickey RC. Medullary thyroid carcinoma: Prognosis of familial versus sporadic disease and the role of radiotherapy. J Clin Endocrinol Metab 1988;67:801. 40. Holzer S, Reiners C, Mann K, et al. Patterns of care for patients with primary differentiated carcinoma of the thyroid gland treated in Germany during 1996. U.S. and German Thyroid Cancer Group. Cancer 2000;89: 192. 41. LiVolsi VA, Asa SL. The demise offollicular carcinoma of the thyroid gland. Thyroid 1994;4:233. 42. Donohue JH, Goldfien SO, Miller TR, et al. Do the prognoses of papillary and follicular thyroid carcinomas differ? Am J Surg 1984;148:167. 43. Ryan 11, Hay H), Grant CS, et al. Flow cytometric DNA measurements in benign and malignant Hiirthle cell tumors of the thyroid. World J Surg 1988; 12:482. 44. Harach HR, Franssila KO, Wasenius VM. Occult papillary carcinoma of the thyroid. A "normal" finding in Finland. A systematic autopsy study. Cancer 1985;56:531. 45. Attie IN, Setzin M, Klein L. Thyroid carcinoma presenting as an enlarged cervical lymph node. Am J Surg 1993;166:428. 46. Harwood J, Clark OH, Dunphy JE. Significance of lymph node metastasis in differentiated thyroid cancer. Am J Surg 1978; 136: 107. 47. Scheumann GFW, Gimm 0, Wegener G, et al. Prognostic significance and surgical management of locoregional lymph node metastases in papillary thyroid cancer. World J Surg 1994;18:559. 48. McDermott WV, Morgan WS, Hamlin E, et al. Cancer of the thyroid. J Clin Endocrinol Metab 1954;16:1336. 49. Rossi RL, Cady B, Silverman ML, et al. Surgically incurable welldifferentiated thyroid carcinoma. Arch Surg 1988;123:569. 50. Ito J, Noguchi S, Murakami N, et al. Factors affecting the prognosis of patients with carcinoma of the thyroid. Surg Gynecol Obstet 1980;150:539. 51. Crile G, Pontius KI, Hawk WA. Factors influencing the survival of patients with follicular carcinoma of the thyroid gland. Surg Gynecol Obstet 1985;160:409. 52. Starnes HF, Brooks DC, Pinkus GS, et al. Surgery for thyroid carcinoma. Cancer 1985;55:1376. 53. Carcangiu ML, Zampi G, Pupi A, et al. Papillary carcinoma of the thyroid. Cancer 1985;55:805. 54. Tubiana M, Schlumberger M, Rougier P, et al. Long-term results and prognostic factors in patients with differentiated thyroid carcinoma. Cancer 1985;55:794. 55. Schroder DM, Chambors A, France CJ, et al. Operative strategy for thyroid cancer. Cancer 1986;58:2320. 56. Hannequin P, Liehn JC, Delisle MJ. Multifactorial analysis of survival in thyroid cancer. Cancer 1986;58: 1749. 57. Grant CS, Hay ID, Gough IR, et al. Local recurrence in papillary thyroid carcinoma: Is extent of surgical resection important? Surgery 1988; I04:954. 58. Hoie J, Stenwig AE, Brennhovd ro. Surgery in papillary thyroid carcinoma: A review of 730 patients. J Surg OncoI1988;37:147.

59. Brooks JR, Starnes F, Brooks DC, et al. Surgical therapy for thyroid carcinoma: A review of 1249 solitary thyroid nodules. Surgery 1988; 104:940. 60. Shah JP, Loree TR, Dharker D, et al. Lobectomy versus total thyroidectomy for differentiated carcinoma of the thyroid: A matched-pair analysis. Am J Surg 1993;166:331. 61. Newman KD, Black T, Heller G, et al. Differentiated thyroid cancer: Determinants of disease progression in patients <21 years of age at diagnosis: A report from the Surgical Discipline Committee of the Children's Cancer Group. Ann Surg 1998;227:533. 62. Buckwalter JA, Thomas CG, Freeman JB. Is childhood thyroid cancer a lethal disease? Ann Surg 1975;181:632. 63. LaQuaglia MP, Corball MT, Heller G, et al. Recurrence and morbidity in differentiated thyroid carcinoma in children. Surgery 1988; I04: 1149. M. Ceccarelli C, Pacini F, Lippi F, et al. Thyroid cancer in children and adolescents. Surgery 1988;104:1143. 65. Gervasoni JE Jr, Taneja C, Chung MA, Cady B. Axillary dissection in the context of biology of lymph node metastases. Am J Surg 2000; 180:278. 66. Simpson WJ, McKinney SE, Carruthers JS, et al. Papillary and follicular thyroid cancer. Am J Med 1987;83:479. 67. McHenry C, Jarosz H, Davis M, et al. Selective postoperative radioactive iodine treatment of thyroid carcinoma. Surgery 1989; I06:956. 68. Cunningham MP, Duda RB, Recant W, et al. Survival discriminants for differentiated thyroid cancer. Am J Surg 1990;160:344. 69. Hay ID, McConahey WM, Goellner JR. Managing patients with papillary thyroid carcinoma: Insights gained from the Mayo Clinic's experience of treating 2,512 consecutive patients during 1940 through 2000. Trans Am Clin Climatol Assoc 2002;113:241. 70. Cady B. Management of tracheal obstruction from thyroid diseases. World J Surg 1982;6:696. 71. Shaha AR. Prognostic factors in papillary thyroid carcinoma and implications of large nodal metastasis. Surgery 2004;135:237. 72. Schlumberger M, Tubiana M, DeVathaire E, et al. Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab 1986;63:960. 73. Ruegemer 11, Hay ro, Bergstralh EJ, et al. Distant metastases in differentiated thyroid carcinoma: A multivariate analysis of prognostic variables. J Clin Endocrinol Metab 1988;67:501. 74. Pacini F, Lippi F, Formica N, et al. Therapeutic doses of iodine-13I reveal undiagnosed metastases in thyroid cancer patients with detectable serum thyroglobulin levels. J Nucl Med 1987;28:1888. 75. Foster RS. Morbidity and mortality after thyroidectomy. Surg Gynecol Obstet 1978;146:423. 76. Shaha A, Jaffee BM. Complications of thyroid surgery performed by residents. Surgery 1988;104:1109. 77. Cady B, Cohn K, Rossi RL. The effect of thyroid hormone administration upon survival in patients with differentiated thyroid carcinoma. Surgery 1983;94:978. 78. Siperstein AE, Zeng Qui-Hua, Gum ET, et al. Adenylate cyclase activity as a predictor of thyroid tumor aggressiveness. World J Surg 1988;12:528. 79. Hamming JF, Schelfhout L, Comelisse CJ, et al. Prognostic value of nuclear DNA content in papillary and follicular thyroid cancer. World J Surg 1988;12:503. 80. Lemoine NR, Mayal ES, Wyllie FS, et al. Activated ras oncogenes in human thyroid cancers. Cancer Res 1988;48:4459.

Growth Factor, Thyroid

Hyperplasia, and Neoplasia Staffan Smeds, MD, PhD • Nils-Erik Heldin, PhD

Thyroid tissue homeostasis is controlled at several levels: directly or indirectly by thyroid-stimulating hormone (TSH), by locally acting growth stimulatory substances (i.e., epidermal growth factor [EGF], transforming growth factor-a [TGF-a], insulin-like growth factors [IGFs], fibroblast growth factors [FGFs], hepatocyte growth factor [HGF], platelet-derived growth factor [PDGF], and the growth inhibitory TGF-~), and also by apoptotic mechanisms regulating cell death. Variation of thyroid volume reflects either the demand of the organism through TSH or a disturbance of the intricate network interaction between the locally acting growth regulatory substances and the expression of their receptors. Many of the latter are related to identified protooncogene products. In nodular goiter, hyperplasia seems related to increased growth propensity, inherited from mother to daughter cells in a subpopulation of cells at multiple sites in the gland. Nodules can, however, be monoclonal, as is characteristic for early neoplastic lesions. Genetic events (i.e., oncogene activation) seem to be operational along both hyperplastic and neoplastic growth deregulation lines. From this early "gray zone" event, further degeneration seems linked to specific mutations that give the neoplasias their characteristic phenotypic expression. Deregulation of the cell cycle by ablation of p53 and Rb gene expression seems to add a further malignant potential to the neoplastic degeneration. Growth regulation of the thyroid gland comprises an intricate network of interaction between regulatory signals and the genetic template for cell reactions. The regulatory mechanisms include autocrine and paracrine signal loops as well as varying oncogene and growth suppressor gene expressions, which interfere with and can disrupt cell cycle transition. Qualitative and quantitative changes of the signal pattern alter the phenotypic expression of thyroid function or growth, and a number of mutations give constitutive genetic lesions that stepwise alter the phenotypic expression of tissue integrity, growth, and function. Integration of the thyroid gland in the homeostasis of the organism is monitored by hormonal, neural, and immunologic systems. In this first level of thyroid control, the TSH is the most important factor for function and growth. On a second

256

level, tissue homeostasis seems controlled by a number of locally acting signal substances, some of which are referred to as growth regulatory factors. On a third level, cell to cell adhesion and parenchyma integrity are controlled by a number of factors, the loss of which results in deregulation of thyroid growth control. 1 At the genetic level, new insights into programmed cell death (apoptosis) add a fourth level of control to the complex hierarchy of thyroid growth control. 2 Apart from fetal and adolescent increase in thyroid volume, the thyroid gland normally does not grow. Each follicle cell is assumed to pass five mitotic cycles during adulthood, indicating small kinetic cell compartments undergoing proliferation and apoptosis.' The rest of the follicle cell population expresses their differentiated functions (i.e., secretion of thyroid hormones that inhibit secretion of pituitary thyrotrophs of TSH by the well-known negative feedback mechanism). The follicle cells, however, retain their capacity to grow (hypertrophy) and multiply (hyperplasia) in response to stimuli. Thus, decreased thyroid hormone secretion, as induced by iodine deficiency or administration of goitrogen or antithyroid drugs, gives increased TSH secretion, with concomitant stimulated thyroid function and growth. The latter shows that a follicle cell is reversibly terminally differentiated. Thyroid follicle cell proliferation is under the control of several factors, including hormones, classic growth factors, and different low-molecular-weight agents. Because both stimulatory and inhibitory factors are described, the net growth effect is a sum of all these stimuli. Most of the knowledge of thyroid growth regulation is from in vitro experiments in different culture systems. In Table 28-1, we have listed the major thyroid growth-promoting and growthinhibiting factors. As seen in Table 28-1, the factors involved in thyroid growth regulation can be divided into three major groups according to the intracellular signal pathway used.

Mitogenic Pathways The pathways through which extracellular signals are transferred into the follicle cell are conveyed by three membraneassociated transducing systems (Fig. 28-1).

Growth Factor, Thyroid Hyperplasia, and Neoplasia - - 257

1. Activation of the guanosine triphosphate (GTP)-binding protein Gsa in the adenylate cyclase (AC), which evokes the cyclic adenosine monophosphate (cAMP) protein kinase A (PKA) signal (the AC-cAMP-PKA pathway). 2. A cAMP-independent mechanism involving activation of membrane-bound tyrosine kinase receptors (RTKs), resulting in an activation of the ras mitogen-activated protein kinase (MAPK) pathway for transduction of the mitogenic signal. 3. Phospholipid-hydrolyzing mechanisms by which a number of agonists act by interaction with phospholipase, which catalyzes the formation of diacylglycerol and inositol triphosphate (from membrane phosphatidylinositol [PI] or polyphosphoinositides), resulting in the mobilization of calcium, the activation of protein kinase C, the release of arachidonic acid (precursor for prostaglandins, thromboxanes, and leukotrienes), and the formation of cyclic guanosine monophosphate by activation of guanylate cyclase (the PI-PKC-Ca 2+ pathway, or PI cascade). The TSH receptor confers the physiologic signal from the hypothalamic-pituitary system to the follicle epithelium primarily for regulation of a thyroid hormone secretion rate. The membrane-bound RTK path may confer information from locally produced factors and neighboring cells in paracrine and autocrine loops, whereas agonist interacting with the phospholipid-hydrolyzing system seems to form a more general route for integration of thyroid function and growth with other surveillance systems. These pathways are usually mitogenic, because activation induces cell replication. It is generally accepted that all pathways are mitogenic. There are, however, distinct species variations, and results from experimental systems cannot be generalized to the human thyroid without careful investigation in well-controlled experimental systems.

Thyroid Growth-Regulating Factors Thyrotropin TSH has traditionally been considered the major stimulator of the thyroid function." TSH is a heterodimeric glycoprotein consisting of noncovalentiy associated a and P chains and has a total molecular weight of about 28 kd. Thyroid follicle cells are stimulated by TSH binding to specific cell surface receptor proteins, the TSH receptor (TSH-R). Activation of the TSH-R results in an increase in the intracellular level of cAMP as the major intracellular second messenger for most of the TSH effects.' However, TSH through the TSH-R has also been demonstrated to increase the PI turnover as a second messenger system for the action of TSH. The amount of TSH needed for stimulation of the PI pathway is 5- to lO-fold greater than that needed for TSH activation of AC.5 TSH-R was shown, by molecular cloning, to belong to the family of receptors with seven membrane-spanning regions, similar to other G-protein-coupled receptors." The general concept ofTSH as a trophic pituitary hormone regulating both function and growth of the thyroid has been questioned. The positive effect on the functional activity is undisputed; however, the stimulatory effect ofTSH on thyroid follicle cell growth is questioned. During the last decade, numerous studies have revealed a more complex system of thyroid growth regulation and cell proliferation. Nevertheless, administration of TSH to rats results in an enlargement of the thyroid as a result of both cell hypertrophy and cell hyperplasia. A rapid increase in the TSH level before increased thyroid growth has also been observed in goitrogentreated experimental animals." Propylthiouracil treatment of rats resulted in a several-fold increase in the thyroid volume

258 - - Thyroid Gland

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FIGURE 28-1. Mitogenic pathways in the regulation of thyroid function and growth. Schematic drawing shows the major pathways involved in the regulation of thyroid function and growth. (1) TheAC/cAMPIPKA pathway: The major stimulator of this pathway in thyrocytes is thyroid-stimulating hormone (TSH), which interacts with the TSH-receptor (TSH-R). Stimulation of the TSH-R leads to an activation of guanosine triphosphate (GTP)-binding regulatory proteins; the Gsa in the plasma membrane activates adenylate cyclase (AC), generating cyclic adenosine monophosphate (cAMP) that activates the protein kinase A (PKA), and the G, linked to the phospholipase C (PLC), which stimulates the phosphatidylinositol (PI) turnover. (2) PI-PKC-Ca2+ pathway:This signal transduction cascade is activated by a number of different receptors (Rn in figure) besides the TSH-R. An activation of the TSH as well as other receptors leads to an increasedPLC activity, resulting in the formation of inositol lA,5,-triphosphate (IP3) and diacylglycerol (DAG) with a subsequentincrease in the intracellular levelof calcium (Ca2+) and PKC activity. Both the PKA and the PKC are serine-threonine kinasesand phosphorylate severaldifferent proteins. (3) Tyrosine kinase receptors (RTK): Ligandbindingto RTK leads to a phosphorylation on tyrosine residues in the receptor molecule. The activatedphosphorylated receptors are linked to many different signaling pathways (all pathways are not included in the figure) via direct binding of signaling proteins containing a src homology 2 (SH2) domain. However, the major mitogenic pathway of many RTKs involves activation of a chain of events in the ras pathway (shown in figure). In short, the phosphorylated RTKinteracts with an adaptorproteincalled Grb2. Grb2 associates with a protein called Sos ("son of sevenless"), leading to the activationof ras. The activated ras GTP leads to an increased activity of raf, followed by a sequential activation of the proteins in the (mitogen-activated protein kinase [MAPK]) cascade of events that ultimately leads to an increased transcriptional activity (MAPKK, MAPK kinase). The negative influence of an organified form of iodine (I-X)on the differentpathways is also shown. ATP = adenosine triphosphate.

as well as in the mitotic index of the thyroid epithelium." Furthermore, TSH has also been observed to have a positive effect on thyrocyte proliferation in human thyroid tissue transplanted into nude mice." However, hemithyroidectomy of dwarf mice (lacking TSH) resulted in a compensatory

growth of the remaining thyroid lobe, showing that factors other than TSH can also stimulate thyroid growth. 10 Although TSH through the TSH-R seems to be the major modulator of thyroid growth, it has been difficult to show a direct mitogenic effect of TSH on thyrocyte proliferation. A number of in vitro studies have been performed with contradictory results; a stimulatory effect of TSH was found in cultures of normal dog," rat,IZ.13 sheep," and human" thyrocytes. In contrast, no effect of TSH was reported in bovine," sheep,'? porcine," and human'? thyroid cells, and even an inhibitory effect of TSH has been observed in porcine thyroid follicle cells." The growth stimulatory effect of TSH observed appeared to be mediated by cAMP because the effect of TSH was mimicked by other stimulators of cAMP, such as forskolin and cholera toxin.I':" A positive involvement of the cAMP-PKA pathway in thyroid growth regulation is strengthened by several observations. First, activating somatic mutations of the TSH-R in patients with hyperfunctioning thyroid adenomas were found. A single point mutation in the third intracellular loop or in the transmembrane (TM) domain VI of the TSH-R gene in hyperfunctioning thyroid nodules resulted in a constitutively activated receptor," Second, activating mutations in the GTP-binding protein, Gsa, oftheAC (denoted as the gsp oncogene) have been identified in hyperfunctioning thyroid adenomas and in constitutively activated differentiated thyroid carcinomas.v-? Third, introduction of cAMP-elevating adenosine receptor under the control of a thyroglobulin promoter in transgenic mice resulted in thyroid hyperplasia.i" Finally, a recessive inactivating mutation of the TSH-R (the hyt mutation; TM domain IV, amino acid 556 proline ~ leucine) has been observed in a hypothyroid mouse strain (hyt/hyt) resulting in a small and hypoplastic thyroid gland. zs.z6 Taken together, all these observations indicate a growth-promoting effect of an increased cAMP level within the thyroid cells. However, as mentioned, there is little evidence for a direct mitogenic action by TSH. Islerz7 showed the need for other factors besides TSH in the regulation of thyroid growth because hypophysectomy in rats abolished the mitogenic effect of injected TSH. Furthermore, injection of TSH in dwarf mice (growth hormone and TSH deficient) did not result in an increased mitotic activity in the thyroid gland.i" Other investigators document that TSH requires IGF-I (or insulin in high concentrations) in culture medium for a full mitogenic effect. A synergistic effect between TSH and EGF on thyroid follicle cell proliferation has been found in vitro; stimulation of porcine thyroid follicle cells with TSH was found to increase the number of high-affinity receptors for EGF as well as the mitogenic response to EGF stimulation.Pv? Thus, TSH may promote growth by facilitating the action of other peptide growth factors.

Epidermal Growth Factor and Transforming Growth Factor-a EGF is a potent mitogen for a variety of cells. It has a molecular weight of 6 kd and stimulates cells through the EGF receptor (EGF-R), a member of the tyrosine kinase superfamily of receptors. The EGF-R is known to bind not only

Growth Factor, Thyroid Hyperplasia, and Neoplasia - -

EGF but also TGF-a. EGF (or urogastrone, human EGF) is produced in many different tissues, including the thyroid. EGF stimulates the mitotic activity of thyroid follicle cells in culture, as first demonstrated by Westermark and Westermark'? in sheep thyrocytes. Subsequent studies documented that EGF is mitogenic for thyrocytes from other species, including dog," porcine.F human.P and bovine" cells in culture. The EGF-Rs have been shown to be localized to the basolateral surface of the thyroid follicle cells,29 and a specific binding of EGF has also been demonstrated to thyroid follicle cells" or membrane preparations." As previously mentioned, a synergistic effect between EGF and TSH has been observed; TSH (through cAMP) increased both the binding'V? and the mitogenic action of EGF in porcine thyrocytes in culture.F Besides the mitogenic action of EGF, an inhibitory effect on the differentiated functions of the thyroid follicle cells has been observed.F Overexpression of the EGF-R has been implicated in the development of thyroid carcinomas. Several reports have found increased binding of iodine 125-EGF to membranes from human thyroid carcinomas compared with membranes from normal thyroid tissue.P-" The expression of EGF-R seems to correlate with the prognosis of the patient (an increased number of EGF-Rs in patients with poor prognosis) and has been suggested as a prognostic factor for thyroid carcinomas.W' However, no prognostic importance of the level of EGF-R expression was found by Mizukami and colleagues." Autocrine mechanisms in thyroid tumors involving the EGF-R have also been reported. Coexpression of the EGF-R and TGF-a has been found in thyroid carcinomas, suggesting an autocrine growth stimulation in tumor cell growth." A several-fold increase in the expression of TGF-a was found in papillary carcinomas and their lymph node metastases.'?

Insulin-Like Growth Factors IGF-I and IGF-II are both implicated in growth regulation of the thyroid epithelium. Thyroid follicle cells have been shown to express high-affinity receptors for both IGF-I and IGF_II.4o.42 There is cross-reactivity among the receptors in the IGF family; IGF-I, IGF-II, and insulin have all been shown to bind to and activate the IGF-I receptor (lGF-I-R), a member of the tyrosine kinase family of receptors. The IGF-I-R is believed to mediate most of the growth stimulatory effects of IGFs in thyroid follicle cells. The IGF-II-R, or mannose-6-phosphate receptor, is believed to be involved in the targeting of lysosomal enzymes to lysosomes rather than in thyroid growth stimulation. A growth stimulatory effect of IGF-I, IGF-II, or insulin (in high concentrations) on thyroid epithelial cells in culture has been reported. 40,43 As mentioned, IGF-I (or insulin in high concentrations) has also been found to act as a permissive factor for the growth-promoting effect of TSH on cultured thyrocytes.!' Withdrawal of insulin-IGF-I from the culture medium results in a decreased mitogenic effect of TSH; hence, IGF-I acts as a permissive factor for the growth stimulatory effects of TSH. TSH has been shown to increase the activity of the IGF-I-Rs in porcine thyrocytes in culture stimulated with IGF-I, indicating the possible opposite situation with TSH facilitating the action of IGFs. 44

259

Normal and neoplastic thyroid epithelial cells have been shown to produce both IGF-I and IGF_II.41,45-47 The simultaneous expression of IGF-I and IGF-I-Rs on human thyroid follicular cells in primary cultures,"? thyroid adenoma cells," and a papillary thyroid carcinoma cell line" has led to speculations about an autocrine stimulatory role in thyroid growth regulation. Furthermore, increased amounts ofIGF-I,82 IGF-I-R,49 and IGF-II-R,42 compared with normal thyroid tissue, have been described from studies of human thyroid neoplasms. The increased expression is believed to contribute to the abnormal growth of the thyroid follicle cells.

Fibroblast Growth Factors Currently, there are nine members of the FGF family (FGF I to 9). FGFs are known to stimulate proliferation, differentiation, and function of several different cell types and play an important role in the regulation of angiogenesis. The cellular responses to FGFs are mediated by four different FGF receptors (FGF-R I to 4), all belonging to the RTK family. Thyroid epithelium has been found to express FGF-Rs50 and produces FGF stored at the basement membrane of the follicle cells. 5o.52 Using in vitro systems of thyroid follicle cells, a growth-promoting effect of FGF has been found. 52.55 The simultaneous expression of FGF-2 (basic FGF) and FGF-R-I (jig) on rat thyroid follicle cells has implicated FGF-2 as an autocrine stimulatory factor in thyroid growth regulation.i? A paracrine role of the FGF produced by the thyrocytes has also been suggested to be involved in the neovascularization observed within the thyroid during goiter development. Greil and colleagues" found an endothelial cell growth stimulatory effect of the factor (suggested to be FGF-2) purified from porcine thyrocytes (Fig. 28-2). As with EGF, addition of FGF results in an inhibition of thyroid function. Addition of FGF led to inhibition of cAMP formation'" and attenuation of the TSH effects. 55 Moreover, administration of FGF-I (acidic FGF) to rats led to the formation of colloid goiter, probably resulting from inhibition of the TSH-induced transport of colloid from the follicle lumen by FGF. 56 Neovascularization Adhesion molecule synthesis

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FIGURE 28-2. Autocrine and paracrine signals. The figure shows a number of identified growth-regulating signal substances that are growth promoting (+) or inhibitory (-) on thyrocytes via corresponding receptors. The signal substances may also act on surrounding stromal cells to give endothelial cell and fibroblast proliferation. IGF = insulin-like growth factor; TGF = transforming growth factor; EGF = epidermal growth factor; FGF = fibroblast growth factor; PDGF = platelet-derived growth factor; R = receptor.

260 - - Thyroid Gland

Hepatocyte Growth Factor HGF/scatter factor is a potent mitogen for several different cell types, primarily cells of epithelial origin. The receptor for HGF (HGF-R) is encoded by the protooncogene c-met, a member of the RTK family. HGF has been found to be one of the most potent mitogens for canine thyrocytes in cell culture.V In conformity with EGF, HGF has a dedifferentiating effect on thyrocytes in vitro." Expression of the HGF-R messenger RNA (mRNA) and protein have been found in both human normal thyroid tissue'" and thyroid carcinomas.59 Di Renzo and coworkers'? found a IOO-fold increase in the expression of the HGF-R protein in 22 of 41 human carcinomas derived from the thyroid epithelium; overexpression was found in papillary and follicular carcinomas but not in the anaplastic carcinomas in the study.

density (Fig. 28-3). Follicles in hyperplastic tissue display a heterogenic expression of both functional characteristics (iodination, peroxidase activity, thyroglobulin synthesis, and endocytosis) and proliferative potential.s? Surprisingly, this variation is observed among thyrocytes in the same follicle in both experimental animals and in human thyroid glands.P?' Thyrocytes with a high replication rate stay adjacent to each other in the follicle wall, indicating that increased growth propensity is inherited from mother to surrounding daughter cells.'? With time, the goitrous gland is composed of a large population of thyrocytes with this abnormal growth pattern.

Platelet-Derived Growth Factor PDGFs are homo- or heterodimers of the four PDGF chains (PDGF A, PDGF B, PDGF C and PDGF D). These PDGF molecules are known to bind with different affinities to two RTKs-namely the PDGF receptor-a (PDGF-R-a) and the PDGF-R-~. PDGF-Rs have been found to be expressed in three of the four human anaplastic carcinoma cell lines that were studied. 60,61 The presence of PDGF receptors has so far not been demonstrated on normal thyrocytes. However, a growth stimulatory effect of PDGF on rat thyrocytes in vitro has been reported.55 In 1993, Matsuo and associates'S found the expression and production of a PDGF-B-like protein in a human papillary carcinoma cell line.

Thyroid Growth-Inhibiting Factors The TGF-~ family consists of three members (TGF ~l to ~3), and three different TGF-~ receptors (TGF-~-R I to III) have been identified. Normal and diseased thyroid tissues express and produce TGF-~ protein (TGF-~l).63 The expression of TGF-~ 1 mRNA was increased in the hyperplastic thyroids of goitrogen-treated rats'" as well as after iodide administration to thyrocytes in vitro. 65 Addition of TGF-~l to thyroid follicle cells has been shown to result in growth inhibition." Grubeck-Loebenstein and colleagues's suggested that TGF-~ has a role in goiter formation because lower production of TGF-~ was observed in thyroid follicle cells from patients with nontoxic goiter than in normal follicle cells.

Hyperplasia It is common knowledge that nodules develop in normal thyroid glands with aging."? In growing thyroids, the development of the goiter is almost invariably accompanied by the development of multiple nodules of varying size. 68 The nodules are generally softer than normal tissue. The surface of a sectioned hyperplastic gland appears granular, and the histopathologic picture shows a dysplastic arrangement with wide variation of follicle size and areas with increased cell

B FIGURE 28-3. Thyroid gland hyperplasia. The cut surface of a hyperplastic nodule (A) in a human thyroid gland shows the smooth

and gel-like appearance of the colloid-rich parenchyma. A section of the corresponding tissue (B) reveals numerous large follicles and areas with high cellular density (hematoxylin and eosin).

Growth Factor, Thyroid Hyperplasia, and Neoplasia - -

Three mechanisms have been proposed to explain nodule formation in multinodular goiters'": 1. The aforementioned tendency of cells with higher growth potential to stay adjacent to each other results in the formation of multiple growth centers and uneven proliferation in the gland, with subsequent nodule formation in different parts of the thyroid gland. 2. A somatic mutation may confer an inheritable growth advantage to a subset of thyrocytes. This mechanism may be operative in clonal tumor formation.P?" 3. The presence of fibrous strands in most thyroid tissue results from scarring, necrosis, and hemorrhage in growing goiters and, with time, disturbs the normal thyroid architecture." Growth stimulation can be caused by external growth signals such as TSH during iodine deficiency, by growthstimulating immunoglobulins, or by any other growthpromoting factors.73-78 In patients with multinodular goiter, serum TSH levels are usually normal. A possible growthpromoting effect of TSH may be due to an inherited subset of thyroid cells that have increased sensitivity to TSH. An increased growth propensity toward TSH (or other external growth-promoting factors) may also be induced by mutations that alter cell cycle intervals (i.e., shorten Goor decrease apoptosis, leading to an increased number of cell multiplication cycles before cell death).

Somatic Mutations Although somatic mutations can occur in normally replicating cells, those with an increased proliferation rate have a higher risk of acquiring somatic mutations (i.e., allelic deletions of tumor suppressor genes and point mutations in oncogenes).68,74.79 By the introduction of specific X chromosome probes, it has been shown that both nonendemic and endemic multinodular goiters contain polyclonal and monoclonal nodules." The clonal analyses have thus shown that a genetic mutation mechanism may play a major role in the formation of nodules in multinodular goiter. Cells with mutations that favor growth slowly clonally outgrow the other thyroid cells (Fig. 28-4).

Neoplasia Early neoplastic lesions are generally monoclonal and arise from a single mutation (or several) in a cell," which results in a greater propensity of these cells to multiply more rapidly or to die more slowly than surrounding cells. With the new knowledge of the monoclonal origin of nodules in hyperplastic disease, the dichotomy between hyperplastic and neoplastic transformation has become less distinct. In a hypothetical overlapping gray zone (Fig. 28-5), the growth of both hyperplastic and neoplastic nodules may be dependent on single lesions, in the hyperplastic case arising from cells with inherited high intrinsic growth potential and in the neoplastic case arising from a single normal precursor cell. Both benign and malignant thyroid neoplasms have been shown to have ras mutations.s" It has, therefore, been

261

Normal cells Population of cells with high { intrinsic growth potential

. . . ..

N~;i,~ ~)i

.... .. .... .~'

\

:

Increasing number of genetic lesions

FIGURE 28-4. The "gray zone." Growth stimulation by increased signal pressure from external sources, increased sensitivity toward normal signal pressure, or autocrine-paracrine growth stimulation gives rise to hyperplasia. Single or multiple genetic lesions give different neoplastic transformations in a stepwise way with the appearance of initial nonmetastasizing benign forms, The "gray zone" indicates a possibility of genetic lesions that may change the growth potential in hyperplastic nodules without obvious neoplastic transformation, as well as early lesions in neoplastic tissue.

proposed that Ha-ras activation is an early or initiating event in the development of thyroid oncogenesis. In fact, in vitro transfection of mutant ras genes extended the proliferative life span of cultured rat thyroid follicle cells from less than 3 to more than 15 doubling times." The transformed thyroid cells spontaneously mutate and form tumorigenic new cell lines with loss of growth factor dependence and differentiated functions. These ras-transfected tumorigenic cells lose their responsiveness to the growth inhibitor TGF-~l and have increased nuclear levels of p53 protein. Benign follicular adenomas appear as single tumors in both normal and hyperplastic thyroid tissue. They form well-delineated firm nodules surrounded by a pseudocapsule. The homogeneous appearance of the epithelial arrangement reflects the currently held opinion that they represent true monoclonal tumors. Further dedifferentiation to malignant neoplasms seems correlated with specific mutational events. Progression toward the follicular phenotype has been reported to correlate with a loss of function of a gene in the llq 13 locus (follicular adenomajf and further dedifferentiation in follicular carcinomas with loss of genetic material in chromosome 3p. Activation of the ret oncogene appears to occur only in papillary thyroid carcinomas.f This protooncogene encodes a transmembrane receptor of the tyrosine kinase family, which fuses with a gene product (RGF) to form a novel chimeric oncogene (retIPTC3).84 p53 mutations have been found primarily in anaplastic thyroid cancers, but one study found them in other thyroid cancers." Thus, loss or decreased activity of this gene product, which appears to regulate growth-inhibiting signals at the G,-S transition of the cell cycle, seems to correlate with continued cell division despite the presence of multiple unrepaired and tumorigenic gene defects. Mutations in the retinoblastoma gene Rb have been observed in differentiated and anaplastic thyroid cancers." The gene encodes a nuclear phosphoprotein that switches

262 - - Thyroid Gland

Conclusion In conclusion, new findings concerning thyroid oncogenes and tumor suppressor genes, as well as studies of growth factors, are starting to explain why patients acquire specific thyroid tumors with different behaviors.

REFERENCES

B FIGURE 28-5. Benign thyroid neoplasia. A, The cut surface of a thyroid lobe with a follicular adenoma shows the presence of a well-encapsulated tumor with a smooth and uniform appearance. B, A section in the periphery of the adenoma shows the uniform appearance of the parenchyma architecture with the presence of only a few follicle structures (hematoxylin and eosin).

between a hyper and low-phosphorylated state in a cell cycle-specific manner and acts by regulating the action of transcription factors. Loss of this phosphoprotein deregulates the cell cycle transition. Mutations of p53 and Rb are present in both follicular and papillary forms of thyroid cancers. The early progression from benign neoplasias into either of the two major forms of differentiated thyroid cancer thus appears to be related to characteristic chromosome and genetic lesions. In more advanced disease with more rapidly growing and aggressive cancers, both major dedifferentiation lines share the loss of p53 and Rb cell cycle regulatory functions.

I. Brabant G, Hoang- Vu C, Cetin Y, et aI.A differentiation marker in thyroid malignancies. Cancer Res 1993;53:4987. 2. Dremier S, Goldstein J, Mosselmann R, et al. Apoptosis in dog thyroid cells. Biochem Biophys Res Commun 1994;200:52. 3. Coclet J, Fourean F, Ketelbant P, et al. Cell population kinetics in dog and human adult thyroid. Clin Endocrinol (Oxf) 1989;31:655. 4. Dumont JE. The action of thyrotropin on thyroid metabolism. In: Harris RS, Munsen PL, Diczfalusy E, Glover J (eds), Vitamins and Hormones, 29. London. Academic Press, 1971, p 287. 5. Laurent E, Mockel J, Van Sande J, et al. Dual activation by thyrotropin of the phospholipase C and cAMP cascades in human thyroid. Mol Cell EndocrinoI1987;52:273. 6. Parmentier M, Libert F, Maenhaut C, et al. Molecular cloning of the thyrotropin receptor. Science 1989;246: 1620. 7. Wynford-Thomas D, Stringer BMJ, Williams ED. Goitrogen-induced thyroid growth in rat: A quantitative morphometric study. J Endocrinol 1982;94:131. 8. Many MC, Denef JF, Haumont S. Precocity of the endothelial proliferation during a course of rapid goitrogenesis. Acta Endocrinol (Copenh) 1984; 105:487. 9. Smeds S, Boeryd B, Jortso E, Lennquist S. Normal and stimulated growth of different human thyroid tissues in nude mice. In: Goretzki PE, Roher HD (eds), Growth Regulation of Thyroid Gland and Thyroid Tumors, Vol 18. Basel, Switzerland, Karger, 1989, p 98. 10. Lewinski A, Bartke A, Smith NKR. Compensatory thyroid hyperplasia in hemithyroidectomized Snell dwarf mice. Endocrinology 1983;113:2317. II. Roger PP, Servais P, Dumont JE. Stimulation by thyrotropin and cyclic AMP of the proliferation of quiescent canine thyroid cells cultured in a defined medium containing insulin. FEBS Lett 1983;157:323. 12. Ambesi-Impiombato FS, Parks LAM, Coon HG. Culture of hormonedependent functional epithelial cells from rat thyroids. Proc Nat! Acad Sci USA 1980;77:3455. 13. Westermark K, Karlsson FA, Westermark B. Thyrotropin modulates EGF receptor function in porcine thyroid follicle cells. Mol Cell Endocrinol 1985;40: 17. 14. Fayet G, Hovsepian S. Strategy of thyroid cell culture in defined media and the isolation of the Ovnis and Porthos cell strains. In: Eggo MC, Burrow GN (eds), Thyroglobulin: The Prothyroid Hormone. New York, Raven Press, 1985, p 211. 15. Roger PP, Taton M, Van Sande J, Dumont JE. Mitogenic effects of thyrotropin and cyclic AMP in differentiated human thyroid cells in vitro. J Clin Endocrinol Metab 1988;66: 1158. 16. Gerard CM, Roger PP, Dumont JE. Thyroglobulin gene expression as a differentiation marker in primary cultures of calf thyroid cells. Mol Cell EndocrinoI1989;61:23. 17. O'Connor MK, Malone JF, Cullen MJ. Long-term cultures of sheep thyroid cells. Acta Endocrinol Suppl (Copenh) 1980;231:5. 18. Heldin NE, Westermark B. Epidermal growth factor, but not thyrotropin, stimulates the expression of c-fos and c-myc messenger ribonucleic acid in porcine thyroid follicle cells in primary culture. Endocrinology 1988;122:1042. 19. Westermark B, Karlsson FA, Wlilinder O. Thyrotropin is not a growth factor for human thyroid cells in culture. Proc Nat! Acad Sci USA 1979;76:2022. 20. Watanabe Y, Amino N, Tamaki H, et al. Bovine thyrotropin inhibits DNA synthesis inversely with stimulation of cyclic AMP production in cultured porcine thyroid follicles. Endocrinol Jpn 1985;32:81. 21. Parma J, Duprez L, Van Sande J, et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 1993;365:649. 22. Suarez HG, du Villard JA, Caillou B, et al. gsp mutations in human thyroid tumours. Oncogene 1991;6:677.

Growth Factor, Thyroid Hyperplasia, and Neoplasia - - 263 23. O'Sullivan C, Barton CM, Staddon SL, et al. Activating point mutations of the gsp oncogene in human thyroid adenomas. Mol Carcinogen 1991;4:345. 24. Ledent C, Dumont JE, Vassart G, Parmentier M. Thyroid expression of an A2 adenosine receptor trans gene induces thyroid hyperplasia and hyperthyroidism. EMBO J 1992; II :537. 25. Beamer WG, Eicher EM, Maltais LJ, Southard JL. Inherited primary hypothyroidism in mice. Science 1981;212:61. 26. Stein SA, Oates EL, Hall CR, et aI. Identification of a point mutation in the thyrotropin receptor of the hytlhyt hypothyroid mouse. Mol Endocrinol 1994;8:129. 27. Isler M. Loss of mitotic response of the thyroid gland to TSH in hypophysectomized rats and its partial restoration by anterior and posterior pituitary hormones. Anat Rec 1974;180:369. 28. Bartke A. The response of dwarf mice to murine thyroid-stimulating hormone. Gen Comp Endocrinol 1968; 11:246. 29. Westermark K, Westermark B, Karlsson FA, Ericson LE. Location of epidermal growth factor receptors on porcine thyroid follicle cells and receptor regulation by thyrotropin. Endocrinology 1986;118:1040. 30. Westermark K, Westermark B. Mitogenic effect of epidermal growth factor on sheep thyroid cells in culture. Exp Cell Res 1982;138:47. 31. Roger PP, Dumont JE. Epidermal growth factor controls the proliferation and the expression of differentiation in canine thyroid cells in primary culture. FEBS Lett 1982;144:209. 32. Westermark K, Karlsson FA, Westermark B. Epidermal growth factor modulates thyroid growth and function in culture. Endocrinology 1983;112:1680. 33. Errick JE, Ing KWA, Eggo MC, Burrow GN. Growth and differentiation in cultured human thyroid cells: Effects of epidermal growth factor and thyrotropin. In Vitro 1986;22:28. 34. Gerard CM, Roger PP. Control of proliferation and differentiation in primary cultures of calf thyroid cells. In: Medeiros-Neto G, Gaitan E (eds), Frontiers in Thyroidology, Vol 1. New York, Plenum, 1985, p 345. 35. Duh Q-Y,Gum ET, Raper SE, Clark OH. Epidermal growth factor receptor in normal and neoplastic thyroid tissue. Surgery 1985;98:1000. 36. Kanamori A, Abe Y,Yajima Y, et al. Epidermal growth factor receptors in plasma membranes of normal and diseased human thyroid glands. J Clin Endocrinol Metab 1989;68:899. 37. Akslen LA, Myking AO, Salvesen H, Varhaug JE. Prognostic impact of EGF-receptor in papillary thyroid carcinoma. Br J Cancer 1993; 68:808. 38. Mizukami Y, Nonomura A, Michigishi T, et al. Immunohistochemical demonstration of epidermal growth factor receptors in normal, benign and malignant thyroid tissue. Int J Onco11992; I:331. 39. Aasland R, Akslen LA, Varhaug JE, Lillehaug JR. Co-expression of the genes encoding transforming growth factor-alpha and its receptor in papillary carcinomas of the thyroid. Int J Cancer 1990;46:382. 40. Tramontano D, Moses AC, Picone R, Ingbar SH. Characterization and regulation of the receptor for insulin-like growth factor-I in the FRTL-5 rat thyroid follicular cell line. Endocrinology 1987;120:785. 41. Bachrach LK, Eggo MC, Hintz RL, Burrow GN. Insulin-like growth factors in sheep thyroid cells: Action, receptors and production. Biochem Biophys Res Commun 1988;154:861. 42. Yashiro T, Tsushima T, Murakami H, et aI. Insulin-like growth factor-II (IGF-II)/mannose-6-phosphate receptors are increased in primary human thyroid neoplasms. Eur J Cancer 1991;27:699. 43. Eggo MC, Bachrach LK, Burrow GN. Role of non-TSH factors in thyroid cell growth. Acta Endocrinol Suppl (Copenh) 1987;281:231. 44. Takahashi SI, Conti M, Van Wyk J. Thyrotropin potentiation of insulinlike growth factor-I dependent deoxyribonucleic acid synthesis in FRTL-5 cells: Mediation by an autocrine amplification factor(s). Endocrinology 1990;126:736. 45. Williams DW, Williams ED, Wynford-Thomas D. Evidence for autocrine production of IGF-I in human thyroid adenomas. Mol Cell Endocrinol 1989;61: 139. 46. Minuto F, Barreca A, Del Monte P, et al. Immunoreactive insulin-like growth factor I (IGF-I) and IGF-I-binding protein content in human thyroid tissue. J Clin Endocrinol Metab 1989;68:621. 47. Tode B, Serio M, Rotella CM, et al. Insulin-like growth factor-I: Autocrine secretion by human thyroid follicular cells in primary culture. J Clin Endocrinol Metab 1989;69:639. 48. Onoda N, Ohmura E, Tsushima T, et aI. Autocrine role of insulin-like growth factor (IGF-I) in a thyroid cancer cell line. Eur J Cancer 1992;28A: 1904.

49. Vannelli GB, Barni T, Modigliani U, et aI. Insulin-like growth factor-I receptors in nonfunctioning thyroid nodules. J Clin Endocrinol Metab 1990;71: 1175. 50. Logan A, Black EG, Gonzalez A-M, et al. Basic fibroblast growth factor: An autocrine mitogen of rat thyroid follicular cells? Endocrinology 1992;130:2363. 51. Greil W, Rafferzeder M, BechtnerG, Gartner R. Release of an endothelial cell growth factor from cultured porcine thyroid follicles. Mol EndocrinoI1989;3:858. 52. Emoto N, Isozaki 0, Arai M, et al. Identification and characterization of basic fibroblast growth factor in porcine thyroids. Endocrinology 1991;128:58. 53. Roger PP, Dumont JE. Factors controlling proliferation and differentiation of canine thyroid cells cultured in reduced serum conditions: Effects of thyrotropin, cyclic AMP and growth factors. Mol Cell EndocrinoI1984;36:79. 54. Black EG, Logan A, Davis JRE, Sheppard MC. Basic fibroblast growth factor affects DNA synthesis and cell function and activates multiple signalling pathways in rat thyroid FRTL-5 and pituitary GH3 cells. J Endocrinol 1990;127:39. 55. Pang X-P, Hershman J. Differential effects of growth factors on [3H]thymidine incorporation and [125I]iodine uptake in FRTL-5 rat thyroid cells. Proc Soc Exp BioI Med 1990;194:240. 56. De Vito WJ, Chanoine J-P, Alex S, et al. Effect of in vivo administration of recombinant acidic fibroblast growth factor on thyroid function in the rat: Induction of colloid goiter. Endocrinology 1992;131:729. 57. Dremier S, Toton M, Roulonval K, et al. Mitogenic dedifferentiating and scattering effects of hepatocyte growth factor on dog thyroid cells. Endocrinology 1994;135:135. 58. Di Renzo MF, Narsimhan RP, Olivero M, et al. Expression of the MetIHGF receptor in normal and neoplastic human tissues. Oncogene 1991;6:1997. 59. Di Renzo MF, Olivero M, Ferro S, et al. Overexpression of the c-METIHGF receptor gene in human thyroid carcinomas. Oncogene 1991;7:2549. 60. Heldin N-E, Gustavsson B, Claesson- Welsh L, et aI. Aberrant expression of receptors for platelet-derived growth factor in an anaplastic thyroid carcinoma cell line. Proc Nat! Acad Sci USA 1988;85:9302. 61. Heldin N-E, Cvejic D, Smeds S, Westermark B. Coexpression of functionally active receptors for thyrotropin and platelet-derived growth factor in human thyroid carcinoma cells. Endocrinology 1991;129:2187. 62. Matsuo K, Tang S-H, Sharifi B, et al. Growth factor production by human thyroid carcinoma cells: Abundant expression of a plateletderived growth factor-B-like protein by a human papillary carcinoma cell line. J Clio Endocrinol Metab 1993;77:996. 63. Grubeck-Loebenstein B, Buchan G, Sadeghi R, et al. Transforming growth factor beta regulates thyroid growth. J Clin Invest 1989;83:764. 64. Logan A, Smith C, Becks Gp, et aI. Enhanced expression of transforming growth factor-beta I during thyroid hyperplasia in rats. J Endocrinol 1994;141:45. 65. Yuasa R, Eggo MC, Meinkoth J, et al. Iodide induces transforming growth factor beta I (TGF-beta 1) mRNA in sheep thyroid cells. Thyroid 1992;2:141. 66. Tsushima T, Arai M, Saji M, et aI. Effects of transforming growth factor-beta on deoxyribonucleic acid synthesis and iodine metabolism in porcine thyroid cells in culture. Endocrinology 1988; 123:1187. 67. Horlocker TT, Hag JE, James EM, et al. Prevalence of incidental nodular thyroid disease detected during high resolution parathyroid ultrasonography. In: Medeiros-Neto GA, Gaitan E (eds), New Frontiers in Thyroidology. New York, Plenum, 1986, p 1309. 68. Studer HK, Peter HJ, Gerber H. Natural heterogeneity of thyroid cells: The basis for understanding thyroid function and nodular goiter growth. Endocr Rev 1989;10:125. 69. Gerber H, BUrgi U, Peter HJ. Etiology and pathogenesis of thyroid nodules. Exp Clin EndocrinoI1993;101:97. 70. Peter HJ, Gerber H, Studer H, Smeds S. Pathogenesis of heterogeneity in human multinodular goiter: A study on growth and function of thyroid tissue transplanted on to nude mice. J Clin Invest 1985;76: 1990. 71. Smeds S, Peter HJ, Jortso E, et aI. Naturally occurring clones of cells with high intrinsic proliferation potential within the follicular epithelium of mouse thyroids. Cancer Res 1987;47: 1646. 72. Goretzki PE, Roher HD. Growth regulation of thyroid gland and thyroid tumours. Front Horm Res 1989;18:1.

264 - - Thyroid Gland 73. Studer H, Gerber H. Pathogenesis of nontoxic goiter. In: Braverman LE, Utiger R (eds), Werner's and Ingbar's the Thyroid, 6th ed. Philadelphia, JB Lippincott, 1991, p 1107. 74. Fey MF, Peter HJ, Hinds HL, et aI. Clonal analysis of human tumors with M27beta, a highly informative polymorphic X-chromosomal probe. J Clin Invest 1992;89:1438. 75. Ramelli F, Studer H, Brugisser D. Pathogenesis of thyroid nodules in multinodular goiter. Am J PathoI1982;109:215. 76. Bidey SP. Control of thyroid cell and follicle growth: Recent advances and current controversies. Trends Endocrinol Metab 1990;1:174. 77. Dumont JE, Maenhaut C, Pirson I, et al. Growth factors controlling the thyroid gland. Baillieres Clin Endocrinol Metab 1991;5:727. 78. Gartner R. Thyroid growth in vitro. Exp Clin Endocrinol 1992; 100:32. 79. Studer H, Gerber H, Zbaren J, Peter HJ. Histomorphological and immuno-histochemical evidence that human nodular goiters grow by episodic replication of multiple clusters of thyroid follicular cells. J Clin Endocrinol Metab 1992;75:1151. 80. Suarez HG, Duvillard JA, Severino M, et al. Presence of mutations of all three ras genes in human thyroid tumours. Oncogene 1990;5:565.

81. Burn JS, Blaydes JP, Wright PA, et al. Stepwise transformation of primary thyroid epithelial cells by a mutant Ha-ras oncogene: An in vitro model of tumor progression. Carcinogen 1992;6: 129. 82. Matsuo K, Tang SH, Fagin JA. Allelotype of human thyroid tumors: Loss of chromosome 11q 13 sequences in follicular neoplasms. Mol EndocrinoI1991;5:1873. 83. Santoro M, Carlomagno F, Hay ID, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest 1992;89:1517. 84. Santoro M, Dathan NA, Berlingieri MT, et aI. Molecular characterization of RET/PTC3; a novel rearranged version of the RET proto-oncogene in a human thyroid papillary carcinoma. Oncogene 1994;9:509. 85. Zou M, Shi Y, Farid NR. p53 mutations in all stages of thyroid carcinomas. J Clin Endocrinol Metab 1993;77:1054. 86. Farid NR, Shi Y, Zou M. Molecular basis of thyroid cancer. Endocr Rev 1994;15:202.

Signal Transduction in Thyroid Neoplasms Serdar T. Tezelman, MD • Allan E. Siperstein, MD

In vivo and in vitro cellular proliferation, differentiation, and protein phosphorylation of thyroid cells are regulated and influenced by many stimulatory and inhibitory hormones, neurotransmitters, and growth factors through several signal transduction systems, including the adenylate cyclase (AC)cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) system, the phospholipase C (PLC)-protein kinase C (PKC) system, and the growth factor-tyrosine kinase signal transduction system. In the past decade, advances in molecular biology and biochemistry have improved our knowledge and understanding of signal transduction systems. Multiple endocrine, paracrine, and autocrine factors, including thyroidstimulating hormone (TSH), epidermal growth factor (EGF), vasoactive intestinal polypeptide (VIP), somatostatin, insulin, insulin-like growth factor I (IGF-I), and estrogen, bind to a variety of cell surface-specific and intracellular receptors on the thyrocyte and cause a specific second messenger response or directly activate PKC, such as 12-0tetradecanoyl phorbol-13 acetate (TPA) (Table 29-1). Multiple mutations or abnormalities in the regulation of thyroid cell growth are responsible for uncontrolled growth and the formation of benign and malignant thyroid neoplasms. Thyrotropin (TSH) is secreted by the anterior pituitary hormone and is a major regulator of thyroid growth and differentiated functions, including thyroid hormone synthesis, formation, and degradation as well as secretion, iodide uptake, iodide organification, thyroid peroxidase, thyroglobulin, and protein synthesis. 1,2 The expression of the thyroglobulin gene is mediated by a cAMP-dependent mechanism and is under the positive control of TSH.3 TSH has a tissuespecific trophic effect on both normal and neoplastic tissue. Although the effect of TSH on thyroid function is well understood, its role in regulating thyroid growth is controversial. The suppression of TSH by thyroid hormone administration is used clinically to decrease the size of benign tumors and to prevent the development of new or recurrent tumors in patients after thyroidectomy for thyroid cancer of follicular origin.i-' A better understanding of signal transduction systems in benign and malignant thyroid tumors should provide us with new diagnostic and therapeutic opportunities.

Signal Transduction Systems It is well known that most eukaryotic cells have at least two signal transduction systems activated by extracellular signals such as hormones, neurotransmitters, and growth factors that bind selectively to specific receptors. All signals are transformed from cell surface receptors through intracellular systems into second messengers through protein phosphorylation. Protein phosphorylation by protein kinase in response to hormone or growth factors is responsible for regulation of cell function. Growth factor-induced protein phosphorylation is a key factor in the signal transduction leading to mitogenic responses. Once the receptor is activated, it leads to activation of at least two signal transduction systems linked through stimulatory guanyl-nucleotide proteins (G s ) to the AC-PKA signaling system and through a guanyl-nucleotide protein termed G; to the phospholipasePKC signaling systems. Activated second messengers initiate an increase in the levels of protooncogene products, which lead to cell proliferation.v? Protooncogenes are genes present in normal cells that code for proteins responsible for normal growth. Growth factors, growth factor receptors, and nuclear proteins are products of protooncogenes that participate in the signal transduction systems.t'? Cell proliferation is regulated by growth-stimulating protooncogenes and growth-inhibiting suppressor genes. Mutations in signal transduction systems, including structural alteration or overexpression, cause protooncogenes to become oncogenes, which results in unregulated cell growth. To date, six signal proteins, including ras and gsp, ret, trk, RET/PTC, and TSHreceptor (TSH-R) oncogenes, and one inhibitory protein, p53, have been identified in thyroid neoplasms." The ras, gsp, and TSH-R oncogenes are found primarily in "hot" (gsp and TSH-R) and "cold" (ras, gsp, and TSH-R) thyroid neoplasms, whereas RET/PTC and trk are more common in papillary thyroid carcinoma. The trk oncogene codes for nerve growth factor. The ras, gsp, and TSH-R are activated genes coding for signal transduction (see Chapter 30). The p53 protein is primarily found in anaplastic thyroid cancers and differentiated thyroid cancer cell lines,"

265

Signal Transduction in Thyroid Neoplasms - -

,- -~ 1

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Growth, differentiated thyroid function

FIGURE 29-1. Adenylate cyclase (AC) signal transduction system, phosphoinositide turnover system, and calcium-calmodulin (Ca/CaM) kinase system. A stimulating hormone (Hs) (e.g., thyroid-stimulating hormone [TSH] or vasoactive intestinal polypeptide), binds to its specific receptor (Rs) that interacts with G, and activates the cyclase enzyme (AC). An inhibitory hormone (Hi) (e.g., somatostatin) binds to its receptor (Ri), which interacts with G, and inhibits the AC. The AC converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA), which phosphorylates cytosolic proteins. cAMP is hydrolyzed by phosphodiesterase (POE) to 5'-AMP. A hormone such as TSH also binds to its specific receptor, which interacts with G, and activates the phospholipase C (PLC)-beta. PLC-gamma is activated by growth factors such as epidermal growth factor (EGF). Both PLC-beta and PLCgamma catalyze phosphatidylinositol-4,5-biphosphate (PIP z) to 1,2-diacylglycerol (DG) and inositol-I,4,5,-triphosphate (lP 3) . DG binds to and activates protein kinase C (PKC). PKC can also be activated directly by tumor-promoting phorbol ester, such as 12-0-tetradecanoyl-phorbol13-acetate (TPA), which is structurally similar to DG. PKC phosphorylates cytosolic proteins. One of the degradation products of DG is arachidonic acid (Ara), which is a precursor of prostaglandin. IP 3 mobilizes intracellular calcium (Ca'") stores and increases the intracellular calcium level. Calcium binds to calmodulin, and the Ca/CaM complex activates the Ca/CaM-dependent protein kinase (Ca/CaM kinase), which also phosphorylates cytosolic proteins. Outlined molecules (TSH receptor [TSH-R] and gsp) are two genes in signal transduction that are activated in thyroid tumors and have point mutations of their coding sequence. GOP = guanosine diphosphate; GTP = guanosine triphosphate; GTPase = guanosine triphosphatase.

increasing the coupling between different growth receptors and PLC. Both ras and gsp hydrolyze GTP and are linked to extracellular signaling of AC,27 An increased amount of stimulatory G protein and perhaps a decreased amount of G, are mechanisms for increased cAMP production in thyroid tumors." There was 3.3-fold more G, protein in the thyroid neoplasms than in normal thyroid tissue, with much greater cAMP production than in normal thyroid tissue. The reason for this is either that there is a normal amount of constitutively activated G, or there is an increased amount of an otherwise normal G s.28 Gsa is also highly expressed in growth hormonesecreting pituitary tumors, insulinomas, pheochromocytomas, corticotropin-producing islet cell tumors of the pancreas, and corticotropin-producing thymic carcinoids.i? Point mutations in the stimulatory G protein called gsp mutations cause the constitutive activation of the stimulatory G protein and increase cAMP production.v-" Thus, all tumors with gsp mutations have a higher basal AC activity and a smaller AC increase after TSH stimulation. Although the gsp oncogenes

have been found to be constitutively activated in follicular or papillary thyroid cancers." gsp mutations are more common in autonomous, or "hot," thyroid nodules.P'" TSH AND TSH-R

TSH acts by binding to specific TSH receptors with consequent stimulation of AC within the plasma membrane that converts ATP to cAMP (see Fig. 29-1). cAMP acts as a second messenger and activates PKA and other intracellular processes including P13K, p70S6k, and ras-related small G protein, Rap I, and modulates thyroid cell survival. 14,17,37-39 The TSH-R is a member of G protein-coupled receptors with a seven-transmembrane region." The gene for the TSH receptor is localized on the long arm of chromosome 14 (14q31).41 Ligands other than TSH such as human chorionic gonadotropin (hCG) and thyroid growth-stimulating antibodies also activate the TSH-R. TSH-Rs have also been found in parafollicular thyroid cells, which is surprising because medullary thyroid cancers that originate from parafollicular cells do not respond to TSH stimulation.f

268 - - Thyroid Gland

relationship between the ratio of TSH stimulated-to-basal AC activity and aggressiveness of thyroid neoplasms.!' Patients with a high TSH stimulated-to-basal AC activity ratio had either benign tumors or stage I (tumor confined to the thyroid) or stage II (regional nodal involvement) thyroid cancers, whereas stage III (tumors with local invasion into soft tissue and muscle) or IV (tumors with distant metastases) patients had a low TSH stimulated-to-basal AC activity ratio (Fig. 29-2). This demonstrates that the average cyclase responsiveness was approximately 18-fold for benign thyroid neoplasms and decreased by about half with each progressive stage to reach a low of a 1.6-fold increase for stages III and IV thyroid cancers (see Fig. 29-2).51 Despite this observation, there does not appear to be any relationship between AC responsiveness and thyroid cancer histologic degree of differentiation." Abnormalities in the TSH-R-AC system might be responsible for the aberrant growth of thyroid neoplasm of follicular origin. The decreased AC responsiveness in thyroid cancers with increasing stage may explain why TSH suppression therapy does not influence the growth pattern of some malignant thyroid tumors. Thus, other growth factors, oncogenes, or signal transduction systems rather than TSH-AC-PKA-cAMP must be involved in the growth of these thyroid tumors. Three adenylyl cyclases including AC-III, AC-VI, and AC-IX are mainly expressed in human and dog thyrocytes.V The different ACs are divided into four distinct subgroups. The first group, including ACs I, III, and VIII, is characterized by a stimulation by the calcium-calmodulin (CaCaM) complex. The second group, including ACs II, IV, and VII, is activated by G beta and gamma subunits and modulated by PKC. The third group, including ACs V and VI, is inhibited by low concentrations of calcium. The last, fourth, group is characterized by insensitivity to calcium. All ACs besides AC-IX are activated by forskolin. 52-54 Kosugi and colleagues demonstrated that a mutation of TSH-R (alanine 623) eliminates TSH-PLC signals but maintains TSH-AC signals.P

TSH increases tritiated thymidine incorporation into DNA as well as cell proliferation.tv" Cholera toxin, dibutyryl cAMP, and forskolin can mimic this TSH effect. Although human thyroid cells in primary culture appear to grow in response to TSH, this growth is not stimulated by dibutyryl CAMP.45 Increasing concentrations of TSH, dibutyryl cAMP, and forskolin failed to affect cell proliferation in some studies." Some thyroid nodules also grow in patients with suppressed TSH levels, documenting that signal transduction systems other than the TSH-AC-cAMPPKA system must also be involved in thyroid cell growth. In addition to PKA activation, another cAMP-dependent mechanism is involved in TSH action, especially cAMPEpac (exchange nucleotide protein directly activated by cAMP)-Rapl cascade in dog thyroid cells." Although TSH and forskolin activate Rapl in a PKA-independent pathway, activation of Rapl is not specific for TSH or CAMP.47 Epac is strongly expressed in the thyroid. However, it has been documented that the cAMP-Epac-Rapl signaling pathway in the thyroid gland does not play a major role in the cold thyroid follicular adenomas." TSH is mitogenic for most animal thyroid cells." Increased serum TSH levels enhance iodine uptake in most differentiated thyroid neoplasms of follicular cell origin. When thyroid hormone is discontinued in preparation for radionuclide scanning or for radioiodine treatment in patients with metastatic thyroid tumor, they sometimes grow or become symptomatic.'? High-affinity TSH-Rs have been reported in benign thyroid tumors and most differentiated thyroid cancers but not in undifferentiated thyroid tumors. 17,50 Thyroid neoplasms, in general, have higher TSHstimulated AC activity than normal thyroid tissue from the same patient.37 The AC activity increases in both normal and neoplastic thyroid tissue in response to TSH, and the consequent increase in cAMP production is probably a key factor responsible for the aberrant growth of some thyroid neoplasms. 12,17,37,51 Of interest, however, is the inverse

RATIO OF TSH STIMULATED TO BASAL CYCLASE ACTIVITY

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CarcinomaStage 2

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Carcinoma- Medullary Stage 3,4 Carcinoma n = 11

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FIGURE 29-2. The adenylate cyclase (AC) responsiveness to thyroidstimulating hormone (TSH) over basal adenylate cyclase activity is shown for each tissue type. Benign lesions show a marked AC response, and there is a progressive decline in AC responsiveness with increasing aggressiveness or stage of the neoplasms, Analysis of the variance shows a significant trend (P < ,02). Medullary carcinomas, which lack TSH receptors, as expected, show no response to TSH (TSH/basalcyclase = 1.05 ± 0.04), (From Siperstein AE, Zeng QH, Gum ET, et al. Adenylate cyclase activity as a predictor of thyroid tumor aggressiveness. World J Surg 1988;12:528.)

Signal Transduction in Thyroid Neoplasms - - 269 Although in one study there were no mutations in the intracytoplasmic TSH-R mutation." mutations in the TSH-R gene (aspartic acid at 619 to glycine and alanine at 623 to isoleucine) have been reported to be present in 3 of 11 thyroid hyperfunctioning follicular adenomas.57 These somatic mutations were found in the carboxyterminal portion of the third cytoplasmic loop of the TSH-R. Although they caused constitutive activation of AC with high basal cAMP levels, there were no appreciable changes in the basal accumulation of inositol phosphates, and the inositol response to TSH stimulation was maintained. TSH-R mutations leading to constitutive activation of the TSH-R would result in autonomous thyroid growth and function. These are the main molecular mechanisms leading to thyroid adenomas and some cases of multinodular goiter/" The constitutively activated TSH-R genes detected in thyroid carcinomas may have an oncogenic role, participating in their development through two pathways, including the cAMP signal transduction pathway and through Gsa and the Ras-dependent mitogen-activated protein kinase (MAPK) pathway through G~, y, and P13K.59TSH controls the subunits of PKA at the transcriptional level and at the translational or posttranslational level. 60 Activating mutations affecting important signal transduction pathway components such as TSH-R and Gsa occur in the majority of autonomously functioning thyroid nodules. However, PKA Go. mutations at the codons investigated do not represent an oncogenic mechanism in the development of thyroid neoplasms.P' TSH also stimulates phosphorylation of the transcription factor cyclic AMP response elements binding protein (CREB) via a cAMPresponsive DNA-binding protein.f Phosphorylated CREB regulates the expression of the oncoprotein C-fOS.63 Thyroid growth-promoting antibodies or thyroid growth immunoglobulins (TGIs), as well as thyroid-stimulating immunoglobulins (TSls), are monoclonal immunoglobulins (lgGs) present in patients with Graves' disease. These antibodies are able to promote the growth of thyroid cells and stimulate the AC-cAMP system by binding to the TSH-R and increasing cAMP.64,65 The TSI or TGI activity can be blocked by antibodies from patients with primary myxedema, Hashimoto's thyroiditis, and Graves' disease. These blocking antibodies also act by binding to TSH-R but do not stimulate cell growth or function. IgGs from patients with nontoxic goiter also have a slight stimulatory effect on thyroid cell growth, but the concentration of IgGs is considerably lower than that found in patients with Graves' disease/" It has been suggested by some that these IgGs may be responsible for recurrent goiter in patients receiving TSH suppression therapy. The glycoprotein hormones, such as TSH, hCG, and human luteinizing hormone (hLH) , have a common alpha subunit and a unique hormone-specific beta subunit. Some patients with molar pregnancy or choriocarcinoma experience goiter and hyperthyroidism as a result of hCG, and women during normal early pregnancy have elevated free thyroxine (T 4) and triiodothyronine (T3).67 hCG is another hormone acting via crossover binding to the TSH-R, increasing cAMP with subsequent increased iodide uptake and thymidine incorporation in rat FRTL-5 thyroid cells. 68 hLH also binds to TSH-R and stimulates cAMP.69 Luteinizing hormone increases iodide uptake and stimulates

thymidine incorporation similarly to hCG in Chinese hamster ovary (CHO) cells transfected with functional human TSH_R.69,70 hLH, however, is a more potent thyroid stimulator of the human TSH-R than hCG in vitro." OTHER RECEPTORS AND CYTOKINES VIP released from nerve endings is one of the important factors for local neuronal control of thyroid function and increases thyroid blood flow." VIP also causes the release of thyroid hormone from thyroid tissue or thyroid cells in culture.P?" VIP exerts its action through a separate VIP membrane receptor that is coupled, like TSH, to stimulatory G proteins and activates AC. 75 VIP stimulates AC activity in normal and neoplastic thyroid tissues in vitro but less than TSH. 75 Although both prostaglandin E 1 and prostaglandin E 2 stimulate AC activity in animal thyroid homogenates, the effect of prostaglandin on thyroid growth is controversial.V" Most benign thyroid tumors as well as differentiated thyroid cancers contain estrogen receptors in the cytosol and in membrane particulate fraction." Neoplastic thyroid tissue has more estrogen receptors than non-neoplastic thyroid tissue. There was, however, no correlation between the number of estrogen receptors and TSH-R in either normal or neoplastic thyroid tissue. The presence of steroid receptors for estrogen, androgen, progesterone, and glucocorticoids in thyroid tumors suggests that endogenous and exogenous steroids may have a direct or indirect effect on the development and growth of these tumors." Somatostatin, a 14-amino acid polypeptide, and its longacting analog octreotide block TSH secretion from the pituitary. Somatostatin acts through an independent cell surface receptor coupled to inhibitory guanylyl-nucleotide regulatory G, proteins (see Fig. 29-1). Activation of G, proteins inhibits AC activity. Octreotide has been used to treat TSHsecreting pituitary adenomas.s" Somatostatin also inhibits the thyroid cells. 81,82 Somatostatin inhibits basal and TSHstimulated AC activity in both normal and neoplastic human thyroid tissue. Somatostatin and tamoxifen also inhibit the growth of papillary and follicular cells in culture.f Although somatostatin inhibits both basal and TSH-stimulated activity in normal and neoplastic human thyroid tissue, studies with specific antibodies to the alpha subunit of G j suggest that G, has only a minimal effect on AC activity.f Tumor necrosis factor (TNF) is a cytokine produced by macrophages. TNF and interleukin (lL)-1 mediate inflammatory processes. TNF binds to its receptor, activates phospholipase A 2 mediated through G proteins, and releases arachidonic acid from phosphatidylinositol (PI).85 Although TNF did not affect either basal or TSH-stimulated cAMP generation, TNF did blunt TSH-stimulated thyroglobulin (Tg) secretion." FRTL-5 cells have TNF receptors and TSH increases the number of TNF receptors." TNF and IL-l administration in animals decreases circulating thyroid hormones and reduces iodide uptake and thyroid hormone response to TSH.88,89 TNF also decreases thyroid cell function such as radioactive iodine uptake and T 3 release as well as the growth of FRTL-5 rat thyroid cells."? IL-l suppressed c-myc protooncogene expression and inhibited the growth of a thyroid papillary cancer cell line.?' However, it failed to inhibit the growth of other thyroid cell lines.

270 - - Thyroid Gland

PI Turnover-Phospholipase-PKC System Binding of TSH or other agonist hormones, neurotransmitters, or circulating growth factors for specific receptors on the thyroid plasma membrane stimulates PI turnover, activates PKC, and increases intracellular calcium. The stimulated receptor interacts with a specific guanine-nucleotide regulatory protein (Gp) that activates the enzyme phospholipase (PLC). PI is a minor component of the cell membrane located in the inner leaflet of the membrane phospholipid bilayer. Three phosphoinositides-PI, phosphatidylinositol4-phosphate, and phosphatidylinositol-4,5-biphosphate (PIPz)-are in dynamic equilibrium in the plasma membrane. PLC converts PIP z into two second messengers: inositol-I-4,5-triphosphate (IP3) and 1,2-diacylglycerol(DAG) (see Fig. 29-1). IP3 increases intracellular calcium concentrations. DAG and calcium activate PKC and mediate cellular processes, including growth and differentiated thyroid function.9z,93 Activated PKC moves from the cytosol to the plasma membrane and phosphorylates both membrane-bound and cytosolic proteins. IP3 is converted into inositol-1,3,4, 5-tetrakisphosphate, which stimulates calcium entry from the cell exterior. Hydrolysis of inositol phospholipid by PLC may increase and prolong the activation of PKC for cell proliferation and differentiation." Activation of the PLC-PKC signal transduction system has stimulatory effects on the growth of certain tissues and an inhibitory effect in others. The human colon cancer cell line CaCo-2 has an increased PLC activity in response to I,25-dihydroxyvitamin D3.95 In other cell systems, increased PLC activity correlates with inhibition of growth." The TSH-R activates PLC through o, in thyroid cells.9z.93,97

The activity ofPLC was increased in ras-transformed NIH3T3 cells or NRK cells.98 Antibody to PIPz inhibited oncogeneinduced mitogenesis.'? Bombesin and bradykinin stimulate inositol phospholipid metabolism in H-ras-transformed cells more than in untransformed cells.l'" Normal forms of p21 Ha-ras increase PLC activity in response to platelet growth factor, whereas the mutated forms of p21 ras increase PLC activity without this growth factor.'?' TSH stimulation of PLC has been demonstrated in animal and human thyroid tissue slices. IOZ,103 The activation of this system is independent of the Ac. 81,103 When rat thyroid glands were exposed to the goitrogen methylthiouracil, the activity of PKC paralleled goiter growth.P' The activity of PKC decreased to less than half of the original level, and goiter regressed after treatment with T4 . Neoplastic thyroid membranes have greater PLC activity than that found in histologically normal thyroid membranes removed from the same patients.l'" PLC responsiveness to TSH in normal, hyperplastic, and neoplastic (papillary, follicular, Hiirthle cell) thyroid membranes have been studied in 56 patients. 106 Although the TSH-PLC-PKC system is intact and PLC activity increased in response to TSH in normal, benign, and stages I and II thyroid cancers, some invasive (stage III) or metastatic (stage IV) cancers failed to increase PLC activity in response to TSH.106 Thus, PLC increase in response to TSH ranged from 1.2-fold to 2-fold stimulation over basal activity in most tissues, whereas there was no significant difference between control and TSH-stimulated PLC activity in stage III or IV thyroid cancers (Fig. 29-3). PKC is also activated by the tumor-promoting phorbol ester TPA. TPA mimics the effects of DAG and activates PKC without phosphoinositide turnover (see Fig. 29-1).107 Both TPA and TSH

FIGURE 29-3. Phospholipase C (PLC) responsiveness to thyroid-stimulating hormone (TSH) in normal, hyperplastic, and neoplastic thyroid membranes. Control (basal) and TSH-stimulated PLC activity were assayed in 56 thyroid and 4 parathyroid adenoma specimens. Patients were stratified into histologic categories (normal thyroid, multinodular goiter, follicular adenoma, carcinoma, and parathyroid adenoma), and carcinomas were stratified further by clinical stage (DeGroot classes I and 2 and classes 3 and 4). All carcinomas were either papillary, follicular, or Hiirthle cell. The number of patients in each group is listed below each category. (From Shaver JK, Tezelman S, Siperstein AE, et al. TSH activates phospholipase C in normal and neoplastic thyroid. Surgery 1993;114:1064.)

Signal Transduction in Thyroid Neoplasms - -

increase growth of thyroid cancer cell line. TSH, however, stimulated invasion and growth in vitro by a PKC rather than by a PKA mechanism. 108 TUMOR-PROMOTING PHORBOL ESTERS

The phorbol ester TPA is a potent promoter of thyroid proliferation and increases PKC activity. 109-1 11 TPA induced DNA synthesis and proliferation of dog thyroid cells.I'? In dog thyroid cells, TPA enhanced the accumulation of c-myc messenger RNA (mRNA) after 3 and 6 hours. I13 TPA stimulated invasion and growth of follicular thyroid cancer cells in vitro.l'" A similar finding has been described in animal thyroid cells. I 14-116 TPA also stimulates tritiated thymidine incorporation and cell proliferation. I 14 Mezerein, telecidin, and aplasia toxin are PKC activators." Inhibitors of PKC are H7 (l-(5-isoquinoline sulfonyl-2-0methylglycerol), AMG-C 16 (I-O-hexadecyl-2-0-methylglycerol), 117 staurosporine, phospholipid-interacting drugs such as chlorpromazine, dibucine, and trifluoperazine. Exogenous PLC mimics the effects ofTPA on differentiated thyroid function in vitro.'!" The PKC inhibitor H7 reverses the effects of TPA and PLC.II? Staurosporine, a microbial alkaloid, acts at the ATP-binding site on protein kinase and is a potent inhibitor of PKC and other protein kinases.118.119 Staurosporine enhanced TSH-stimulated iodide organification.!'? In the presence of staurosporine, TPA did not inhibit TSH-stimulated iodide organification. 117 Staurosporine also inhibited growth and invasion of a follicular thyroid cancer cell line in a dose-dependent manner and abolished the effect of TSH.108

Calcium-Calmodulin-Dependent Protein Kinase System During phosphoinositide turnover, IP 3 increases intracellular calcium by mobilizing intracellular calcium stores from the endoplasmic reticulum. Calcium binds calmodulin. Increased Ca-CaM levels activate a Ca-CaM-dependent protein kinase, a third protein kinase, which results in phosphorylation of cytosolic proteins (see Fig. 29-1). Both increased PKC activity and increased intracellular calcium activate the fos and myc oncogenes in the cell nucleus. 120 Trifluoperazine inhibits the Ca-CaM-dependent protein kinase.!" Although epidemiologically increased calcium consumption enhances the incidence of goiter in areas of endemic goiter, it is unknown whether increased intracellular calcium is responsible for thyroid cell growth and differentiation." In calf thyroid tissue slices, TSH stimulates increased intracellular calcium levels, which increase iodine accumulation, glucose oxidation, hydrogen peroxide generation, and Tg transport as well as organification.l" Calcium ionophores increase intracellular calcium levels and thereby stimulate Tg and thyroid hormone secretion. Although clones for at least six different AC types have been isolated and expressed in animal cells, only types I and III AC are stimulated by calmodulin and calcium. 123

Growth Factor-Tyrosine Kinase System Thyroid growth is influenced by TSH and other hormones as well as many growth factors. The polypeptide growth factors, including EGF, IGF-I, and transforming growth factor

271

(TGF)-a. act via tyrosine kinase (Fig. 29_4).124 Growth factors bind to specific receptors on the thyrocyte.!" Phosphorylation of the receptor causes accumulation of signal transduction proteins, including PI -modulating enzyme, IP 3, kinase, PKC, serine-threonine kinase RAF, G'TPase-activating protein (GAP), MAP kinase kinase (MAPKK), MAPK, extracellular signal-regulated kinase (ERK)-l, and ERK_2.126-128 In general, growth factors activate their own receptors, leading to phosphorylation on specific tyrosine residues and creating specific binding sites for src homology and to various proteins. I15.129,130 The p21 ras then becomes activated, and MAPK is also stimulated on both threonine and tyrosine.P? The ras protein hydrolyzes the active bound GTP to GDP, the inactive form, and inorganic phosphate (see Fig. 29-4). Intracellular calcium can modulate the MAPK cascade via activation of the monomeric G protein p21 ras through calcium-dependent tyrosine kinase and calmodulin. 128 Activation of GTP hydrolysis is regulated by GAPS.l27,131 The GTP-bound ras transmits signals in thyroid cells. Activated ras, in tum, causes activation of raf-l, which then phosphorylates and activates the specific activators of MKK and MAPK (see Fig. 29_2).132,133 The activating phosphorylation of MAPK is an important process of both the phorbol ester-PKC system and the growth factor-tyrosine kinase system. This is, however, not involved in the mitogenic cAMP pathway. EGF binds to its EGF receptor (EGF-R), which has three domains, including extracellular receptor domain, transmembrane domain, and intracellular tyrosine dornain.F' Activation of tyrosine kinase phosphorylates cellular proteins and autophosphorylates itself. Tyrosinespecific protein kinase is associated with oncogene products of the retroviral src gene family. The intracellular domain of EGF-R is also activated by PKC. In A431 cells, EGF also activates the phosphoinositide turnover-PKC-calcium system with an increase in DAG and calcium influx. 134 IGF-I also stimulates cell proliferation and DNA synthesis in rat FRTL-5 thyroid cells." IGF-I is also involved in the growth of human thyroid cancer cells.45.135 TGF-a. is structurally related to EGF and binds to the EGF-R. TGF-a. is another potent mitogen of follicular cells.l'" Expression of TGF-a. at both mRNA and protein levels has been demonstrated in thyroid follicular cells, and TGF-a. has an autocrine function in normal thyroid follicular cells.!" TGF-~, in contrast, is a potent inhibitor of follicular cell proliferation. 138 TGF-~ stimulates endothelial secretion in thyroid tissues as well as endothelial synthesis and binding in thyroid follicular cells.P? TGF-~ binds its receptor and keeps the p105rb in an unphosphorylated stater'? by inhibiting kinase or stimulating phosphatase. 141 Genistein, an isoflavone, is a specific inhibitor of tyrosine kinase, including the EGF-R kinase, pp60-v-arc, and pp 11O-gag-fes.142 Genistein also inhibits the activity of serine- and threoninespecific kinases such as cAMP-dependent protein kinase, PKC, and phosphorylase kinase. 142 Genistein decreased the EGF-stimulated increase in tyrosine phosphorylation in A431 cells. 142 Genistein also arrests cell cycle progression at G TM.143 EPIDERMAL GROWTH FACTOR

EGF is a 53-amino acid polypeptide isolated from the male mouse submaxillary gland. EGF binds to a specific EGF-R

272 - - Thyroid Gland

Transcription factors: CREB, fos/jun, myc, srf, E2F

FIGURE 29-4. Growth factor-tyrosine kinase (Tyr K) system. Growth factor (e.g., epidermal growth factor [EGF], transforming growth factor [TGF]-alpha, insulin-like growth factor I, nerve growth factor) binds to its receptor, which has three domains: (1) an extracellular receptor domain (R); (2) a transmembrane domain (T); and (3) an intracellular tyrosine kinase domain (K). The binding of a growth factor to its receptor activates a Tyr K, which phosphorylates cellular protein and autophosphorylates. The intracellular domain is also phosphorylated by protein kinase C (PKC). PI3-K, PLC-gamma, and PKC are involved in the regulation of ras. Ras protein hydrolyzes the bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Activation of GTP hydrolysis is regulated by GTP-activating proteins (GAPs). Ras-GTP, active form, activates raf-I, PKC, mitogen-activated protein (MAP) kinase kinase (MAPKK), and MAP kinase (MAPK). Raf-l, PKC, and MAPK phosphorylate transcription factors.

situated primarily on the basolateral membrane of the thyroid

cells.l" The autophosphorylated EGF-R increases tyrosine kinase, which stimulates PI turnover. EGF-R is the product of the erb B protooncogene.lv The intracellular domain of EGF-R is also phosphorylated by PKC. EGF acts in a paracrine or autocrine manner to stimulate thyroid growth.v" Many organs, including the submaxillary gland, thyroid, pancreas, duodenum, jejunum, and kidneys, have high concentrations of EGE The thyroid gland contains 5 nglg of EGE147 EGF-Rs have been identified in animal thyroid tissues and in human normal and neoplastic thyroid tissues. 148,149 Both TSH-Rs and EGF-Rs have a basolateral distribution in thyroid cells. EGF stimulates DNA synthesis and cell proliferation in animal and human thyroid cells in culture and inhibits TSH-induced differentiation, 144,150,151 EGF stimulates the PLC-PKC-calcium system.P" EGF-Rs are present in most normal and neoplastic thyroid tissues, and neoplastic thyroid tissues have more EGF-Rs than do non-neoplastic human thyroid tissues.!" EGF binding is also higher in neoplastic than in normal thyroid tissue. Higher EGF binding occurs in tumors from patients with a

poorer prognosis. 149 There is a positive correlation between EGF binding and TSH binding and between EGF binding and TSH-stimulated Ac. 152 Thus, as suggested by Duh and Westermark and their colleagues, TSH increases EGF-Rs by increasing intracellular cAMP.152-154 Follicular tumors, including adenomas and carcinomas, have higher EGF binding and TSH binding than other thyroid tissues.r" EGF stimulates the expression of c-fos and c-myc oncogenes in porcine thyroid cells.l'" Differentiated thyroid formation is stimulated by TSH via cAMP, and it is inhibited by EGF and TPA,124,156 EGF is mitogenic in sheep thyroid cells in culture 157 but has no apparent mitogenic effect in cultured bovine or rat thyroid tissue. EGF, in contrast with TSH, not only stimulates thyroid growth but also enhances invasion of follicular and papillary thyroid cancers in vitro. 158 EGF also activates MAPK p42 mapk (ERK-2) and p44 mapk (i.e., ERK_l).132·135 MAPK mediates the activation of cytosolie enzymes and nuclear transcription factor.132 Activated MAPKs are important in mitogenic signaling. In dog thyroid epithelial cells, EGF and phorbol esters increase MAPK phosphorylation on tyrosine, threonine, and serine.130

Signal Transduction in Thyroid Neoplasms - - 273

Desensitization of Signal Transduction Continuous agonist stimulation of receptors usually leads to a decrease in receptor-mediated AC activity and cAMP levels. This process is termed desensitization. Desensitization, or a decreased response to the same or repetitive stimuli, is an important physiologic process and a well-described mechanism of receptor-signaling modulation that occurs in a variety of cell systems. There are two types of desensitization: homologous and heterologous. Homologous desensitization is agonist specific, whereas heterologous desensitization occurs when stimulation of another receptor or postreceptor stimulator leads to desensitization of the receptor. Defective desensitization could impair various steps in the signal transduction pathway, including receptor-G protein coupling, G protein activation by GTP, and G protein-effector interaction. 159 Receptor mutations could lead to enhanced or reduced desensitization. 160.161 The reduction in cAMP generation observed during desensitization could be due to either a less efficient coupling of receptor to G, or an enhanced efficiency of coupling of receptor to G j.159,162 Three independent mechanisms are responsible for desensitization: phosphorylation, sequestration, and downregulation. The first step in desensitization involves an agonist-induced phosphorylation of the receptor, resulting in the functional uncoupling of the receptors from the effectors downstream in the signaling system. Thus, receptor phosphorylation is a primary mechanism leading to desensitization162-165 involving at least two kinases: phosphorylation by cAMP-dependent PKA and phosphorylation by ~-adrenergic receptor kinase.166-168 PKA-mediated phosphorylation is cAMP dependent and plays a major role only in heterologous receptor kinase-mediated desensitization. 163 ~-Adrenergic phosphorylation is cAMP independent and is responsible for homologous desensitization.l''? Phosphorylation may promote binding of other proteins to the receptor. These proteins are termed arrestins because they arrest signal transduction, perhaps by blocking G protein-receptor coupling. 159,167 After exposure to an agonist, receptors are sequestered in the plasma membrane within a few minutes. Sequestration refers to rapid, agonist-induced translocation of ~-adrenergic receptor away from the plasma membrane to a distinct compartment deficient in G; Downregulation is a process biochemically distinct from sequestration and results in degradation of the receptor. Heterologous desensitization in lymphoma cells requires an increase in intracellular cAMP level.170 Prior exposure of human normal thyroid tissue to TSH either in vivo or in vitro causes desensitization of AC.I7I - 174 TSH-induced homologous desensitization has been described in human and animal normal thyroid cells.172-1 80 After the cloning of the human TSH_R,181-184 the stable expression of TSH-R in nonthyroidal cells such as CHO cells has been used in desensitization studies.l'" Although one study suggested that TSH stimulation failed to cause desensitization in CHO cells transfected with human TSH_R,185 a subsequent study did document that human TSH-R-transfected CHO cells do desensitize.l'" The latter investigation is important because it documents that no specific thyroid factors other

than increased levels of cAMP are required.l'" Primary differentiated thyroid cancers, in general, desensitize similar to normal thyroid cells, whereas some metastatic tumors do not (Fig. 29-5). Loss of the desensitization ability could be responsible for the growth of thyroid cancers in TSH-suppressed patients and perhaps for metastatic disease. Desensitization of TSH-Rs in neoplastic cells is caused by increased levels of cAMP. 186.187 TPA itself had no direct effect on cAMP levels in all thyroid cancer lines, but it did cause desensitization of the AC response to subsequent stimulation by TSH.187 The activation of PKC appears to be responsible for the heterologous desensitization because staurosporine, a potent PKC inhibitor, abolished or inhibited the effect ofTPA on desensitization. 187 Prolonged TPA treatment leads to PKC downregulation as a result of depletion

Incubation

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121 LNM 1 EJ LNM 2

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cAMP (pmol/well)

FIGURE 29-5. Homologous desensitization of cyclic adenosine monophosphate (cAMP) to thyroid-stimulating hormone (TSH) stimulation in neoplastic thyroid cells from six patients. Cells were cultured in 24 well plates for 3 days and for the last 24 hours in medium lacking TSH and fetal calf serum until 95% confluence. These cells were preincubated for 4 hours in either control medium without TSH (CON) or in medium supplemented with TSH (10 mU/mL) and washed three times with phosphate-buffered saline, pH 7.4. The cells were then incubated for 30 minutes in control medium and in medium supplemented with TSH (10 mU/mL) and I mM isobutylmethylxanthine. Intracellular cAMP was then measured by radioimmunoassay. Each bar represents the mean ± SD of 18 experiments. Neoplastic thyroid cells (white bar) showed desensitization after pretreatment with TSH for 4 hours, whereas two of three metastatic cell lines (type I, hatched bar) had an increased cAMP level in response to TSH stimulation, and both failed to desensitize. The third metastatic cell line both failed to increase cAMP level in response to TSH and failed to desensitize (type II). P < .002. (Data courtesy of Tezelman S, Shaver JK, Grossman RF, et al. Mechanism of homologous and heterologous desensitization in human neoplastic thyroid cells. Unpublished personal data, 1996.)

274 - - Thyroid Gland of phorbol ester-binding studies in many cell types.l" The effects of PKC downregulation on TSH-stimulated iodide organification have been demonstrated in porcine thyroid cells. 189 Like TPA, EGF had no direct effect on cAMP levels, but it did cause desensitization of cAMP production to subsequent TSH stimulation.'?" The EGF-induced desensitization of TSH-AC signal transduction system was abolished by coincubation with EGF-R antibody (EGF-R monoclonal antibody 528) and by genistein.l'" Desensitization apparatus, phosphodiesterase expression, and CREB may be activated in functioning thyroid adenomas.P"!"

Interaction (Cross-Talk) of the Different Signal Transduction Systems Cellular responses to external stimuli involve an integration of inputs from hormones, neurotransmitters, and growth factors. This integration is able to interact with distinct second messengers. The effect of one signal transduction system may alter the response of another, as already mentioned. This is called cross-talk. Although TSH stimulates both the AC system and the phosphoinositide turnover-calcium systems in animal cell cultures and human neoplastic membranes,43.106 the response patterns of protein phosphorylation to TSH and TPA are different and not reproduced by elevating cAMP by IBMX. 194 TSH and TPA had no additive effect on the proliferation of dog thyroid cells. 195.196 TPA, however, reduced the cAMP response to TSH when both agonists were incubated in dog and pig thyroid cells.197-199 TSH decreased cAMPdependent PKA activity in dog thyroid cells,2oo but the simultaneous presence of TPA and TSH, in contrast, inhibited TSH-induced downregulation of PKA 1.197 TPA had a biphasic effect on TSH-induced stimulation of cAMP production in pig thyrocytes.l'" TPA potentiated the effect of TSH when pig thyroid cells were exposed simultaneously to TSH and TPA for 10 minutes, but after 20 minutes TPA inhibited the cAMP response to TSH.198 TPA blocked the TSH effect and prevented cAMP-dependent PKA activity.!" Graves' disease IgG can increase PLC activity as well as cAMP production in rat FRTL-5 thyroid cells. PKC modulates different signal transduction systems, leading to positive or negative cross-talk with calmodulin kinase.P' Increased activation of calmodulin kinase by PKC results from PKCmediated phosphorylation of calmodulin-binding proteins.i" Studies demonstrated that when neoplastic thyroid cells are coincubated with TPA and TSH for 4 hours or longer, TPA decreased the cAMP response compared with that when cells are stimulated with TSH alone.I" This effect of TPA is abolished by coincubation with staurosporine.P? Although EGF does not change the level of cAMP directly, TSH increases cAMP levels, which then stimulates the production of EGF-Rs.I53·154 TSH induces proliferation and differentiation expression in dog thyroid cells, whereas EGF and TPA induce proliferation and dedifferentiation. When dog thyrocytes were simultaneously exposed to both TSH and EGF, the expression of protooncogenes, such as c-myc, was lower than with exposure to either EGF or TSH alone. 203 Pretreatment with TSH or forskolin increases the

response of pig thyroid cells to EGF, probably because of increasing numbers of EGF receptors.'>' TSH increases both thyroid cell growth and differentiation, whereas EGF increases only thyroid cell growth and inhibits cell differentiation. EGF also inhibits TSH-mediated thyroglobulin synthesis, morphologic differentiation, and iodide uptake, as well as organification. I44•204-206 In general the PKC- and PTK-mediated pathways are triggered by TPA and EGF.207 Increased concentrations of intracellular cAMP block activation of raf-; and MAPK in fibroblasts.l'" Thus, EGFdependent MAPK activation was blocked by forskolin or IBMX. PKA probably phosphorylates and inactivates MAPKs. Dibutyryl cAMP blocks DNA synthesis and also signal transmission from ras by inhibiting raj activation. 132 The incubation of EGF and TSH together induced a significant decrease in cAMP response to TSH compared with the cAMP response that resulted after stimulation with TSH alone. 190 Thus, EGF inhibits TSH-stimulated cAMP production. The inhibition of cAMP was abolished when neoplastic thyroid cells were incubated with TSH, EGF, and EGF-R-monoclonal antibody 528. 190 Natriuretic peptides (NPs) and their receptors (NP-R) have been identified in thyroid gland. 208 Although atrial natriuretic factor inhibits cAMP formation and thyroglobulin production in primary thyrocyte cultures through subsequent activation ofGi NAPs, binding to NP-R can activate AC.209

Summary The growth pattern of thyroid cells is complex and is under the control of various signal transduction systems, including the AC-cAMP-PKA system, the PLC-PKC-system, the Ca-CaM-kinase system, and the growth factor-tyrosine kinase system. Extracellular signals such as hormones, neurotransmitters, and growth factors bind to their specific receptors and stimulate intracellular transduction systems into second messengers. The TSH-AC signal transduction system has been well investigated in benign and malignant thyroid tumors. The TSH-PLC and EGF-tyrosine kinase system, as well as other signal systems, has also been studied. Derangements in the signal transduction systems cause abnormal growth and behavior of thyroid follicular cells. The interactions or cross-talk between signaling systems play an important role in the growth pattern of normal and abnormal thyrocytes. A better understanding of the various factors that influence the particular signal transduction system and of specific alterations in signaling that correlate with changes in behavior should lead to new therapies.

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186. 187.

188.

189. 190.

191. 192. 193. 194.

195.

196. 197.

198.

199.

200. 201.

202. 203.

204. 205.

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Oncogenes in Thyroid Tumors Peter E. Goretzki, MD • Victor Gorelev, MD • Dietmar Simon, MD • Hans-Dietrich Roeher, MD

The knowledge that a variety of environmental conditions, such as exposure to external radiation or chemicals, or chronic inflammatory processes and viral infections can induce neoplasms initiated studies seeking the explanation for these associations. Cells can be infected with RNA- or DNA-containing viruses, and the viral genome becomes inserted into the genetic code of the host cell.' As the cells divide, the viral DNA is transcribed and translated, producing a protein that may act as a growth factor, as a growth factor receptor, in signal transduction, or in the transcription of other genes. In the latter situation, it may interfere with apoptosis. Tumor development after viral infection occurs as a result of insertion and activation of viral oncogenes in host cells. 1 Subsequent investigation documented that eukaryotic cells harbor genes similar to viral oncogenes, which started the hunt for additional protooncogenes. Radiation and chemical toxins lead to tumor development and malignancy by causing multiple genetic changes that accumulate in affected cells (Fig. 30-1). These genetic changes may be single base pair changes (i.e, point mutations), insertions, deletions, rearrangements, and translocations. These genetic modifications affect encoded protein structure (i.e., mutations) or amplify certain genes (i.e., translocation), which then alter normal regulatory processes, turning protooncogenes into oncogenes.' Protooncogenes can be defined as genes involved in cell growth and cell differentiation that gain oncogenic potential and support tumor development and tumor propagation when amplified or structurally modulated. Thyroid tumors of follicular cell origin appear to develop by means of multiple genetic changes in cells rather than by activation of a single oncogene.v' Oncogene products can be divided into different protein families with specific cellular functions (e.g., growth factor, growth factor receptor, signal-transducing protein), and they may act on cell surfaces, within the cell cytoplasm, or within the nucleus-that is, inhibitors and activators of transcription (Fig. 30_2).2.5 Some variations of these general rules are related to the physiologic characteristics of specific tissues. Oncogenes can be deduced from their similarity to viral genes and from genes encoding proteins involved in the physiologic pathways of cell stimulation.P" Constitutive activation by specific mutations was demonstrated in vitro for the thyroid-specific growth factor receptor (i.e., thyrotropin or thyroid-stimulating

280

hormone [TSH] receptor) and the signal-transducing protein (gsp) connected to this receptor (i.e., alpha subunit of the Gs protein [Gs-a]). The field of oncogene research focuses on genetics and incorporates information from microbiology (e.g., viral infectious diseases), embryology, physiology (e.g., proteins important in growth and differentiation), epidemiology (e.g., prevalence of thyroid cancer in Russia before and after the Chernobyl catastrophe), toxicology, and radiology (e.g., effect of radiation on oncogene structure and expression). In this chapter, we review the roles of oncogenes in human thyroid tumors.

Oncogenes Connected to Thyroid-Stimulating Hormone Thyroid-Stimulating Hormone Receptor Mutations The idea that physiologic pathways may be constitutively activated by genetic alterations of single components of these pathways was compelling but hard to prove. For thyroid tumors, the TSH receptor (TSH-R) had to be cloned before studies of the structure and expression of this receptor could be performed. Cloning of the human TSH-R by Parmentier and colleagues in 1989 9 was an important breakthrough in this field. The knowledge that all G protein-related receptors develop from a common progenitor and demonstrate specific protein structures (i.e., an intracellular carboxyterminal end, an extracellular ligand-specific end, and a seven-transmembrane loop region) made it possible to use experiences from p-adrenergic receptor studies for TSH-R investigations. Liggett'? and Hausdorff"! and their colleagues used sitespecific deletions of the p-adrenergic receptor. They were able to modulate specifically hormone-stimulated cyclic adenosine monophosphate (cAMP) production of transfected cells with wild-type or deleted p-adrenergic receptors.F Because various groups had demonstrated the growthstimulating effect of TSH in human tumors and had demonstrated an enhanced cAMP response to TSH in differentiated thyroid tumors.P:" the question arose whether tumorspecific changes in the cAMP response were caused by TSH-R mutations. Several groups screened human thyroid

Oncogenes in Thyroid Tumors - - 281

FIGURE 30-1. Multistep mutation

theoryof thyroidtumordevelopment. Mutations A-M and N-W are mutations that lead to cell death or early apoptosis (i.e., programmed cell death). Mutation X provides growth advantage but no immortalization (i.e.,cooperative mutationsin benign tumor development). Y-Z mutations cooperate in tumor development, including mutations that interfere with apoptosis and may lead to immortalization and to uncontrolled malignant tumor growth.

UNCONTROLLED GROWTH

tumors for activating mutations in the TSH-R gene, and Parma" and Paschke'? and their coworkers found somatic mutations in the TSH-R gene from the DNA of autonomously functioning thyroid adenomas. Kopp and colleagues" demonstrated TSH-R mutations in a patient with congenital hyperthyroidism and an autonomously functioning goiter; the mutated genes increased basal cAMP production when transfected into COS cells. Nonhyperfunctioning thyroid adenomas and differentiated thyroid cancer, however, lacked the stimulating mutations of the TSH-R gene, as demonstrated by Matsuo and associates.'? Activating TSH-R mutations are restricted to some benign thyroid tumors with functional hyperactivity.

FIGURE 30-2. Oncogenes in human thyroid tumors.

Oncogeneproducts may be divided into receptor proteins, proteins for transducingsystems, and nuclear transcription factors or inhibitors of transcription. Known protooncogenes for thyroid tumors activated by mutation, translocation,or amplificationare the gene for the thyroidstimulating, hormone receptor (leading to benign hyperfunctioning adenomas); genes for receptors with tyrosine kinase activity, such as egf-r, trk, ret, and neu (demonstrated in differentiated thyroid cancer [DTC] and medullary thyroid cancer [MTC]; the PDGF-r gene (demonstratedin anaplastic thyroid cancer); and genes for proteins in transducing systems with guanosine triphosphatase activity, such as ras and gsp (demonstrated in benign and malignant thyroid tumors). Intranuclear protooncogenes,such as c-myc, c-fos, and c-jun, are amplified by external stimulation, but their primary importance in the development and propagationof human thyroid tumors has not been proved.

G Protein Mutations Activating mutations of the alpha subunit of the G protein that enhances cellular cAMP were first demonstrated in growth hormone-secreting pituitary tumors by Vallar and coworkers in 1987.20 Further investigations by Landis" and Masters" and their colleagues biochemically identified and characterized the effect of these stimulating mutations that inhibit G protein-specific guanosine triphosphatase (GTPase) activity. The mutated stimulating G protein (Gs) has a much lower GTPase activity than wild-type Gs. The reduced susceptibility of GTP to hydrolysis may increase the period of Gs in the GTP-bound state. Because Gs-GTP

FUNCTION

ONCOGENE

TUMOR TYPE

RECEPTOR

tsh-r egf-r; trk ret; neu pdgf-r

BENIGN DTC;MTC

TRANSDUCING SYSTEM

ras; gsp

BENIGN & DTC.MTC

NUCLEAR FACTOR

myc; fos; jun second. effects

UNDIF.CA

282 - - Thyroid Gland 1)

PRIMER

c201

I

236bp

BstZ1

2)

PRIMER

BstZ1

190bp 220bp

•

rt 201 rnut201

DNA AMPLIFICATION BY PCR

DIGESTION BY BstZ1

3)

PRIMER

106 bp PRIMER

AMPLIFICATION OF MUTANT DNA mut201 wt201 ssDNA

wt201/mut201 nondigested 1.PCR product

FIGURE 30-3. Detection of gsp mutations at codon 201 by two-step restriction fragment length polymorphism-dependent polymerase chain reaction (PCR). In the first step, PCR primers are used to amplify a part of the gsp gene, including codon 201, with a tota11ength of 236 base pairs (bp). This product demonstrates two restriction sites for the enzyme BstZ1, with one inside codon 201 at the 5' end and one at the 3' end. In the second step, digesting the product with BstZl causes a new product of 190 bp in the case of wild-type (wt) gsp at codon 201 and a product of 220 bp in the case of mutated (mut) gsp at codon 201. However, parts of undigested wild-type gsp genes may still be present, even in optimal reaction conditions. In the third step, a second PCR with the first 5' end primer and an inner 3' end primer amplifies only mutant gsp and uncut wild-type gsp, yielding a product of 106 bp. A second digestion with BstZl does not change the 106-bp product in the case of the mutant gsp at codon 20 I, but it gives rise to an additional 60-bp product in the case of noncut wild-type gsp.

represents the biologically active protein, some Gs mutations enhance the amount of biologically active Gs protein. In 1990, Lyons and coauthors-' demonstrated an activating Gs protein mutation (i.e., mutation of the gsp gene) in an autonomously functioning multinodular goiter, a finding that was confirmed by Suarez and colleagues.s' Sullivan and associates.P and our group.! Unlike pituitary tumors, multinodular goiter and various benign and malignant thyroid tumors are polyclonalv-" and demonstrate a low level of gsp.8 Specific techniques were applied to isolate and amplify gsp mutations in thyroid tumors: mutation-specific oligonucleotide hybridization of asymmetric polymerase chain reaction products" and two-step restriction fragment length polymorphism methods (Figs. 30-3 and 30_4).29 By correlating these results with subcloning techniques, we demonstrated gsp mutations in 35% of all 86 investigated differentiated thyroid cancers and C-cell carcinomas of the thyroid (Table 30-1). The proportion of cells bearing gsp varies between 3% and 43%.30 When sensitive molecular biologic technique's are applied, gsp mutations can frequently be detected in differentiated thyroid tumors of patients from low-iodine areas. Whether these results are different in tumors from patients with sufficient iodine supplementation, as hypothesized by us in 1992,8 awaits further investigation. We demonstrated enhanced expression of Gs-a when the gene is mutated (Table 30_2).30 This contrasts with the effect of chronic external Gs stimulation. For example, cholera toxin causes tachyphylaxis, and Gs-a expression decreases with time." Activating mutations of the TSH-R and Gs-a enhance basal cAMP production directly and enhance it indirectly by the lack of downregulation and overexpression of mutated gsp-encoded protein.

Low abundant mutation detectable (Lane 9 and 11)

FIGURE 30-4. Two-step restnction fragment length polymorphism method. Seven thyroid tumor tissues were tested by electrophoresis before and after the second digestion of the polymerase chain reaction (PCR)-amplified gsp gene, including codon 201. Lane 7 shows the DNA ladder for checking the length of PCR products. Lanes I, 3, 5, 8, 10, 12, and 14 demonstrate undigested second PCR products of gsp with lengths of about 220 bp (upper arrow). Lanes 2, 4, 6, 9, 11, 13, and 15 demonstrate DNA after the second BstZI digestion, with partial digestion at lanes 2, 4, 6, 13, and 15 but no digestion of the DNA product at lanes 9 and 11 (lower arrow). These two tissues (8/9 and 10111) harbor mutant gsp at codon 201, but tissues 1/2,3/4,5/6, 12/13, and 14/15 do not. The sensitivity of detecting gsp mutations at codon 201 was less than 3% (controlled by subcloning).

Oncogenes in Thyroid Tumors - - 283

Stimulating mutations of Gs-a, demonstrable in benign (especially autonomous nodules) and malignant differentiated thyroid tumors, are important somatic mutations in the development and propagation of thyroid tumors. The mutations increase cAMP production and Gs-a expression, which stimulates cellular growth.

ras Family Oncogenes Activating point mutations in three human ras genes (i.e., Harvey ras [H-ras] on chromosome 11, Kirsten ras [K-ras] on chromosome 12, and N-ras on chromosome 1) have been demonstrated in numerous tumors, including thyroid tumors.Approximately 40% to 50% of colon cancers, more than 80% of pancreatic cancers and cholangiocarcinomas, and 30% to 40% of lung cancers harbor specific ras mutations.P'" Ras encodes a small protein, p21, of 21,000 D that has no intrinsic GTPase activity. p21 forms a complex with a GTPase-activating protein, GAP, that enhances the GTPase activity of p21 more than 4000 times. This GAPinduced GTP hydrolysis is reduced by a factor of 1000 by mutant ras-encoded proteins when the mutations occur at codon 12, 13, or 61. Although ras mutations in colon, pancreatic, and other cancers are mainly restricted to one or two different ras genes, some researchers dealing with thyroid tumors have found all three ras genes (on three different chromosomes) mutated at different sites (Table 30_3).8.35-40 Although some

groups mainly found H-ras mutations, others predominantly demonstrated N-ras mutations (see Table 30-3). Some of these differences may be explained by variations in methodology, with possible errors generated when only hybridization techniques were applied. Hybridization techniques can yield false-positive and false-negative results, as demonstrated by Chen and Viola.41 Even in cases of comparable technical procedures, results vary significantly between groups. The prevalence of ras mutations in thyroid tumors therefore remains questionable. Most studies have shown that the prevalence of ras mutations was not significantly different in benign and malignant thyroid tumors, nor was it different in tissues from patients living in low- or highiodine areas (Table 30_4).8.30 Exposure to low-dose therapeutic radiation seems to increase the K-ras mutations in histologically normal thyroid tissues and in tissues from thyroid tumors. Fogelfeld and colleagues'? demonstrated an increase in K-ras mutations in thyroid tumor tissue from 0% (0 of 18 patients) to 62% (8 of 13 patients) after radiation therapy. Confirmation of this interesting finding is pending. Nevertheless, some of the differences in the prevalence of ras mutations in thyroid tumors may be caused by regional differences in environmental conditions.>' similar to aflatoxin-induced hepatocellular carcinomas occurring in Asia but not in Europe.

Oncogenes Acting as Growth Hormone Receptors with Tyrosine Kinase Activity Thyrocyte-activating growth factors not related to the cAMP system, such as epidermal growth factor (EGF) and hepatocyte growth factor (HGF), act by stimulating membrane receptors with tyrosine kinase activity." These receptors by themselves may acquire oncogenic potential through truncation of regulatory elements, producing secondary overactivity,44 or by protein overexpression after gene translocation and rearrangement with other promoter regions. The latter mechanism has been demonstrated for ret (ligand still unknown) and trk products (i.e., nerve growth factor receptor) in human papillary thyroid cancer.45,46 Point mutations of the kinase domain of ret also change this protooncogene to an effective oncogene, causing C-cell carcinomas and

284 - - Thyroid Gland

pheochromocytomas in multiple endocrine neoplasia type 2A (MEN 2A), MEN 2B, and medullary thyroid carcinoma (MTC).47

Epidermal Growth Factor Receptor and Neu/HER2/Erb-B2 and coMet EGF has been demonstrated to be one of the most efficient growth factors for thyrocytes in vitro and in vivo in numerous experiments.w'" EGF-receptor (EGF-R) overexpression, compared with that in normal tissue from the same patients, has been found in membrane fractions from thyroid tumors.V-? No mutation-induced activation of EGF-R has been demonstrated in thyroid tumors, questioning the role of EGF-R in thyroid tumor development and propagation. Further studies were initiated when an EGF-R-related truncated receptor, Neu/HER2/Erb-B2, was discovered in breast cancer patients and predicted early hematogenous spread of tumor and a bad prognosis.P>' Few studies of neuencoded protein expression in human thyroid cancers exist, and their results are controversial. Haugen and coworkers'" found increased messenger RNA (mRNA) and overexpression of neu-encoded protein in 12 of 17 (71%) papillary

thyroid cancers but not in follicular adenomas (0 of 5) or in follicular carcinomas (0 of 5). Simon and associates'? demonstrated overexpression of neu-encoded protein in only 5 of 23 (22%) papillary tumors but in 6 of 17 (35%) follicular thyroid cancers. Studies of Lemoine" and Auguste'" and their colleagues failed to demonstrate amplified mRNA or overexpressed neu-encoded protein in 20 follicular thyroid cancers and 21 thyroid adenomas (Table 30-5). The EGF-R-related oncogene neu/HER2/erb-B2 is therefore of questionable importance in differentiated thyroid cancers. Additional interest was generated by studies of the hepatocyte growth factor receptor (HGF-R), which is expressed in liver tissue and in various other human tissues, including the thyroid. The high levels of c-met mRNA in thyroid tissues contrasts with low or undetectable HGF-R protein expression. 59 The reason for this inhibited translation in normal thyroid tissue is unknown. In papillary thyroid carcinomas, HGF-R protein is expressed 100-fold more than in normal thyroid tissue, making this protein and its c-met gene a good candidate in the search for thyroid oncogenes.Pv" Further studies with more tumor samples and using thyrocyte transfection assays are needed to prove this hypothesis.

Oncogenes in Thyroid Tumors - - 285

ret and trk Oncogenes Transfection experiments by Donghi'" and Grieco" and their colleagues in 1989 and 1990 demonstrated a papillary thyroid carcinoma-specific oncogene (pte) that transformed fibroblasts (NIH 3T3 cells) into colony-forming cells. The gene was cloned and identified as the ret protooncogene by Takahashi and Cooper in 1985. 62 The gene was translocated and rearranged on the same chromosome 10 to an unknown 5' sequence.P The expression of the trk protooncogene, which codes for the receptor for nerve growth factor, was detected in a few thyroid carcinomas, but little other information is available. About 30% of papillary thyroid carcinomas from patients in Italy have a ret rearrangement, but no other thyroid tumors from Italian patients and no nonthyroid tumors had ret rearrangements.s'r'" Further studies of thyroid tissues from the United States and Asia confirmed the almost complete specificity of pte (i.e., ret rearrangement) to papillary thyroid carcinomas, although with a prevalence of only 5% to 17% and 0% to 3%, respectively (Table 30_6).67-69 Nevertheless, the ret oncogene has oncogenetic potential proved by transfection assay and has tissue specificity to papillary thyroid cancer. Whether the ret oncogene initiates the primary step from normal thyrocyte to papillary thyroid carcinoma or from highly differentiated papillary thyroid carcinoma to a less differentiated tumor state is unknown. The pte oncogene gained general interest when it was mapped to the same region on chromosome 1Oq11-12 as the MEN 2A gene. Studies of the tyrosine kinase domain of the ret protooncogene by Mulligan and coworkersf'-" revealed that specific germline mutations of ret led to MEN 2A, MEN 2B, and familial MTC. Further investigations demonstrated somatic mutations of ret in sporadic MTC as well, but these and the mutations in patients with MEN 2B were located at sites of ret different from those of the mutations identified in MEN 2A patients." In 1994, Lips and associates.F using the same molecular genetic techniques, documented that patients who have a ret protooncogene mutation develop MTC and that ret-negative patients are not at risk. Documentation of the presence or absence of ret oncogenes is a more accurate method than using stimulated calcitonin determinations for detecting this disorder. It is the first molecular genetic test in thyroidology with direct clinical importance (i.e., early thyroidectomy), and it should save lives and money.

Intranuclear Oncogenes Nuclear protooncogenes involved in thyroid growth are c-myc, c-jun, and c-fos. They were characterized by their similarity to viral oncogenes. Unlike most oncogenes encoding cell surface receptors or signal-transducing proteins, nuclear protooncogenes function by means of gene amplification. Because external stimulation of cells by growth factors activates cellular receptors, signal-transducing proteins, second messengers, and nuclear protooncogenes by means of increased gene expression, it is difficult to determine whether alterations in nuclear protooncogenes are primary or secondary cellular phenomena. For example, it is difficult to know whether increased staining for c-mye in thyroid adenomas and thyroid carcinomas, as demonstrated by Auguste and associates." is a primary or secondary phenomenon. In general, c-mye and c-fos protooncogenes are expressed after stimulation of the thyroid by TSH and cAMP, which increase thyroid growth and differentiation. EGF and TPA cause thyroid growth and dedifferentiation mainly by enhancing c-jun protooncogene expression. C-fos and c-jun expression can inhibit the thyroid hormone receptor. The thyroid hormone receptor, however, may inhibit the induction of C-fOS 73,74 and thus play the role of an antagonist to cell-specific protooncogenes. Understanding this direct regulatory loop of tissue-specific and growth-inhibiting intranuclear hormone receptors with intranuclear protooncogenes may increase our knowledge of thyroid growth and tumor development in low-iodine areas. In 1991, Heldin and Westermark" demonstrated the loss of a specific tumor suppressor gene, which coded for a nuclear thyroid-specific transcription factor (TIFI), in anaplastic thyroid carcinomas.

Summary Molecular biologic studies have gathered substantial information about the pathogenesis of thyroid neoplasia. Activ~ting mutations of the TSH-R and the signal-transducing protem encoded by gsp have been identified in thyroid neoplasms. These activating mutations enhance cellular cAMP production, which stimulates thyrocyte growth. TSH-R-activating mutations result in the development of autonomously functioning thyroid adenomas, and activating

286 - - Thyroid Gland

gsp mutations are found in benign and malignant thyroid tumors. Activating mutations of other GTP-binding proteins, such as the ras oncogene product p2I, have also been detected in benign and malignant thyroid tumors. The prevalence and the distribution of H-ras, N-ras, and K-ras mutations vary considerably among studies. Different results have also been obtained for growth factor receptors with tyrosine kinase activity, such as EGF-R, neu (also called erb-B2 or HER2) proteins, and HGF-R, which were found to be overexpressed in some malignant thyroid tumors, but all lacked any mutations or deletions that might have predicted the altered receptors could result in thyroid neoplasia. ret rearrangements contribute to the development of papillary thyroid cancer, and point mutations in ret cause the MEN 2A and MEN 2B syndromes and familial form of MTC. Genetic testing is a simple and effective method for detecting affected family members. Whether the interaction of the nuclear thyroid hormone receptor and nuclear protooncogenes can explain goiter development and thyroid tumors in iodinedeficient areas awaits further investigation. This exciting research should lead to important advances in our understanding and treatment of patients with thyroid neoplasia. Recently B type Raf kinase (BRAF) activating mutations have been identified in papillary thyroid cancers. Raf kinase is a key component of the Ras-+Raf--+MEK--+MAP/ERK signaling pathway involved in cell growth and tumorigenesis. BRAF is the strongest activator of this signaling system and is located on chromosome 7. The most frequent BRAF mutation is a Tl796A transversion point mutation in exon 15 which causes a V599E aminoacid missense mutation resulting in activation of BRAF kinase. 76 •77 BRAF mutations occur in approximately 35 to 70% of papillary thyroid cancers. It is not found in follicular thyroid cancer, Hurthle cell cancer, or benign thyroid adenomas, and occurs in about 20% of anaplastic thyroid cancers.Y'? There does not appear to be any overlap between BRAF, RETIPTC and ras mutations in papillary thyroid cancers.

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12. Hausdorff WP, Hnatowich M, O'Dowd BF, et al. A mutation of the ~2-adrenergic receptor impairs agonist activation of adenylyl cyclase without affecting high affinity agonist binding. J Bioi Chern 1990;265:1388. 13. Goretzki PE, Frilling A, Simon D, et al. Growth regulation of normal thyroids and thyroid tumors in man. Recent Results Cancer Res 1990;118:48. 14. Ledent C, Parmentier M, Maenhaut C, et al. The TSH cyclic AMP cascade in the control of thyroid cell proliferation: The story of a concept. Thyroidology 1991;3:97. 15. Clark OH, Gerend PL, Davis M, et al. Characterization of the thyrotropin receptor-adenylate cyclase system in neoplastic human thyroid tissue. J Clin Endocrinol Metab 1983;57:140. 16. Parma J, Duprez L, VanSande J, et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 1993;365:649. 17. Paschke R, Tonacchera M, VanSande J, et al. Identification and functional characterization of two new somatic mutations causing constitutive activation of the thyrotropin receptor in hyperfunctioning autonomous adenomas of the thyroid. J Clin Endocrinol Metab 1994; 79:1785. 18. Kopp P,VanSande J, Parma J, et al. Congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med 1995;332:150. 19. Matsuo K, Friedman E, Gejman PV, et al. The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: Structural studies of the TSH-R and the alpha-subunit of Gs in human thyroid neoplasms. J Clin Endocrinol Metab 1993;76:1446. 20. Vallar L, Spada A, Giannattasio G. Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature 1987; 330:566. 21. Landis CA, Masters SB, Spada A, et al. GTPase inhibiting mutations activate alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 1989;340:692. 22. Masters SB, Miller RT, Chi MH, et al. Mutations in the GTP-binding site of Gs alter stimulation of adenylyl cyclase. J Bioi Chem 1989;264:15467. 23. Lyons J, Landis CA, Harsh G, et al. Two G-protein oncogenes in human endocrine tumors. Science 1990;249:655. 24. Suarez HG, DuVillard JA, Caillou B, et al. Gsp mutations in human thyroid tumours. Oncogene 1991;6:677. 25. O'Sullivan C, Barton CM, Staddon SL, et al. Activating point mutations of the gsp oncogene in human thyroid adenomas. Mol Carcinog 1991;4:345. 26. Herman V, Fagin J, Gonsky R, et al. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 1990;71:1427. 27. Namba H, Matsuo K, Fagin J. Clonal composition of benign and malignant thyroid tumors. J Clin Invest 1990;86:218. 28. Gorelov VN, Roher HD, Goretzki PE. A method to increase the sensitivity of mutation specific oligonucleotide hybridization using asymmetric polymerase-chain reaction (PCR). Biochem Biophys Res Commun 1994;200:365. 29. Goretzki PE, Gorelov V, WeiAmann K, et al. Mutation and expression of alpha Gs in differentiated thyroid carcinoma (DTC) and medullary thyroid carcinoma (MTC). Exp Clin Endocrinol 1993;101:54. 30. Gorelov VN, Gyenes M, Neser F, et al. Distribution of Gs-alpha activating mutations in human thyroid tumors measured by subcloning. J Cancer Res Clin Oncol 1996;122:453. 31. Milligan G, Unson CG, Wakelam JO. Cholera toxin treatment produces down-regulation of the alpha-subunit of the stimulatory guanine-nucleotide-binding protein (Gs). Biochem J 1989;262:643. 32. Bos JL, Fearon ER, Hamilton SR, et al. Prevalence of ras gene mutations in human colorectal cancer. Nature 1987;327:293. 33. Bos JL. Ras oncogenes in human cancer: A review. Cancer Res 1989; 49:4682. 34. Anderson MW, Reynolds SH, You M, et al. Role of proto-oncogene activation in carcinogenesis. Environ Health Perspect 1992;98:13. 35. Lemoine NR, Mayall ES, Wyllie FS, et al. High expression of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene 1989;4:159. 36. Suarez HG, DuVillard JA, Caillou B, et al. Detection of activated ras oncogenes in human thyroid carcinomas. Oncogene 1988;2:403. 37. Wright PA, Lemoine NR, Mayall ES. Papillary and follicular thyroid carcinomas show a different pattern of ras oncogene mutation. Br J Cancer 1989;6:576.

Oncogenes in Thyroid Tumors - - 287 38. Namba H, Gutman RA, Matsuo K, et aI. H-ras protooncogene mutations in human thyroid neoplasms. J Clin Endocrinol Metab 1990; 71:223. 39. Schark C, Fulton N, Jacoby R, et al. N-ras 61 oncogene mutations in Hiirthle cell tumors. Surgery 1990;108:994. 40. Karga H, Lee JK, Vickery AL, et al. Ras oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab 1991; 73:832. 41. Chen J, Viola MV. A method to detect ras point mutations in small subpopulations of cells. Anal Biochem 1991;195:51. 42. Fogelfeld L, Merchant PS, Zitman R, et al. Prevalence of K-ras point mutations in radiation-induced thyroid cancer [Abstract 66). American Thyroid Association Meeting, Tampa, Florida, 1993. 43. Ullrich A, Schlesinger S1. Tyrosine-kinase receptors. Cell 1990; 61:203. 44. King CR, Borrello I, Bellot F, et al. EGF binding to its receptor triggers a rapid tyrosine phosphorylation of the erbB-2 protein in the mammary tumor cell line SK-BR-3. EMBO J 1988;7:1647. 45. Bongarzone I, Pierotti MA, Monzini N, et aI. High frequency of activation of tyrosine oncogenes in human papillary thyroid carcinoma. Oncogene 1989;4:1457. 46. Grieco M, Santoro M, Berlingieri MT, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 1990;60:557. 47. Mulligan LM, Kwok JBJ, Healey CS, et al. Germ-line mutations of the ret proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993;363:458. 48. Westermark K, Karlsson FA, Westermark B. Epidermal growth factor modulates thyroid growth and function in culture. Endocrinology 1983;112:71. 49. Tseng YCL, Burman KD, Schaudies RP, et al. Effects of epidermal growth factor on thyroglobulin and adenosine 3',5'-monophosphate production by cultured human thyrocytes. J Clin Endocrinol Metab 1989;71:771. 50. Hoelting T, Siperstein AE, Clark OH, et al. Epidermal growth factor enhances proliferation, migration, and invasion of follicular and papillary thyroid cancer in vitro and in vivo. J Clin Endocrinol Metab 1994;79:401. 51. Duh QY, Gum ET, Gerend PL, et al. Epidermal growth factor receptors in normal and neoplastic thyroid tissue. Surgery 1985;98:1000. 52. Masuda H, Sugenoya A, Kobayashi S, et al. Epidermal growth factor receptor on human thyroid neoplasm. World J Surg 1988;12:616. 53. DePotter CR, Beghin C, Makar AP, et aI. The neu-oncogene protein as a predictive factor for haematogenous metastases in breast cancer patients. Int J Cancer 1990;45:55. 54. Kury F, Sliutz G, Schemper H, et al. Her-2 oncogene amplification and overall survival of breast carcinoma patients. Eur J Cancer 1990;26:946. 55. Haugen DRF, Akslen LA, Varhaug lE, et al. Expression of c-erbB-2 protein in papillary thyroid carcinoma. Br J Cancer 1992;65:832. 56. Simon D, Goretzki PE, Roher HD. The significance of c-neu and p53 in endocrine tumors. Langenbecks Arch Chir Suppl 1993;2:69. 57. Lemoine NR, Wyllie FS, Lillehaug JR, et al. Absence of abnormalities of the c-erbB-I and c-erbB-2 proto-oncogenes in human thyroid neoplasia. Eur J Cancer 1990;26:777. 58. Auguste LJ, Masood S, Westerband A, et al. Oncogene expression in follicular neoplasms of the thyroid. Am J Surg 1992;164:592.

59. DiRenzo MF, Narsimhan RP, Olivero M, et al. Expression of the metlHGF receptor in normal and neoplastic human tissues. Oncogene 1991;6:1997. 60. Prat M, Narsimhan RP, Crepaldi T, et al. The receptor encoded by the human cometoncogene is expressed in hepatocytes, epithelial cells and solid tumors. Int J Cancer 1991;49:323. 61. Donghi R, Sozzi G, Pierotti MA, et aI. The oncogene associated with human papillary thyroid carcinoma (PTC) is assigned to chromosome IOqI I -q 12 in the same region as multiple endocrine neoplasia type 2A (MEN 2A). Oncogene 1989;4:321. 62. Takahashi M, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 1985;42:581. 63. Fabien N, Paulin C, Santoro M, et al. Detection of ret oncogene activation in human papillary thyroid carcinomas by in situ hybridisation. Br J Cancer 1992;66:1094. 64. Santoro M, Carlomagno F, Hay ill, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer study type. J Clin Invest 1992;89:1517. 65. Santoro M, Sabino N, Ishizaka Y, et al. Involvement of RET oncogene in human tumours: Specificity of RET activation to thyroid tumours. Br J Cancer 1993;68:460. 66. Jhiang SM, Caruso DR, Gilmore E, et al. Detection of PTe oncogene in human thyroid cancers. Oncogene 1991;7:1331. 67. Namba H, Yamashita S, Pei HC, et al. Lack of PTC gene (ret protooncogene rearrangement) in human thyroid tumors. Endocrinol Jpn 1991;38:627. 68. Waijwalku W, Nakamura S, Hasegawa Y, et al. Low frequency of rearrangements in the ret and trk proto-oncogenes in Japanese thyroid papillary carcinomas. Jpn J Cancer Res 1992;83:671. 69. Zou M, Shi Y, Farid NR. Low rate of ret proto-oncogene activation (PTC/ret-TPC) in papillary thyroid carcinomas from Saudi Arabia. Cancer 1994;73: 176. 70. Mulligan LM, Eng C, Healy CS, et al. Specific mutations of the ret proto-oncogenes are related to disease phenotype in MEN2A and FMTC. Nat Genet 1994;6:70. 71. Zedenius J, Wallin G, Hamberger B, et al. Somatic and MEN2A de novo mutations identified in the ret proto-oncogene by screening of sporadic MTCs. Hum Mol Genet 1994;3:1259. 72. Lips CJM, Landsvater RM, Hoeppener JWM, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994;331:828. 73. Rascle A, Ghysdael J, Samarut 1. c-Erb, but not v-ErhA, competes with a putative erythroid repressor for binding to the carbonic anhydrase II promoter. Oncogene 1994;9:2853. 74. Zhang XK, Wills KN, Husmann M, et al. Novel pathway for thyroid hormone receptor action through interaction withjun andfos oncogene activities. Mol Cell Bioi 1991;11:6016. 75. Heldin NE, Westermark B. The molecular biology of the human anaplastic thyroid carcinoma cell. Thyroidology 1991;3: 127. 76. Xing M, Vasko V, Tallini G, et al. BRAF TRI796A transversion mutation in various thyroid neoplasms. J Clin Endocrinol Metab 2004; 89:1365. 77. Kimura ET, Nikiforova MN, Zhu Z, et al. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RETIPTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 2003;63:1454.

Thyroid Oncogenesis Electron Kebebew, MD

Genetic alterations are the cornerstone of carcinogenesis. Genetic changes can be due to hereditary predisposition, acquired from viral infections (viral oncogenes), and result from environmental exposures to external or ionized radiation or even from chronic inflammatory conditions. The resulting genetic alterations ultimately lead to "transformation" of the cell toward a state of uncontrolled cell growth, disrupted normal cellular differentiation or apoptosis, and an invasive and metastatic cellular phenotype. The multistep hypothesis of carcinogenesis has been the framework on which genetic alterations have been investigated. 1The accumulation of multiple genetic events results in the developmentof cancer (Fig. 31-IA).1.2 These genetic modifications can be point mutations (single base pair changes), insertions, deletions, rearrangements, or translocations. When such genetic changes occur, they can lead to an oncogene, which can function in a dominant or recessive manner. An oncogene has the potential to induce or unsuccessfully suppress oncogenesis. A protooncogene is a gene that regulates cellular growth and/or cell differentiation that, when altered or amplified, leads to the development or progression of a neoplasm ("dominant" or "gain of function" genetic change). The functional products of protooncogenes have been classified at the cellular level as (I) growth factors, (2) membrane or intracellular receptors, (3) signal transduction system proteins, and (4) nuclear transcriptional activators or inhibitors. In contrast to dominant or gain of function oncogenes, tumor suppressor genes function to control cellular growth, but in a recessive fashion. The loss of function of the tumor suppressor gene product leads to unregulated cellular growth. Protooncogenes and tumor suppressor genes can occur as germline or somatic genetic mutations. The integrated study of molecular biology, epidemiology, embryology, physiology, and clinical medicine has led to significant advances in our understanding of oncogenesis. Many investigators have helped provide insight into the genetic mechanisms involved in thyroid tumorigenesis and its potential for clinical application in determining the prognosis of patients with thyroid cancer and in identifying individuals at risk of developing thyroid cancer. A working oncogenesis model has been proposed for thyroid cancers of follicular cell

288

origin (Fig. 31-lB).3 The main genetic abnormality (germline RET protooncogene point mutations) that occurs in the less

common thyroid cancer of parafollicular cell origin (medullary thyroid cancer) is well characterized and has led to earlier screening and treatment of patients with hereditary medullary thyroid cancer (see Chap. 15). This has translated into improved patient outcome." This chapter discusses our current knowledge of oncogenesis in follicular cells of the thyroid, a working model for thyroid carcinogenesis, and the potential clinical applications of these findings. The important growth factors and signal transduction factors that also influence the initiation or progression of thyroid neoplasms are discussed in Chapters 28 and 29.

Oncogenesis in Thyroid Cancers of Follicular Cell Origin Oncogene Receptor Proteins THYROID-STIMULATING HORMONE RECEPTOR

The thyroid-stimulating hormone (TSH) receptor is a transmembrane glycoprotein that is G protein coupled. TSH, acting through its receptor, is the main regulator of thyrocyte function and growth. Its function is mediated via the adenylate cyclase and phospholipase C intracellular pathways.' Constitutively activating mutations in the TSH receptor occur in the transmembrane segment and intracytoplasmic loop in hot thyroid nodules (""30%) but are usually absent in cold thyroid nodules or thyroid cancers (Table 31_1).5-10 Unfortunately, the frequency of TSH receptor-activating mutations observed in hot thyroid nodules has been variable, ranging from 3% to 82%.5-12 This discrepancy is likely due to several factors such as small sample size, screening of only part of the TSH receptor gene, less sensitive screening techniques (single-strand conformation polymorphism), inaccurate characterization of thyroid nodule function, and the quality of DNA in tissue samples studied.P In general, TSH receptor-activating mutations lead to some benign hot nodules but not to malignant thyroid neoplasms or cold thyroid nodules. 13

Thyroid Oncogenesis - -

289

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IGF

B FIGURE 31-1. A, General multistep theory of genetic alterations in carcinogenesis. B. The genetic events that occur in thyroid oncogenesis (the main genetic events are in bold). The dashed lines for each histologic type of thyroid cancers indicate that an adenoma-to-carcinoma progression is not necessarily always the sequence of progression in carcinogenesis. PTC = papillary thyroid carcinoma; FfC = follicular thyroid carcinoma; HCC = Hiirthle cell carcinoma; EGF = epidermal growth factor; TGF~ = transforming growth factor beta; IGF = insulin-like growth factor; TSH-R = thyroid-stimulating hormone receptor.

290 - - Thyroid Gland

Tyrosine Kinase Receptors Tyrosine kinase receptor proteins are a well-recognized group of oncoproteins that are implicated i~ several hu~an cancers and include almost 50 receptor protems. The tyrosme kinase genes classically encode a transmembrane recep~or ~rotein. Ligand binding to the tyrosine kinase leads to actrvation, dimerization of the receptors, and then transphosphorylation of tyrosine kinase residues, with downstream activation of the tyrosine kinase genes. Several tyrosine kinase gene alterations are implicated in thyroid carcinogenesis; RET/PTC, TRK, c-erb-2 and met activate thyrocyte growth through a cyclic adenosine monophosphate-independent system. RETIPTC ONCOGENE

The RET/PTC protooncogene maps to chromosome 10qll.2, and five activating chromosomal rearrangements have been characterized.l-" The RET/PTC chimeric genes have

been designated RET/PTC] to RET/PTC5. 15 Permanent activation of the tyrosine kinase results from the 5' foreign genes." The five foreign genes fused to the RET tyrosine kinase domain occur almost exclusively in papillary thyroid cancer (see Table 31-1). The frequency of RET/PTC activating somatic mutations in sporadic papillary thyroid cancer is variable, ranging from 2.5% to 85%.2.17-30 This wide ran~e in the prevalence of the RET/PTC rearrangement genes m papillary thyroid cancer may be due to geographic variation, the age of patients studied, or the sensitivity of experimental techniques employed or a consequence of ionized radiation or external radiation exposures.P'" For example, in thyroid neoplasms associated with the Chernobyl accident, 55% to 85% of the thyroid cancers had RET/PTC rearrangement oncogenes, and only a few were observed in follicular adenoma.19,21.23,26 RETIPTC3 was the most common rearrangement identified in association with radiation exposure. 16.23 The reason for the difference in distribution of the RET/PTC

Thyroid Oncogenesis - - 291

chimeric subtype genes and its relation to radiation exposure remains unclear. The RET/PTC rearrangement genes have been identified in occult papillary thyroid cancer; therefore, it is considered to be an early event in the formation of papillary thyroid cancer.'? Some investigators have found that the presence of RET/PTC in patients with papillary thyroid cancer is associated with young age, radiation exposure, and lymph node metastasis but not distant metastasis. 17,26,28,29 TRK ONCOGENE

The TRK protooncogene is located on chromosome lq2l-22. 32 TRK encodes for the receptor for nerve growth factor and results from chromosomal rearrangements.P> This chimeric gene is ubiquitously expressed and results in a constitutively activated tyrosine kinase protein. Four chimeric genes have been identified: three intrachromosomal rearrangements (TRK, TRK-Tl, and TRK-T2) and one interchromosomal rearrangement (TRK-T3). The TRK protooncogene occurs infrequently in papillary thyroid cancer (6% to 20%) and has been detected in patients with and without radiationassociated papillary thyroid cancers (see Table 31_1).32-34 MET ONCOGENE

Hepatocyte growth factor (scatter factor) binds the MET transmembrane tyrosine kinase receptor.P Activation of the MET receptor promotes a mitogen response, cellular motility, and cellular mvasion.F-" In normal cells, MET activation is a ligand-dependent transient event, whereas in tumor cells MET activity is often constitutively upregulated.A'" MET is overexpressed in about 75% of papillary thyroid cancers and poorly differentiated cancer and in only 22% of follicular thyroid cancers. 38-40 MET overexpression may be associated with tumor multicentricity and less tumor angiogenesis in papillary thyroid cancer. 39,4O In contrast, absent or low MET expression in papillary thyroid cancer has been associated with a higher risk of distant metastasis." Although results are discrepant, it is possible that MET plays a role in the progression of thyroid cancers to an aggressive phenotype and probably occurs as a late event, because MET is overexpressed in more aggressive thyroid cancers. 38,41.42 c-erb-2 ONCOGENE

The c-erb-2 oncogene (also referred to as HER and neu) encodes a transmembrane glycoprotein with tyrosine kinase activity." This epidermal growth factor (EGF) receptorrelated protein is truncated and has been demonstrated to be predictive of prognosis in several human cancers.tv" Because EGF, acting through the EGF receptor, is an important regulator of thyroid cell growth, several groups have studied c-erb-2 oncoprotein expression in thyroid cancers. 45-48 The role of c-erb-2 in thyroid tumorigenesis is controversial. Some investigators have found that the c-erb-2 protein is overexpressed in papillary thyroid cancer but not detected in follicular adenoma, follicular carcinoma, medullary carcinoma, and anaplastic carcinoma." Overamplification or rearrangement of the c-erb-2 oncogene has not been demonstrated in either benign or malignant thyroid neoplasms.f-" Therefore, it remains to be determined if the c-erb-2 oncoprotein is an important factor in thyroid tumorigenesis.

Activating Oncogene G Proteins ras Oncogene The ras oncogene encodes a 21-kd protein (p21) that functions in signal transduction from receptor proteins belonging to the tyrosine kinase family of receptors. Three ras proteins (H, K, N) exist in an active state when they are anchored to the inner membrane and bound to guanosine triphosphate (GTP) and in a resting state when they are bound to guanosine diphosphate (GDP). Activating point mutations in the ras oncogene commonly occur in codons 12 and 13 in the GTP-binding domain and in codons 59 and 61 in the guanosine triphosphatase (GTPase) domain." Mutations in the ras gene result in growth stimulation and the inhibition of differentiation in thyrocytes. The three ras oncogenes in thyroid tumors are randomly distributed and have a similar frequency (7% to 92%,30% overall) (see Table 31-1). Although the ras oncogenes are the most common genetic alteration reported in thyroid neoplasms, there have been some discrepancies in the frequency of ras mutations observed in several different studies.50-55.55•.55b It has been suggested, but not established, that the amount of iodine intake, external radiation exposure, experimental techniques used, and demographic differences might account for this discrepancy. Transversion point mutations may be associated with radiation-associated thyroid tumors.50 Since most investigations suggest that ras mutations occur in similar frequencies in benign thyroid adenomas and thyroid cancers, it appears that they occur as an early genetic event in thyroid carcinogenesis. Some investigators have also suggested that ras mutations may be associated with a poor prognosis in patients with papillary thyroid cancer. 56

gsp Oncogene The stimulatory GTP-binding protein (gsp) participates in the TSH signal transduction pathway by mediating the stimulation of adenylate cyclase. Activating point mutations in the stimulatory G protein gene (commonly in codons 201 and 227) result in the gsp oncogene. The gsp oncoprotein has decreased GTPase activity and leads to a G protein that is constitutively activated, which results in high adenylate cyclase activity. Point mutations in the inhibitory G protein gene also result in high adenylate cyclase activity.57 Similar to TSH-activating mutations, the gsp oncogene has been detected mostly in hot thyroid nodules (7% to 28%) and less frequently in nonfunctioning thyroid adenomas and thyroid cancers (see Table 31_1).8.10.12,13,58 The overall low prevalence of the gsp oncogene in hot thyroid nodules suggests that other genetic alterations such as TSH receptor mutations are responsible for most hot thyroid nodules. 58. The simultaneous occurrence of gsp and ras mutations may be associated with more aggressive papillary and follicular thyroid cancers.P

Nuclear Oncogenes Nuclear protooncogene proteins such as myc, jun, and

fos have also been evaluated in thyroid tumorigenesis. Most investigators have found that c-myc and c-fos are

292 - - Thyroid Gland overexpressed in benign and malignant thyroid neoplasm.v-" Although c-myc expression has been demonstrated to be a marker of aggressiveness in certain human cancers, this has not been consistently observed in thyroid cancer. 59-62 The N-myc oncogene expression is highest in thyroid cancer cell lines and in undifferentiated thyroid cancers. Most Hiirthle cell cancers (up to 100%) are positive for N-myc by immunohistochemistry, whereas only 17% of follicular thyroid cancers are N-myc positive.F Although the nuclear oncogenes are overexpressed in thyroid neoplasms at the messenger RNA and protein levels, no gene amplification of the c-myc and c-fos oncogenes has been observed in benign or malignant thyroid tumors.r" Therefore, it is unclear if increased nuclear protooncogene expression occuts as a primary event or secondarily to external stimuli activating cell receptors or signal transduction proteins upstream. Nonetheless, the c-myc and c-fos oncogenes probably playa role in thyroid carcinogenesis.

PAXB-PPARy1 The PAX8-PPARyl oncogene results from chromosomal translocation t(2;3)(q13;p25). This leads to fusion of the thyroid transcription factor PAX8 to domains A to F of the peroxisome proliferator-activated receptor (PAX8-PPARyl).63 This finding was recently reported and its expression characterized in thyroid tissues.P The fusion protein was detected only in follicular thyroid cancers but not in papillary thyroid cancer, follicular adenoma, or multinodular goiter.v' This novel finding needs confirmation in a larger sample size but corroborates the cytogenetic findings that suggest a putative tumor suppressor gene on chromosome 3p was possibly specific to follicular thyroid cancer."

Tumor Suppressor Genes p53 The p53 tumor suppressor gene is one of the most common genetic alterations observed in human cancers. The p53 gene, located on chromosome 17p 13, encodes a 53-kd nuclear phosphoprotein and functions as a key cell cycle regulator. p53 mutations lead to altered protein conformations that are nonfunctional and accumulate in the cell nucleus. A p53 mutation needs to occur in only one allele to lead to deregulated cellular growth. Most p53 gene mutations (98%) occur in exons 5 through 8. 64a p53 mutations are primarily present in poorly differentiated and undifferentiated thyroid cancers and in immortalized thyroid cancer cell lines (see Table 31_1).55.65-68b Radiation exposure may result in p53 point mutations.P" Increased p53 immunostaining may be useful in predicting the aggressiveness of thyroid

Some investigators have observed mutant Rb alleles in thyroid cancer (~55%), but no Rb mutations have been reported in benign thyroid tumors. 71-73 The role of the Rb protein in thyroid oncogenesis remains unclear, and the discrepant reports may be due to experimental techniques employed.

APe The tumor suppressor adenomatous polyposis coli (APC) gene has been established as the predisposing gerrnline mutation for familial adenomatous polyposis coli (FAP). It has been speculated that the APC gene may play a role in thyroid tumorigenesis because of the increased incidence of thyroid cancer in patients with FAP (Gardner's syndrome)." No mutation of the APC gene has been observed in benign, malignant, or normal thyroid tissue. 74.75 The APC gene probably does not playa significant role in thyroid cancers of follicular cell origin.

MTS-1 and MTS-2 The multiple tumor suppressor (MTS)-l (p161NK4A) and MTS-2 (p15INK4B) genes regulate cell cycles. Loss of function of p15INK4b and p16INK4a results in impaired control of the cell cycle and contributes to the transformation of several cell types." Although it has been commonly observed in a variety of human cancers, altered p15INK4b and p16INK4a genes in thyroid neoplasms primarily have been found in immortalized thyroid cancer cell lines and not in thyroid tumors.Y" Therefore, the p15INK4b and p 16INK4a tumor suppressor genes do not appear to play a significant role in thyroid oncogenesis or may represent a late event.

PTEN PTEN (MMAC or TEPI) is a tyrosine phosphatase protein located on chromosome lOq23.3 and has a tumor suppressor effect by antagonizing tyrosine kinase activity."? PTEN is responsible for Cowden's syndrome.t" Cowden's syndrome is an autosomal dominant hereditary syndrome characterized by formation of hamartomas in several organs and an increased risk of thyroid and breast cancer," Because Cowden's syndrome is associated with an increased risk of thyroid cancer, the PTEN tumor suppressor gene has been studied in thyroid tumors. PTEN gene mutations have been identified mostly in benign thyroid adenomas (26%) and infrequently in thyroid cancer of follicular cell origin (6%).81 This would suggest that the PTEN tumor suppressor gene does not play a significant role in malignant thyroid tumor and questions the progression of thyroid adenoma to thyroid cancer.

cancers."?

Summary

Rb

Our understanding of the genes and genetic changes involved in the pathogenesis of thyroid neoplasms has increased greatly in the last decade. Some of the genetic changes have been consistently demonstrated and are specific to certain thyroid cancers. On the other hand, investigators have reported discrepancies in the frequency of some of the protooncogenes

The retinoblastoma gene is located on chromosome 13q14 and encodes a 11O-kd nuclear phosphoprotein (Rb). The Rb protein also regulates cell cycle progression. Rb mutations can occur as germline or somatic mutations in various tumors.

Thyroid Oncogenesis - - 293

and tumor suppressor genes, most likely due to different experimental techniques. The reported prognostic importance of the many oncogenes studied to date needs to be confmned. Molecular prognostication can lead to better selection of patients with thyroid cancer who would benefit from postoperative radioactive iodine therapy or thyroid hormone suppression therapy. It is well established that activating TSH receptor mutations and gsp oncogenes leads to toxic thyroid nodules, but other unidentified genes probably also playa role. The ras oncogene is an early event in thyroid tumorigenesis and could be a predictor of tumor aggressiveness. The altered function or deregulated expression of the tyrosine kinase receptors (RETIPTC, TRK, c-erb-2, and met) in thyroid cancer may provide a useful molecular therapeutic target gene for patients who do not respond to conventional therapy (e.g., tyrosine kinase inhibitors). It is certain that if the commitment and breadth of the research effort continue in thyroid oncogenesis, a fruitful result in regard to more accurate prognostication, diagnosis (e.g., preoperative differentiation of thyroid follicular adenoma from follicular carcinoma), and molecular gene treatment targeting will result in even better outcomes for patients with thyroid cancer of follicular cell origin.

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Mechanisms and Regulation of Invasion in Thyroid Cancer Michael W. Yeh, MD • Michael J. Demeure, MD • Kevin Packman, MD

The management of invasive and metastatic disease represents the single greatest challenge in the treatment of cancer today. I Although most differentiated thyroid cancers are adequately treated with surgical resection and radioiodine therapy, poorly differentiated and undifferentiated cancers, whose behavior is characterized by aggressive local invasion and metastasis, are often lethal.' Furthermore, metastatic foci of differentiated thyroid cancer frequently fail to take up sufficient quantities of radioiodine to be successfully ablated.' Because conventional chemotherapy and radiotherapy have yielded disappointing results in the treatment of aggressive thyroid cancers.v' new strategies for inhibiting tumor growth, invasion, and angiogenesis (itself an invasive process) are needed. Thyroid nodules are a common problem, affecting roughly 4% of the U.S. population. Fine-needle aspiration, which has emerged as the single most useful test in the evaluation of nodular thyroid disease, is useful in distinguishing between benign and malignant growths in most cases," Difficulty arises in the work-up of follicular and Hiirthle cell neoplasms, which can currently be diagnosed as malignant only after permanent pathologic examination reveals capsular or vascular invasion, or both.? Similar issues arise in the management of adrenal neoplasms and neuroendocrine tumors of the gastrointestinal tract. s.s• Because only about 15% offollicular thyroid neoplasms are eventually proved to be malignant, many patients undergo surgery unnecessarily. Thus, it is hoped that an increased understanding of the invasion process in follicular thyroid cancer (FTC) may allow the development of reliable cytologic or molecular indicators of tumor behavior. Histologically, invasion through the epithelial basement membrane marks the progression from carcinoma in situ to carcinoma. The invasion process is thought to involve at least three major components: (1) adhesion to the extracellular matrix, (2) proteolysis of the collagen barrier, and (3) migration into adjacent tissues (Fig. 32-1).9 These steps, however, are interlinked and inseparable. A number of intracellular and extracellular signaling molecules have been implicated in the positive and negative regulation of invasive behavior. These molecules have also linked the regulators

and effectors of invasion to the related processes of inflammation and angiogenesis.P'F This chapter is intended to describe some of the many cellular mechanisms that appear to be associated with invasion in thyroid cancer and human cancers as a whole.

Cytoskeleton: Structure and Function In many ways, the cytoskeleton is analogous to the skeleton of the human body in that it provides form and shape to the cell, but its function is much more complex. It is important in cell movement, cell division, adhesion, and communication with other cells and extracellular matrix as well as the regulation of many intracellular processes. The cytoskeleton is composed of filamentous structures generally classified according to size, including microtubules (22 nm), intermediate filaments (8 to 10 nm), and microfilaments (7 nm).

Microtubules Microtubules are composed primarily of tubulin, a 55-kd protein. In its polymerized form, tubulin forms a microtubular network radiating from the perinuclear region of the cell. This network is important in regulating and maintaining the location of endoplasmic reticulum and Golgi apparatus within the cell. During cell division, microtubules are rapidly organized as part of the mitotic spindle. During the transition from metaphase to anaphase, duplicated chromosomes are pulled apart by contracting spindle microtubules toward the centrosomes of each daughter cell. Anticancer drugs such as vincristine and vinblastine inhibit the formation of microtubules and are hence thought to be antimitotic. One additional function of the microtubules is that they are important in cellular distribution of intermediate filaments and cortical actin filaments. Disruption of the microtubules of cultured cells by colchicine, however, does not necessarily prevent cell locomotion, which seems more dependent on the actin microfilaments. 295

296 - - Thyroid Gland

FIGURE 32-1. Schematic depicting the multistep process of cancer cell invasion through the basement membrane. Cells must separate from their primary tumor mass and then degrade a basement membrane barrier to allow infiltration.

Intermediate Filaments Intermediate filaments are composed of different types of proteins, depending on the type of cell, that form relatively stable polymers.P Cytokeratins are specific to epithelial cells, whereas vimentin is found in mesenchymal cells, desmin in muscle cells, and glial fibrillary acidic protein in neural cells. Because specificity is maintained after transition to malignancy, anaplastic-appearing tumor cells may often be characterized by immunohistochemistry using antibodies recognizing specific intermediate filament proteins. Closely related to the microtubule system, intermediate filaments form a delicate network surrounding the nucleus that extend into the cytoplasm toward the cell periphery. In epithelial cells, keratin intermediate filaments join with the cell membrane at desmosomes, which are specialized junctions between adjoining cells. As such, intermediate filaments are thought to provide structural integrity and tensile strength to epithelial membranes. Experiments with mouse and rat tumor cell lines suggest that enhanced expression of intermediate filaments may be related to the ability of tumor cells to invade and merastasize.P:"

Actin Microfilaments The actin cytoskeleton is important in determining and maintaining cell shape and polarity but is also known to be involved in a diverse array of other cellular functions, including the transmission of intracellular signals and protein synthesis by the sorting of messenger RNA (mRNA)P The actin cytoskeleton interacts with the cell surface membrane at multiple levels, including junctional complexes, apical microvilli, cellular adhesion molecules, and integrins. Microfilaments are composed primarily of actin. In a fully polymerized state, actin forms stress fibers anchoring a cell to its matrix through adhesion plaques. Cells interact with their matrix through heterodimeric receptors, consisting of an a and a ~ subunit, known as integrins. The prototypic adhesion plaque is composed of an a5~1 integrin (fibronectin receptor)

interacting with talin, vinculin, o-actinin, and capping proteins. This assembly forms the attachment point for one end of an actin stress fiber. These focal contacts are sites of communication of the cell with its external environment. The loss of actin stress fibers has been associated with oncogenic transformation and increased metastatic potential. Abnormally low cellular levels of F-actin have been suggested as a marker of transformation in human bladder tumors." A disordered actin microfilament architecture has been associated with increased metastatic potential in several tumor models, including murine melanoma and fibrosarcoma models.P-" A loss of order in the actin microfilament architecture has also been observed as a late phenomenon in the progression of human colonic polyps to cancer," Mutated forms of actin have been shown to either increase or decrease metastatic potential. Transfection of a mutated form of ~-actin with the substitution of a leucine for an arginine at position 28 reduces the metastatic potential of highly aggressive murine B16 melanoma cells." These cells developed organized actin stress fibers, were less motile in vitro, were less invasive in collagen gels, and produced fewer lung metastases in mice after tail vein inoculation. On the other hand, transformed HUT-14 human fibroblasts, which express a mutant actin with a single amino acid substitution at position 244, resulted in fewer actin filaments and enhanced invasiveness.P The actin system is dynamic in locomotion and in transmitting cellular signals. Cells migrate by advancing a leading edge. Motile cells have polarity, with a leading edge exhibiting microspikes and lamellipodia, both of which are dependent on actin filaments. Cell movement is associated with rearrangement of actin architecture at the advancing cell border by actin polymerization and depolymerization.s' When two migrating cells come in contact, advancement of the leading edge immediately stops. This inhibition of locomotion is thought to be mediated by a rapid alteration in the actin-based cortical cytoskeleton. The actin cytoskeleton has been linked to chemotactic receptors associated with G proteins and cyclic adenosine monophosphate (cAMP),25 and in response to a chemotactic stimulus, increased cellular cAMP promotes F-actin assembly.-" Thyrotropin has been shown to induce stress fibers in cultured thyroid cancer cells.'? Just how perturbations in actin structure and function affect thyroid cancer growth and behavior is not known but is an exciting area for investigation. Most work on thyroid-stimulating hormone (TSH) effects has centered on its ability to induce thyrocyte growth. Perturbation of cell growth control results in tumors, but tumorigenicity is independent of metastatic phenotype." Because not all tumors have the ability to invade and metastasize, it follows that the cellular characteristics related to invasion such as matrix attachment, protease production, and locomotion are under separate control from the cell properties regulating growth.

Cell-Extracellular Matrix and Cell-Cell Contacts A prominent feature of carcinomas is the uncontrolled growth of epithelial cells. Contact inhibition of growth and replication of epithelial cells is dependent on anchorage to

Mechanisms and Regulation of Invasion in Thyroid Cancer - - 297

underlying substratum. The progression of tumors from a benign to a malignant state is thought to be associated with diminished cell-cell adhesion and a loss of contact inhibition of growth.i? Normal epithelial cells are polarized and have a limited ability to move because they are anchored to a basement membrane by integrins and to neighboring cells by cadherins.'? Generally, cell locomotion is inversely related to the number and extent of focal adhesion plaques." Invasion and tumorigenicity also seem to be inversely related to the number and integrity of adhesion contacts.

Integrins and Malignancy There is extensive interest in the cellular receptors for key matrix components because of the interaction of tumor cells with the extracellular matrix. These extracellular matrix receptors, which span the cellular membrane and interact with the actin cytoskeleton, are known as integrins (Fig. 32-2). Integrins make up a family of glycoproteins that generally exist as heterodimers, consisting of an a and a ~ subunit. The 18 a subunits and 8 ~ subunits that have been identified can exist in a number of combinations, each with a different binding specificity. Several studies have shown that malignant change is associated with significant alterations in the quantity, distribution, and type of integrins expressed on the cell surface.P This has perhaps been best demonstrated in

Actin microfilaments

a-Actinin

Cell membrane

FIGURE 32-2. Schematic depicting organization of an integrinmediated adhesion plaque. Association with the actin cytoskeleton and tyrosine phosphorylation-signaling proteins is demonstrated. Such adhesion plaques are thought to be activated by engagement of the integrins with extracellular matrix.

melanoma, where the onset of <Xv~3 integrin expression on the invasive front is closely correlated with vertical invasion and increased metastatic potential.F Likewise, upregulation of the laminin-specific Ut;~4 integrin correlates with progression from a benign to malignant phenotype in several cell types, including those of thyroid origin.P Transformed cells commonly express markedly diminished levels of a5~1 fibronectin receptor but may exhibit increased levels of the a3~1 integrin, which under certain conditions may also function as a fibronectin receptor." This observation corresponds with the finding that increased expression of the a5~1 integrin receptor resulting from a transferred gene reduces cell migration.P In some cells transformed by ras or tyrosine kinase oncogenes, there is diminished expression of the a 5 integrin subunit (fibronectin receptor).34.36.37 Our laboratory reported this type of derangement in cultured human FTC cells. Highly invasive clones of the FTC cell line exhibited diminished expression of the a5 subunit of the integrin fibronectin receptor relative to a less invasive clone. Fibronectin production, on the other hand, was not diminished.Fr" Focal adhesion kinase (FAK) is an intracellular tyrosine kinase that becomes phosphorylated and activated in response to integrin binding of extracellular matrix ligands. FAK is thought to be one of the major mechanisms by which integrins influence intracellular signaling pathways that control cell motility, growth, and survival. Invasive and metastatic tumors of the colon, breast, prostate, and thyroid are known to overexpress FAK. 39,40 Unlike normal cells, which depend on appropriate contact with the extracellular matrix in order to survive and proliferate, neoplastic cells are capable of growing under anchorage-independent conditions. FAK may confer this property upon neoplastic cells, as evidenced by the fact that its overexpression can rescue epithelial cells from apoptosis in an anchorage-independent environment." Cells derived from FAK-null mice display impaired migration and a decreased ability to remodel contacts with the extracellular matrix.f

Cadherins and Catenins Cadherins make up another major group of adhesion molecules involved in cell-cell and cell-matrix interactions. E-cadherin, a subtype associated with epithelial tissues, forms contacts with cadherin molecules on nearby cells in a calcium-dependent fashion that has been described as a cell adhesion "zipper."43 This process is also dependent on a series of interactions between E-cadherin and a family of intracellular proteins called catenins (Fig. 32-3). Catenins, which include n-catenin, ~-catenin, y-catenin, and pl20ctn, bind the intracellular domain of cadherins to the actin cytoskeleton.r' Several distinct lines of evidence suggest that loss of cadherin expression is a critical step in cancer development and progression. It has long been thought that the disruption of normal cell-cell adhesion in transformed cells is a major contributor to the invasive phenotype. The observation that E-cadherin expression was diminished or lost in many human cancers led to studies suggesting that alterations in cadherin or catenin function played a causative role in promoting invasion. Gerrnline mutations in CDR] (the gene

298 - - Thyroid Gland Cell membrane

== E-cadherin~s~~~~ Catenins

FIGURE 32-3. Demonstration of the cell-cell adherens junction

mediated by E-cadherins. Interaction with the actin cytoskeleton is mediated by a complex that includes catenins and other, as yet uncharacterized proteins. a-Actinin serves as an actin cross-linking protein.

encoding E-cadherin) confer a high risk for certain types of gastric cancer," and somatic mutations in CDHI have been detected in malignancies of the breast, ovary, endometrium, and stomach. Both transcriptional repression of CDHI and hypermethylation of the CDHI promoter have been found in several tumor types, supporting the idea that loss of E-cadherin expression contributes to malignant change.t" Treatment of normal epithelial cells with anti-E-cadherin antibodies has been shown to induce invasive behavior, whereas transfection of wild-type E-cadherin into neoplastic cells was seen to suppress invasion.f" A few reports exist on the potential association of E-cadherin expression in thyroid neoplasms. When studied using immunohistochemistry and Northern blot analysis, normal thyroid tissue and cells from benign thyroid disorders such as goiter or follicular adenomas exhibit high levels of E-cadherins, whereas anaplastic thyroid cancers exhibit very low or no E-cadherins. The expression of E-cadherins in recurrent thyroid cancers or in tumors with known metastases, regardless of the histologic type, was found to be low or negligible.t? Another more recent report corroborates these findings in that patients with tumors expressing low levels ofE-cadherin were more likely to acquire metastatic disease than those whose tumors expressed normal levels of E-cadherin. 5o Notably, hypermethylation of the CDHI promoter was found in more than 80% of papillary thyroid cancer cell lines tested in one study. A significant portion of follicular, Hiirthle cell, and poorly differentiated carcinomas were similarly affected." ~-Catenin alterations in cancer have been extensively studied as a result of their close association with colorectal carcinogenesis. Highly penetrant germline mutations in the adenomatous polyposis coli (APe) gene were found to cluster at a region of the gene responsible for the binding and degradation of ~-catenin. 52 As mentioned earlier, catenins playa critical structural role in cells by linking cadherins with the actin cytoskeleton, allowing the formation of stable and functional adherens junctions. This interaction is regulated in part by tyrosine phosphorylation of ~-catenin, which causes separation of the cadherin-catenin unit and an increase in the quantity of free ~-catenin in the cytosol.

Epithelial cell migration has been shown to be dependent on this process, which has the general effect of decreasing cellcell adhesiveness." Activation of receptor tyrosine kinases belonging to the erb-B family and others (discussed later) is known to trigger ~-catenin phosphorylation. Because inactivating ~-catenin mutations have not been consistently found in human cancers, focus has turned to post-transcriptional events affecting catenin function, particularly in regard to its important role in signal transduction. The current body of evidence suggests that ~-catenin exists in two distinct pools, one involving cellular adhesion and another involving gene transcription through the Wnt pathway, which plays a crucial role in normal embryonic development. Wnt binding at the cell surface results in an increase in free ~-catenin, which translocates to the nucleus and activates the lymphoid enhancer factorff-cell factor (LEFffCF) family of DNA binding proteins. These, in tum, activate a number of genes promoting cell growth and invasion, such as c-MYC,54 cyclin Dl,55 matrix metalloproteinase-L'" and a growing list of other candidates. As much of the data regarding ~-catenin signaling is quite recent, much about the role of this pathway in cancer development and progression remains poorly understood. Some cross-talk between the two pools of ~-catenin is thought to occur. An excess of E-cadherin can interfere with LEFffCF signaling by sequestering ~-catenin,57 and high levels of Wnt activity can occupy sufficient quantities of ~-catenin to remove it from its role in cellular adhesion." This begs the question of whether the inactivation of E-cadherin and loss of cell-cell adhesion, with resultant increases in free cytosolic ~-catenin, are sufficient to stimulate LEFffCF transcription. As it turns out, E-cadherin loss is not sufficient to have such transcriptional effects.l? suggesting that a degradative pathway exists to limit excess ~-catenin accumulation.

Proteases in Tumor Invasion Proteolysis of extracellular matrix components is thought to be an essential component of tumor invasion. Derangements in the expression and activity of proteases have been found in almost every malignancy studied, strongly implicating them as causative agents in malignant progression. Several classes of proteases capable of degrading the collagens, glycoproteins, and proteoglycans that make up the extracellular matrix have been identified, including matrix metalloproteinases, serine proteases, carboxyl proteases, and glycosidases. Research to date suggests that the former two classes play the most significant role in carcinogenesis. In humans, matrix metalloproteinases (MMPs) make up a family of at least 21 zinc-dependent enzymes that, collectively, are capable of degrading all components of the basement membrane (Table 32-1). MMPs are generally released in an inactive form and require cleavage in the extracellular space in order to gain full activity. Upregulation of MMPs has been widely found in human malignancies and correlates with advanced tumor stage, increased invasion and metastasis, and poor prognosis." In animal studies, minimally invasive cells can acquire malignant characteristics when MMP expression is elevated." Conversely, highly

Mechanisms and Regulation of Invasion in Thyroid Cancer - - 299

invasive cells can be rendered more quiescent when MMP expression is reduced or when endogenous inhibitors of MMPs (tissue inhibitors of metalloproteinases, TlMPs) are overexpressed.P MMP-2 and MMP-9 have received particular attention in the cancer literature because of their ability to degrade type IV collagen, the principal component of the extracellular matrix. Membrane type 1 MMP (MTl-MMP), the first identified member of the membrane-associated MMPs, is also of special interest because of its role in activating pro-MMP-2. Indeed, elevated levels of MMP-2 have been found in thyroid cancer homogenates, as has a positive correlation between MMP-2 activation and the presence of lymph node metastases.P MMPs and their cleavage products have been shown to play important roles in the regulation of cell growth and survival, angiogenesis, and the immune response to cancer. Small molecules released by proteolysis have been demonstrated to have potent biologic effects in both normal tissue and the tumor tissue microenvironment. It is important to note that products of MMP activity have sometimes been found to have an antitumor effect and that elevated levels of TIMPs in tumors or adjacent normal tissues have correlated both positively and negatively with prognosis in different studies." In other words, although the weight of evidence suggests that excess MMP activity favors tumor growth and invasion, to state merely that MMPs are "bad" in cancer

progression would be a gross oversimplification. Further understanding of the functions of MMPs has revealed that they collectively exert both positive and negative regulatory effects on cancer progression. This fact may partially explain why clinical trials of MMP inhibitors in cancer therapy have generally not yielded positive results (discussed further later). Among serine proteases, the enzyme most prominently implicated in cancer progression has been urokinase plasminogen activator (uPA). uPA converts plasminogen to plasmin, a broad-spectrum protease that is capable of degrading many components of the extracellular matrix as well as activating pro-MMPs.65 Invading tumor cells have been shown to express a cell surface receptor for uPA (uPAR), which focuses proteolytic activity at the invasive front. As with the MMPs, uPA activity is negatively controlled by the endogenous inhibitors PAI-l and PAI-2. Elevated expression of uPA has been reported in malignancies of the breast, colon and rectum, stomach, urogenital tract, and other tissues.P" The plasmin activation system is known to contribute to matrix degradation by thyroid carcinoma cell lines.s? but little more is known about its role in thyroid cancer. Our laboratory has extensively studied the role of proteases and their inhibitors in thyroid cancer invasion in vitro. It is well established that epidermal growth factor (EGF) enhances invasion in thyroid cancer cell lines of papillary and follicular origins.f We found that EGF upregulates

300 - - Thyroid Gland earlier, EGF is a potent stimulator of thyroid cancer cell invasion. In some cases, in vitro invasion by EGF-stimulated cells was found to be seven times greater than that of cells studied in a growth factor-free environment. In previous reports from our group, TSH was also shown to enhance

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CIl

a. EGF AG1478 GM-6001 Col-3 (llg/mL)

+

+ +

+

+

+ +

+

+

5

10

5

10

FIGURE 32-4. Epidermal growth factor (EGF) stimulates invasion by thyroid cancer cells in vitro. Cells treated with EGF, AG 1478 (tyrosine kinase inhibitor), GM-6001 (peptidomimetic matrix metalloproteinase [MMPj inhibitor), and Col-3 (tetracycline MMP inhibitor). EGF was administered at a dose of 10 ng/ml., AG 1478 at 10 11M, and GM-6001 at 100 j.lM. Col-3 was administered at 5 and 10 j.lg/mL, as indicated. Data expressed as mean ± 1 standard deviation. Brackets indicate pairwise comparisons. **p < .0001 by analysis of variance.

MMP-9 and MTl-MMP expression in these cells and that MMP-2 activation in the extracellular space parallels MTl-MMP expression.P" EGF-stimulated invasion in thyroid cancer cell lines is antagonized by both synthetic MMP inhibitors and EGF receptor tyrosine kinase inhibitors (Fig. 32-4), but not by the serine protease inhibitor aprotinin. Our findings suggest that EGF acts by altering MMP gene transcription downstream of its receptor and that, at least in our model, serine proteases do not contribute significantly to invasion.

Regulators of Invasion Several growth factors have been identified as important paracrine regulators of cancer growth and spread. Chief among these are those that bind receptor tyrosine kinases, such as EGF, hepatocyte growth factor/scatter factor (HGF/SF), transforming growth factors, and platelet-derived growth factor. Elevated expression of EGF receptors (EGFRs) and related Erb-B receptors has been found in many human malignancies. In cancers of the breast, head and neck, urogenital tract, and other tissues, Erb-B receptor overexpression is associated with poor prognosis." The Erb-B2 receptor, also known as Her-2/neu, is of particular interest because of its ability to form cell surface heterodimers with other Erb-B family receptors, thus augmenting receptor tyrosine kinase signaling." Our initial interest in studying the role of EGF in thyroid cancer stemmed from the fact that EGF is highly expressed in the normal human thyroid, at levels more than twice those found in other major organs." Several groups, including our own, have identified Erb-B receptors on the surface of thyroid cancer cells, and we have found that thyroid cancer cell lines overexpress both the EGFR and Erb-B2 when compared with normal thyrocytes. As mentioned

Both EGF and HGF/SF have been shown to increase protease expression and invasion in human cancers.V" Furthermore, they are reported to induce the dismantling of adherens junctions, possibly by disrupting the cadherincatenin linkage to the actin cytoskeleton." Similar paracrine signals are known to regulate the epithelial-mesenchymal transformation during normal embryonal development, which mirrors the pathologic events of malignant progression in many ways. Thus, proteins that maintain normal epithelial cell architecture, such as E-cadherin and catenin, are now being seen as invasion or metastasis suppressors. Stromal cells have been recognized as having an active role in both the progression and inhibition of malignant invasion. Stromal cells secrete a variety of proteases, and cancer cells may stimulate them to synthesize MMPs in a paracrine fashion by releasing growth factors and human extracellular matrix metalloproteinase inducer (EMMPRJN76). Coculture with activated stromal cells can confer a malignant phenotype on immortal cells that generally display benign behavior.T" On the other hand, tumor stroma has in many cases been found to harbor large quantities of protease inhibitors,"? suggesting that normal fibroblasts may mount an adaptive "tumoristatic" response.

Molecular Cross-Talk in Malignant Progression As previously mentioned, although adhesion, proteolysis, and migration can be considered individually, the three are actually inseparable events in the process of invasion. Likewise, research has shed light on a myriad of interlinkages between the processes of cancer growth, survival, invasion, and angiogenesis. What follows is a brief discussion of molecular cross-talk between these systems, with particular reference to the adhesion molecules and proteases mentioned previously. Angiogenesis, a process central to tumor growth and survival, is an MMP-dependent process. As cancer cells employ MMPs to invade into adjacent normal tissues, endothelial cells stimulated by proangiogenic tumor signals require MMP activity to invade into the tumor substance. Both endogenous and synthetic MMP inhibitors have been shown to block angiogenesis by interfering with endothelial cell attachment, proliferation, migration, and growth. Small molecules released by proteolysis of the extracellular matrix, including growth factors and angiostatin, act as both positive and negative regulators of angiogenesis.t" The activation of pro-MMPs is a critical step in the regulation of extracellular matrix proteolysis. MMP-2 activation is known to take place on the cell surface, where MTl-MMP cleaves pro-MMP-2 into its active form in the presence of permissive concentrations of TIMP-2. Studies of cancer cells and angiogenic endothelial cells suggest that aV~3 integrin binds the carboxyterrninal PEX domain of MMP-2 and

Mechanisms and Regulation of Invasion in Thyroid Cancer - -

301

that this interaction may localize proteolytic activity to the invasive front of cells. 81,82 Treatment of cancer cells with anti-integrin antibodies has been shown to increase MMP-2 secretion as well as cell invasiveness, and other studies suggest that signaling through FAK upregulates MMP_9. 83,84 Integrins and the uPAIuPAR system are known to interact and exert reciprocal regulatory actions on one another, but these processes are just beginning to be understood. As mentioned before, aV~3 integrin is expressed on activated endothelial cells. Antagonists of aV~3 integrin are known to disrupt blood vessel formation in the chick allantoic membrane and other bioassay systems. In vivo, Uv~3 integrin antagonists block tumor angiogenesis and, in some cases, can cause tumor regression.f The role of cadherin-catenin signaling in promoting tumor growth and MMP-7 expression has already been mentioned. E-cadherin is also a substrate for MMP-3 and MMP-7. Cleavage of E-cadherin results in release of the soluble extracellular E-cadherin fragment, which has been found to promote tumor cell invasion by acting in a paracrine manner.f" The soluble E-cadherin fragment is thought to interfere with normal E-cadherin function in nearby cells and possibly to activate other signaling pathways that remain to be identified.

Trastuzumab (Herceptin), a humanized monoclonal antibody directed against Erb-B2 (Her-2), has undergone several phase II and phase III clinical trials that have demonstrated a survival benefit in patients with Her-2-overexpressing breast cancers." These studies have led to the licensing of trastuzumab in many countries for use in combination with paclitaxel. EGFR antagonists are also being aggressively investigated. Cetuximab (IMC-225, Erbitux), a monoclonal antibody that binds the extracellular domain of EGFR, has been investigated in phase II and phase III trials in colorectal cancer, non-small cell lung cancer (NSCLC), and squamous cell carcinomas of the head and neck. Early results show good response rates and few toxicities. ZD1839 (Iressa) is a synthetic inhibitor ofthe EGFR tyrosine kinase. It belongs to a growing list of small-molecule receptor tyrosine kinase inhibitors that display high specificity for certain receptor tyrosine kinase subtypes. ZD 1839 has undergone phase I and II trials in the treatment of NSCLC and glioblastoma multiforme. It is generally well tolerated and appears to have some antitumor effect. Imatinib mesylate (Gleevec), which inhibits the KIT tyrosine kinase, has been approved in the United States for the treatment of chronic myeloid leukemia and stromal tumors of the gastrointestinal tract.

Implications for Clinical Therapeutics

Summary

Pharmacologic agents targeting specific mechanisms of tumor growth, invasion, and angiogenesis represent an emerging class of anticancer therapies. Although the vast majority of such drugs are in the preclinical or early clinical investigative stages, their great potential warrants pursuit from clinicians and scientists. The cadherin-catenin system has received the most attention in colorectal carcinoma, in which nonsteroidal anti-inflammatory drugs have been shown to exert an antineoplastic effect that may be mediated by reductions in intracellular ~-catenin.87 Interest in integrin antagonists has generally focused on their antiangiogenic activity. Medi-522 (Vitaxin), a monoclonal antibody with activity against aV~3 integrin, has entered phase IIII clinical trials in patients with advanced solid tumors and lymphoma. Proteases are an attractive potential target for cancer chemotherapy because they lie at the crossroads of several central processes in malignant progression. Antagonists of the uPAIuPAR system, which include small-molecule serine protease inhibitors and a truncated form ofuPAR, are undergoing early clinical trials. Synthetic MMP inhibitors, including marimastat, batimastat, BMS-275291, BAY 12-9566, Col-3, and others, have received substantial interest and were utilized in several phase III trials during the late 1990s. Unfortunately, results of these studies have been largely disappointing, with several studies terminating early because of adverse outcomes.f Such findings have highlighted the complex actions of MMPs as both positive and negative regulators of cancer progression; further understanding of their functions is needed at the basic science level. Perhaps the greatest immediate potential for emerging anticancer therapy lies with growth factor antagonists.

The process whereby malignant cancer cells invade and metastasize is complex, but current studies are elucidating the cellular mechanisms in each step of the involved pathways. Cancerous cells must detach from their primary tumors, disrupt restraining basement membrane barriers, and move into their surrounding matrix to enter the blood and lymph channels, allowing distant spread. Each of the mechanisms involved is a normal cellular property that has been coopted to promote malignant progression. Research has shed light on the complex and pleiotropic effects of adhesion molecules, proteases, and growth factors in cancer. Rational drug design has allowed clinicians and scientists to make promising early inroads into novel therapies that target tumor growth, angiogenesis, and invasion. Further basic science and clinical research are required before viable treatments for advanced malignancies become a reality.

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35. Ruoslahti E, Giancotti FG. Integrins and tumor cell dissemination. Cancer Cells 1989;1:119. 36. Hynes RO. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 1992;69: II. 37. Akiyama SK, Larjava H, Yamada KM. Differences in the biosynthesis and localization of the fibronectin receptor in normal and transformed cultured human cells. Cancer Res 1990;50: 1601. 38. Demeure Ml, Doffek KM, Rezaee M, et al. Diminished expression of the alpha 5 beta I integrin (fibronectin receptor) by invasive clones of a human follicular thyroid cancer cell line. World J Surg 1994;18:569. 39. Owens LV, Xu L, Craven RJ. Overexpression of the focal adhesion kinase (p125 FAK) in invasivehuman tumors. Cancer Res 1995;55:539. 40. Weiner TM, Liu ET, Craven RJ, Cance WG. Expression of focal adhesion kinase gene and invasive cancer. Lancet 1993;342:1024. 41. Frisch SM, Vuori K, Ruoslahti E, Chan Hui PY. Control of adhesiondependent cell survival by focal adhesion kinase. J Cell BioI 1996;134:793. 42. Hie 0, Furuta Y, Kanazawa S, et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 1995;377:539. 43. Shapiro L, Fannon AM, Kwong PO, et al. Structural basis of cell-cell adhesion by cadherins. Nature 1995;374:327. 44. Bremnes RM, Veve R, Hirsch FR, Franklin WA. The E-cadherin cellcell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cancer 2002;36:115. 45. Gayther SA, Gorringe KL, Ramus SJ, et al. Identification of germ-line E-cadherin mutations in gastric cancer families of European origin. Cancer Res 1998;58:4086. 46. Hajra KM, Fearon ER. Cadherin and catenin alterations in human cancer. Genes Chromosomes Cancer 2002;34:255. 47. Behrens 1, Mareel MM, van Roy FM, Birchmeier W. Dissecting tumor cell invasion: Epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Bioi 1989;108:2435. 48. Vleminckx K, Vakaet LJ, Mareel MM, et al. Genetic manipulation with E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 1991;66:107. 49. Brabant G, Hoang- Vu C, Cetin Y, et al. E-cadherin: A differentiation marker in thyroid malignancies. Cancer Res 1993;53:4987. 50. Scheumann GF, Hoang-Vu C, Cetin Y, et al. Clinical significance of E-cadherin as a prognostic marker in thyroid carcinomas. J Clin Endocrinol Metab 1995;80:2168. 51. Graff JR, Greenberg VE, Herman lG, et al. Distinct patterns of E-cadherin CpG island methylation in papillary, follicular, Hiirthle's cell, and poorly differentiated human thyroid carcinoma. Cancer Res 1998;58:2063. 52. Lamlum H, Hyas M, Rowan A, et al. The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: A new facet to Knudson's 'two-hit' hypothesis. Nat Med 1999;5:1071. 53. Muller T, Choidas A, Reichmann E, Ullrich A. Phosphorylation and free pool of beta-catenin are regulated by tyrosine kinases and tyrosine phosphatases during epithelial cell migration. J Cell Bioi 1995;130:67. 54. He TC, Sparks AB, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science 1998;281:1509. 55. Tetsu 0, McCormick F. Beta-catenin regulates expression of cyclin 01 in colon carcinoma. Nature 1999;398:422. 56. Crawford HC, Fingleton BM, Rudolph-Owen LA, et al. The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene 1999;18:2883. 57. Gottardi CJ, Wong E, Gumbiner BM. E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesionindependent manner. J Cell Bioi 2001 ;153:1049. 58. Osawa M, Kemler R. Molecular organization of the uvomorulincatenin complex. 1 Cell Bioi 1992;116:989. 59. van de Wettering M, Barker N, Harkes IC, et al. Mutant E-cadherin breast cancer cells do not display constitutive Wnt signaling. Cancer Res 2001;61:278. 60. Werb Z. ECM and cell surface proteolysis: Regulating cellular ecology. Cell 1997;91:439. 61. Coussens LM, Werb Z. Matrix metalloproteinases and the development of cancer. Chern Bioi 1996;3:895. 62. Irnren S, Kohn DB, Shimada H, et al. Overexpression of tissue inhibitor of metalloproteinases-2 by retroviral-mediated gene transfer in vivo inhibits tumor growth and invasion. Cancer Res 1996;56:2891.

Mechanisms and Regulation of Invasion in Thyroid Cancer - - 303 63. Nakamura H, Ueno H, Yamashita K, et al. Enhanced production and activation of progelatinase A mediated by membrane-type I matrix metalloproteinase in human papillary thyroid carcinomas. Cancer Res 1999;59:467. 64. Shi Y, Parhar RS, Zou M, et al. Tissue inhibitor of metalloproteinases-I (TIMP-I) mRNA is elevated in advanced stages of thyroid carcinoma. Br J Cancer 1999;79:1234. 65. Duffy MJ, Maguire TM, McDermott EW, O'Higgins N. Urokinase plasminogen activator: A prognostic marker in multiple types of cancer. J Surg OncoI1999;71:130. 66. Schmitt M, Harbeck N, Thomssen C, et al. Clinical impact of the plasminogen activation system in tumor invasion and metastasis: Prognostic relevance and target for therapy. Thromb Haemost 1997;78:285. 67. Smit JW, van der Pluijm G, Romijn HA, et al. Degradation of extracellular matrix by metastatic follicular thyroid carcinoma cell lines: Role of the plasmin activation system. Thyroid 1999;9:913. 68. Hoelting T, Siperstein AE, Clark OH, Duh QY. Epidermal growth factor enhances proliferation, migration, and invasion of follicular and papillary thyroid cancer in vitro and in vivo. J Clin Endocrinol Metab 1994;79:401. 69. Yeh MW, Rougier JP, Park JW, et al. Thyroid cancer cell invasion is regulated though epidermal growth factor receptor-dependent activation of MMP2/gelatinase A. Cancer Res (submitted). 70. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001;37(SuppI4):S9. 71. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000;19:6550. 72. Kajikawa K, Yasui W, Sumiyoshi H, et al. Expression of epidermal growth factor in human tissues. Immunohistochemical and biochemical analysis. Virchows Arch A Pathol Anat Histopathol 1991;418:27. 73. Hoelting T, Tezelman S, Siperstein AE, et al. Biphasic effects of thyrotropin on invasion and growth of papillary and follicular thyroid cancer in vitro. Thyroid 1995;5:35. 74. Harvey P, Clark 1M, Jaurand MC, et al. Hepatocyte growth factor/ scatter factor enhances the invasion of mesothelioma cell lines and the expression of matrix metalloproteinases. Br J Cancer 2000;83: 1147. 75. O-Charoenrat P, Modjtahedi H, Rhys-Evans P, et al. Epidermal growth factor-like ligands differentially up-regulate matrix metalloproteinase 9 in head and neck squamous carcinoma cells. Cancer Res 2000; 60: 1121.

76. Guo H, Zucker S, Gordon MK, et al. Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cells. J Bioi Chern 1997;272:24. 77. Atula S, Grenman R, Syrjanen S. Fibroblasts can modulate the phenotype of malignant epithelial cells in vitro. Exp Cell Res 1997;235:180. 78. Skobe M, Fusenig N. Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. Proc Natl Acad Sci USA 1998;95: 1050. 79. Chang C, Werb Z. The many faces of metalloproteases: Cell growth, invasion, angiogenesis and metastasis. Trends Cell Bioi 2001; II :S37. 80. Stetler-Stevenson WG. Matrix metalloproteinases in angiogenesis: A moving target for therapeutic intervention. J Clin Invest 1999; 103:1237. 81. Brooks PC, Stromblad S, Sanders LC, et al. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3.Cell 1996;85:683. 82. Brooks PC, Silletti S, von Schalsa TL, et al. Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell 1998;92:391. 83. Seftor RE, Seftor EA, Stetler-Stevenson WG, Hendrix MJ. The 72 kDa type IV collagenase is modulated via differential expression of alpha v beta 3 and alpha 5 beta I integrins during human melanoma invasion. Cancer Res 1993;53:3411. 84. Shibata K, Kikkawa F, Nawa A, et al. Both focal adhesion kinase and e-Ras are required for the enhanced matrix metalloproteinase 9 secretion by fibronectin in ovarian cancer cells. Cancer Res 1998;58:900. 85. Eliceiri BP, Cheresh DA. The role of alpha v integrins during angiogenesis: Insights into potential mechanisms of action and clinical development. J Clin Invest 1999; 103:1227. 86. Noe V, Fingleton B, Jacobs K, et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 2001;114:111. 87. Bright-Thomas RM, Hargest R. APC, beta-catenin, and hTCF-4; an unholy trinity in the genesis of colorectal cancer. Eur J Surg Oncol 2003;29: 107. 88. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science 2002;295:2387. 89. Harries M, Smith 1. The development and clinical use of trastuzumab (Herceptin). Endocr Relat Cancer 2002;9:75.

Surgical Management of Recurrent and Intrathoracic Goiters Antonio Sitges-Serra, MD • Juan J. Sancho, MD

Recurrent and intrathoracic goiters may pose considerable problems to the surgeon. Surgery is often indicated because local complications are common, and it requires thorough knowledge of the potentially distorted anatomy found at exploration. An appropriate preoperative assessment is essential because thyroid function may be abnormal, there may be sequelae from previous surgery, and precise anatomic definition of the lesion is important for a safe and expeditious operation. Symptoms may differ considerably from those found in uncomplicated goiters and may include airway compression, superior vena cava syndrome, and dysphonia, simulating a thyroid malignancy. Finally, the highest rates of postoperative vocal cord paralysis are reported after surgery for recurrent and complex intrathoracic goiters, suggesting that there is still room for improvement of surgical technique in this area. In this chapter, the pathogenesis, clinical presentation, preoperative assessment, and surgical approach to recurrent and intrathoracic goiters are discussed.

Recurrent Goiter Prevalence Palpable recurrence of nontoxic nodular goiter is seen in 2.5% to 20% of patients who have had previous thyroid surgery for the same condition; there seems to be a trend toward higher recurrence rates and probably more clinically complicated recurrences with longer follow-up. 1 Miccoli and colleaguesreported palpable recurrences in up to 25% to 30% of their patients after 3 years of follow-up, and this figure increased to 75% when strict echographic criteria were used for detecting small nodules. Although these authors noted that the aim of their surgical intervention was to "completely remove the thyroid nodules detected in the preoperative ultrasound," many surgeons would agree that such a high incidence of recurrent benign goiter was somehow related to an excessively conservative initial operation. Cohen-Kerem and coworkers- carefully observed 100 patients operated on for

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multinodular goiter with a less than total thyroidectomy for a mean of 93 months. The recurrence rate in this group was 21%, although only 4% of patients with a recurrence required a reoperation within that period.

Causes of Goiter Recurrence EXTENT OF THE INITIAL SURGICAL PROCEDURE

It has been known for a century that conservative surgery for multinodular goiter is associated with goiter recurrence. Kocher reported an 18% recurrence rate after enucleation of thyroid nodules." For this reason, bilateral thyroid resection had already been advocated by pioneers in thyroid surgery, such as Johann Mikulicz, Donald Balfour, Charles Mayo, George Crile, and Thomas Dunhill." From those times until 2 decades ago, subtotal thyroidectomy was considered the standard surgical treatment for multinodular goiter and for Graves' disease. Recurrences are still observed, however, because either this time-honored principle is ignored or goiter recurs in the contralateral lobe after total lobectomy for apparently uninodular disease. Furthermore, prolonged follow-up of large series of patients has shown that even bilateral subtotal thyroidectomy is associated with a substantial recurrence rate. Conservative initial operation can be incriminated as the main cause of goiter recurrence. Inadequate resections, such as isthmusectomy, nodule enucleation, subtotal lobectomy, and bilateral resection preserving the upper pole of the thyroid lobes, are still frequently found to have been the initial operations in patients with goiter recurrence. In the study by Bistrup and associates,' a recurrence rate of 19% was probably related to the number of atypical surgical procedures (six isthmusectomies and seven enucleations). In Anderson and colleagues' report," 38 subtotal lobectomies were followed by eight recurrences, independent of whether thyroxine (T 4 ) was administered postoperatively. These atypical surgical procedures on the thyroid gland should be abandoned. Recurrence after total lobectomy or appropriate subtotal

Surgical Management of Recurrent and Intrathoracic Goiters - -

bilateral thyroidectomy poses more conceptual questions. Did lobectomy miss significant contralateral disease? If so, should the extent of surgery be dictated by preoperative ultrasonographic findings? Should the contralateral lobe be thoroughly explored at the time of planned lobectomy? Do the remnant size and location determine recurrence? Most surgeons believe that when nodules are not palpable in the contralateral lobe preoperatively, a lobectomy is all that is required. Excessive reliance on lobectomy, however, may predispose to recurrence as a result of untreated contralateral disease-"; up to 45% of clinically solitary nodules show other associated nodules on echography." The extent of surgery for multinodular goiter is also questioned; subtotal bilateral, total on one side and subtotal on the other, and total thyroidectomy are currently practiced by experienced endocrine surgeons. A very low (2.5%) recurrence rate (l % after lobectomy and 3% after bilateral operation) was reported by Kraimps and colleagues- after a selectively aggressive policy. These authors carried out lobectomy only if the contralateral lobe did not have palpable nodules during the operation. They performed total lobectomy of the most affected lobe plus subtotal resection of the contralateral lobe in multinodular goiters. In their opinion, recurrence was almost always due to growth of nodules left behind at the initial operation. If we compare these results with the 10% recurrence rate reported in the comprehensive study by Berglund and coworkers," two facts deserve attention and may substantiate the opinion of the French group: (1) the time for the recurrence to appear was double in French patients (8 versus 4 years after the initial thyroidectomy) and (2) more extensive surgery was carried out by the French team (45% lobectomy and 53% bilateral operation versus 76% lobectomy and 24% bilateral operation, respectively). In a 7-year followup study after thyroidectomy," patients with recurrent goiter were compared with those without goiter. Again, unilateral resection had been performed more often in patients with recurrence (85%) than in patients without recurrence (61%). These data suggest that the extent of the initial procedure is probably a crucial factor in determining recurrence and support the contention that conservative initial procedures are associated with higher and earlier recurrence as a result of growth of preexistent nodules. From only the point of view of recurrence, total thyroidectomy would be the preferred surgical treatment for multinodular goiter. to In the hands of Reeve and colleagues, this operation has resulted in almost no permanent complications and more and more endocrine surgeons are using this approach.'! It should be stressed, however, that recurrent laryngeal nerve palsy or permanent hypoparathyroidism should not occur after thyroidectomy for benign disease, and that surgical judgment and experience are essential when a radical approach is considered. THE CONTROVERSY OF POSTOPERATIVE THYROXINE SUPPLEMENTATION

Whether T4 supplementation influences goiter recurrence rate after thyroidectomy is a matter of controversy. T4 replacement therapy is compulsory for patients rendered hypothyroid by thyroidectomy, and there is no question about giving these patients replacement therapy to keep their thyroid-stimulating hormone (TSH) levels in the normal range. On the other

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hand, there are no hard clinical data to support T 4 supplementation in euthyroid patients to prevent recurrence. Because TSH may stimulate thyroid remnant growth, there may be sound theoretical reasons to keep the serum TSH concentrations low after thyroidectomy. Success with this approach, however, has been far from uniform because factors other than TSH influence thyroid growth and, eventually, goiter recurrence.v'? Despite some contrary evidence, 13 during the 1980s some authorities were recommending routine T 4 supplementation to prevent recurrences after surgery for nontoxic goiter,":" This recommendation was largely empirical and based on the understanding of the effects of TSH on thyroid tissue growth." More recent reports, however, do not support the benefit of routine T4 supplementation in preventing goiter recurrence. In a retrospective study, Berglund and colleagues? showed no difference in recurrence rates between patients who received T4 and those who did not after partial thyroidectomy for benign goiter. The recurrence rate was 10% in 29 patients receiving "prophylactic" T4, 7% in 46 patients receiving replacement T4 treatment, and 11% in 186 patients not receiving T4. There were no differences in the TSH levels between patients with and without recurrence. A prospective, randomized study by Bistrup and colleagues' evaluated 100 patients consecutively operated on for nontoxic goiter. The treatment group received 100 ug of L-thyroxine per day. Sixty-nine patients had completed a 9-year follow-up, and the rate of palpable recurrence was 14.5% in treated patients versus 21.8% (not significant) in untreated patients. As in Berglund's series, recurrence was independent of TSH status. An aggressive TSH suppression approach was proposed by Miccoli and coauthors.? who randomly assigned their patients to substitutive (100 ug/day) or suppressive (2.2 to 3 ug/kg per day) T 4 therapy. At 3 years, a 78% recurrence rate (palpable plus echographically detected) was observed in the former group and 21% in the TSH-suppressed group. These recurrence rates are the highest reported to date, and doubts were expressed by discussants of the article about the appropriateness of the initial operation. It is unlikely that TSH-suppressive T4 therapy will ever be widely adopted to prevent recurrence of benign thyroid disease. It requires close monitoring for life as well as fine adjustment of the T4 dosage. It demands strict compliance with the assigned treatment and can have detrimental side effects. 1 Subclinical hyperthyroidism induced by suppressive doses of T4 may increase skeletal bone loss, particularly in postmenopausal women, and may have adverse effects in elderly persons with heart disease.l?"? Because many patients operated on for nontoxic goiter are young, it is difficult to justify suppressive treatment for life, whereas appropriate surgery may result in long-term recurrence rates below 5%. From the data reviewed, it is our opinion that prevention of recurrence ultimately depends on more aggressive resection. Routine postoperative T 4 supplementation seems unjustified.P OTHER FACTORS INFLUENCING GOITER RECURRENCE

Family history has been implicated in the postoperative recurrence of goiter, and some authors recommend T 4 supplementation if there is a positive family history." In the study by Berghout and colleagues," a family history of

306 - - Thyroid Gland goiter was found twice as often in patients with recurrent goiter at follow-up as in those without recurrence (65% versus 37%). Familial history was not found to influence recurrence in the series by Kraimps and associates'': patients with a positive family history had the same recurrence rate as those without a positive family history. Note, however, that the recurrence rate in this series of patients treated with extensive operations was only 2.5%. It has been claimed that recurrences may be higher in patients living in iodinedeficient regions and that this happens even when suppressive doses of T4 are administered.' On the other hand, Steiner and Zimmermann.P working in an endemic area, reported a reduction of recurrence by postoperative T4 supplementation. There are no obvious reasons for these discrepancies. A more recent issue is related to the intrinsic growth behavior of recurrent goiters. Harrer and coworkers'? found that most nodules within multinodular goiters that had regrown after a first subtotal thyroidectomy were of polyclonal rather than monoclonal composition. This suggests that these lesions are generated by de novo proliferation of cohorts of different thyrocytes sharing the common trait of an exceedingly high intrinsic growth rate or, alternatively, by unknown growthstimulating molecular events acting focally on clusters of cells derived from different ancestors.

the initial procedure. These cases, however, usually represent delayed treatment of a known, long-standing recurrence. COMPARTMENTAL SYNDROMES

Fibrosis resulting from previous surgery around the recurrent goiter and adjacent structures can cause severe compressive symptoms, even in the absence of a large thyroid mass. Fixation of strap muscles to the trachea closes the thyroid bed medially, preventing central bulging of the goiter, and contributes to an increase of the thyroid compartment pressure. In contrast, multinodular goiters that have not been operated on can expand quite freely in the neck and may attain a considerable size before causing compression syndromes. Dysphagia, dyspnea, and dysphonia are among the most common symptoms in patients with benign recurrent goiters referred for surgery (see Table 33-1). Vocal cord paralysis is occasionally seen as a manifestation of compartmental syndrome in patients who do not recall voice changes after the initial procedure until some years later. The following is an illustrative example.

Clinical Presentation Recurrent goiter may arise with symptoms and signs varying from a barely palpable asymptomatic nodule to a large cervicothoracic mass causing compartmental syndromes. Clinical presentation is different if patients are diagnosed during a regular follow-up study, in which recurrences are often asymptomatic, or if they come from surgical series, in which more severe symptoms are commonly required. In Berglund's follow-up study," only 4 of the 26 recurrences observed required surgery: 2 because of suspicion of malignancy and 2 because of compression symptoms. In the remaining 22 patients, recurrences were small and of little clinical significance. On the other hand, in the surgical series of Roeher and Goretzki," three quarters of patients complained of severe compressive symptoms (Table 33-1). TIME AFTER INITIAL SURGERY

The interval between thyroidectomy and clinical recurrence or reoperation varies. Clinical recurrence after a correct initial operation is rarely seen before 4 to 6 years. The mean interval from reported series varies from 4 to 9 years, but many patients are referred to the surgeon 15 to 20 years after

When it occurs on the same side as the recurrent goiter, vocal cord paralysis does not necessarily imply that the nerve was injured at the initial operation; it may be compressed or stretched and may regain its function when the thyroid remnant has been removed. Recovery rate in this circumstance has been reported to be 38%.24 HYPERTHYROIDISM

Dorbach and Schicha" evaluated thyroid function in 69 patients with recurrent goiter a mean of 13.8 years after thyroidectomy. A continuous increase in thyroid autonomy was noted at the rate of about 4% per year. At 20 years, 70% of recurrent goiters were functionally autonomous; thereafter, the prevalence of thyroid autonomy increased only marginally to reach about 90% in the 40th postoperative year. In the Roeher and Goretzki series,'> 18% of patients had clinical hyperthyroidism. It appears that more and more cells become autonomous over time in recurrent goiter, and this is another argument for early surgical treatment.

Preoperative Assessment Physical examination of patients with recurrent goiters may reveal a hard cervical mass, barely movable on swallowing,

Surgical Management of Recurrent and Intrathoracic Goiters - - 307

sometimes resembling a carcinoma. Fine-needle aspiration confirms the diagnosis of benign goiter in virtually all cases, although occasionally carcinoma may be suspected. On the other hand, a recurrent thyroid nodule after partial thyroidectomy for cancer may represent a benign nodule arising in the contralateral lobe." If possible, the operative notes and pathology reports from the initial thyroidectomy should be obtained. Initial conservative surgery (isthmusectomy, enucleation) makes re-exploration easier than initial extensive surgery, which may involve both sides of the neck. One or more parathyroid glands may have been resected with the thyroid, and this information may change the surgical strategy to prevent permanent hypoparathyroidism. Laryngoscopy should be performed routinely to ascertain whether prior surgery or recurrent goiter may have caused vocal cord paralysis. Normal voice should not prevent the surgeon from ordering a laryngoscopy because contralateral vocal cord compensation may minimize the clinical sequelae of previous nerve injury. Results of laryngoscopy should be made known to the patient when the physician discusses the risk of postoperative complications. As in other thyroid diseases, thyroid function should be determined before surgery. Patients presenting with hyperthyroidism should be treated with antithyroid drugs. Because most, if not all, thyroid tissue will be removed, the patient must be aware that T4 replacement therapy will be necessary for life. Serum calcium measurements are recommended. Patients with recurrent goiters are usually normocalcernic, but the true status of each parathyroid gland cannot be ascertained from preoperative calcium or parathyroid hormone (PTH) studies. Consequently, the surgeon must be extremely careful to identify and to preserve all viable parathyroid tissue. Preoperative or intraoperative PTH assays on blood drawn from the lowermost part of both internal jugular veins could be used to determine whether parathyroid glands are missing on one side. This might help the surgeon in planning a more conservative surgery or in proceeding to parathyroid autotransplantation if viability of identified parathyroid glands seems doubtful.

Surgical Approach Surgeons dealing with recurrent goiters need to be experienced in regular thyroid surgery and versatile enough to recognize potential dangers, prevent technical mishaps, and adapt their surgical strategy to the often unforeseen findings at cervical exploration. The aim of surgical treatment for recurrent goiter is to relieve the patients from compression symptoms and to prevent any further recurrence. Total thyroidectomy is thus the treatment of choice. This principal aim should be balanced against the risk of nerve injury and hypoparathyroidism. The surgeon should be satisfied carrying out a lesser procedure if, because of local conditions, risk of injuring the recurrent nerve or the parathyroid glands seems too high. In these cases, exhaustive hilar dissection can be avoided and an intracapsular near-total or subtotal resection can be performed. The surgical approach to recurrent goiters depends mainly on three factors: the type of initial procedure and the size and location of the recurrence.

If the initial procedure was a conservative operation (isthmusectomy or nodule enucleation), reoperation should not be too difficult because the dorsal aspects of both thyroid lobes were probably left undisturbed. A midline or lateral approach for total or subtotal resection is usually possible, and surgery is similar to a standard procedure for multinodular goiter. The ease of finding the recurrent nerve and parathyroid is influenced by the size and anatomy of the underlying goiter. If the initial procedure was a totallobectomy, chances are the contralateral lobe was not mobilized, and total thyroidectomy may be carried out with little difficulty with few, if any, postoperative complications.P In these cases, a lateral approach facilitates the exposure of the upper pole and dorsal aspect of the remaining lobe. The prior collar incision should be used. The skin flaps are elevated, and the lateral space of the neck is entered. The superficial neck fascia is divided sharply between the anterior border of the sternocleidomastoid muscle and the sternothyroid muscle. The dissection is deepened and the intermediate tendon of the omohyoid muscle transected. The medial cervical fascia is then incised along the vascular sheaths, and the middle thyroid vein is identified and ligated. At this stage, if the goiter is large or if the patient's neck is short or difficult to hyperextend, exposure of the upper thyroid vessels may require dividing the strap muscles lateral to the thyroid cartilage. The upper pole vessels are ligated on the surface of the thyroid to avoid injury to the superior laryngeal nerve, and the thyroid is mobilized medially. Locating and encircling the main trunk of the superior thyroid artery at this stage helps to define better the anatomy of the goiter and to identify the recurrent laryngeal nerve. The upper parathyroid gland and the recurrent nerve are found, and the dissection is continued downward. If the thyroid has an intrathoracic extension, the hilum may lie very posteriorly, and it may be preferable at this stage to pull the thyroid out of the thorax before identifying the recurrent laryngeal nerve (see later discussion of surgical approach to intrathoracic goiter). Care is taken to identify the thyrothymic ligament and ligate it on the surface of the thyroid to avoid damaging an intrathymic inferior parathyroid. The lower pole of the thyroid is inspected to uncover any subcapsular inferior parathyroid gland that may require dissection or resection and autotransplantation if preservation of its blood supply is not feasible. Medial rotation is completed, and the remaining isthmus is peeled off the trachea and the strap muscles that are usually adherent to it. The most difficult procedure for recurrent goiter is completion thyroidectomy after subtotal unilateral or bilateral resection and reoperation to excise a remnant that has developed into a large thyroid nodule. In these cases, the surgeon should proceed laterally. The most difficult step of this procedure is dissecting the relapsing thyroid nodule off its dorsal and lateral (vascular) adhesions and dissecting the hilum of the inferior thyroid artery where the recurrent nerve and the upper parathyroid gland may be encased in fibrous tissue. Identifying the nerve in the lowermost part of the neck and tracing it to the vascular hilum, where it intertwines with the terminal branches of the inferior thyroid artery, may be a helpful maneuver. Alternatively, if dissection is deemed too dangerous, the surgeon may perform subtotal or near-total intracapsular resection,8.15.26 leaving

308 - - Thyroid Gland 0.5 to 2 g of thyroid tissue. In contrast to thyroidectomy for cancer, there is no absolute need for total resection in benign recurrent goiter, particularly if this increases the risk of postoperative complications. As discussed earlier, when operating on patients with prior vocal cord paralysis, one should always attempt to identify and preserve the recurrent laryngeal nerve. Large recurrent goiters often have an intrathoracic extension because the undisturbed structures of the upper mediastinum allow the enlarging thyroid mass to expand caudally. Their management is discussed later in this chapter.

and a 1.2% rate by Al-Suliman and colleagues.P It is not possible to know with certainty how much viable parathyroid tissue remains, and where it remains, in a patient with recurrent goiter. One of our patients experienced permanent hypoparathyroidism after a completion thyroidectomy after a prior total lobectomy.

Postoperative Complications At the beginning of this century, Theodor Kocher warned against the risks of reoperative thyroid surgery." Beahrs and Sakulsky'? reported a high incidence of nerve palsies when recurrent diffuse toxic goiter was treated by repeated thyroidectomy. Although reoperation for Graves' disease is no longer performed because of the alternative of radioiodine ablation, reoperation for compressive or hyperfunctioning recurrent goiter still accounts for about 5% of thyroidectomies in specialized units. This is currently the type of thyroid operation with the highest rate of permanent recurrent nerve palsy and hypoparathyroidlsm.P'P'" The risk of permanent vocal cord paralysis was evaluated by Weitensfelder and colleagues in a series of 525 thyroidectomies." The probability of recurrent nerve injury increased in the following sequence: uncomplicated nodule < goiter < thyroid cancer < recurrent goiter. Early palsies (3.2%) were more frequent than permanent ones (0.8%); only one in four early palsies became permanent. This 75% recovery rate was similar to the 86% rate reported by Jatzko and colleagues." The prevalence of permanent vocal cord paralysis after repeated thyroidectomy for recurrent benign goiter in reports from specialized thyroid units is shown in Table 33-2. Permanent nerve injury is observed in very experienced hands, even when subtotal resections were performed at reoperation. Permanent hypoparathyroidism seems to be a problem of less importance than recurrent nerve injury. In the series of Levin" and Jatzko-? and their coworkers, no patient experienced permanent hypoparathyroidism after repeated thyroidectomy for recurrent benign goiter. A 3% permanent hypocalcemia rate was reported by Kraimps and colleagues"

Uncertainty about prior parathyroid status should make the surgeon very cautious when identifying and dissecting the parathyroid glands, particularly if the initial operation was done in a nonspecialized setting. As suggested earlier, intraoperative bilateral PTH assays may assist the surgeon in decision making.

Intrathoracic Goiter Mediastinal extension is common in large, bulky, multinodular goiters. Negative intrathoracic pressure and gravity facilitate the descent of an enlarged thyroid gland. Intrathoracic goiter is rarely «2%) a purely mediastinal tumor developing in an embryonic ectopic remnant or in a fragment of goiter left behind after an initial thyroidectomy.W" Because lateral and medial expansion may be limited after previous surgery, recurrent goiters often have more mediastinal prolongation. Between 3% and 20% of all intrathoracic goiters have undergone previous thyroid resections and are recurrent goiters.24.33-37

Definition and Prevalence Review of the definitions of intrathoracic goiter shows no consensus on when a goiter should be considered intrathoracic. The most commonly accepted definition would include all goiters with a lower pole lying below the thoracic outlet." Other groups refer to substernal goiter only in cases in which at least 50% of the thyroid mass is located below the thoracic inlet. 33.34 The Lahey Clinic group defined mediastinal goiters as "those with a major intrathoracic component that required reaching into the mediastinum for its dissection.v" This lack of agreement is reflected in the reported prevalences for intrathoracic goiter, which range from 4% to 20% of all operations for multinodular goiters. Intrathoracic goiters are also referred to as substernal goiters. Although the majority of intrathoracic goiters are anteriorly situated and thus are truly substernal, others may lie in the posterior mediastinum. Consequently, the term intrathoracic is preferred.

Surgical Management of Recurrent and Intrathoracic Goiters - - 309

Clinical Presentation Intrathoracic goiters usually occur late in life and have a peak incidence in the sixth decade. The average ratio between females and males is 3 to 4:1.38,39 In 20% to 30% of patients, the thyroid can be barely palpable or not palpable at all in the neck (grades I and II), and the thoracic extension represents most of the bulk of the goiter.35.36 Between 6% and 40% of patients reported in surgical series have no symptoms but have undergone thyroidectomy as prophylaxis against the potentially severe complications of a large intrathoracic thyroid mass. In these asymptomatic cases, substernal goiters are usually incidentally discovered on a plain chest radiograph.f The most common clinical manifestations of substernal goiters are related to compression or displacement of the adjacent visceral, neural, and vascular structures (Table 33-3). Tracheal obstruction and resulting upper airway compression symptoms were observed in 20% to 56% of the patients operated on for intrathoracic goiter in some reports. Ranging from mild to severe, these symptoms are isolated dyspnea, dyspnea with cyanosis, dyspnea with cyanosis prohibiting physical efforts, suffocation, and choking requiring immediate resuscitation." Dyspnea or cough may be worsened by some positions, such as lying flat or rolling on one side. The mechanism leading to airway obstruction is compression of the trachea by a goiter expanding between bone structures (spine, sternum, and first rib). Melliere and colleagues" observed severe airway compression by goiters in 58 patients (2% of their thyroidectomy cases). Fifteen were thyroid malignancies and 43 were benign goiters, of which 16 had an intrathoracic substernal extension compressing the airway. Shaha and coworkers'? cared for 24 patients admitted during a 4-year period with acute life-threatening airway distress resulting from thyroid enlargement (in 9 patients, immediate intubation was required). Twenty of these patients had benign goiter, 15 of them with marked substernal extension. In patients requiring emergency care for acute airway obstruction, surgery should be performed as soon as possible, and patients should not be weaned from the ventilator before surgery because this may be followed by acute asphyxia." Occasionally, dyspnea resulting from upper airway obstruction can mimic lung disease. In these cases, it may be difficult to determine precisely which component is the main reason for the dyspnea. Lung function tests aided by flow-loop studies may be very helpful in determining the degree of airway obstruction.

Stephenson and associates'? determined peak expiratory flow to investigatethe functional impact of substernal goiters. The preoperative peak expiratory flow ratio (observed to predicted) was significantly lower in patients with intrathoracic goiter, with a positive predictive value of 90%. This reduced peak expiratory flow improved after thyroidectomy. This test, along with failure of the peak airflow and forced expiratory volume to respond to bronchodilators, may be helpful in identifying the patients with respiratory disease and associated intrathoracic goiters who may benefit from thyroidectomy. The following is an illustrative example.

Entrapment of the recurrent laryngeal nerve or laryngeal distortion may be the major cause of hoarseness found in about one third of patients who have undergone thyroidectomy for intrathoracic goiter. Cho and coauthors-! reported that vocal cord paralysis from benign thyroid conditions may be particularly prevalent among patients with large substernal goiters, and they attributed this to nerve compression, ischemia, or stretching. The true prevalence of preoperative vocal cord paralysis in substernal goiters,

310 - - Thyroid Gland

FIGURE 33-1. A, Chest radiograph of a 72-year-old woman with dyspnea, reduced peak expiratory flow, and a massively calcified cervicothoracic goiter. B, Computed tomography (CT) scan section at the level of the subcricoid trachea showing narrowing of the airway lumen. C, CT scan section showing marked narrowingof the trachea at the thoracic outlet. D, Downward extension of the goiter to the aortic arch 2 em above the carina,

however, is difficult to determine because laryngoscopy has been carried out very selectively in symptomatic patients. Furthermore, the rate of hoarseness is probably higher than that of well-documented vocal cord dysfunction. As discussed earlier, vocal cord paralysis can be reversed by thyroidectomy.24,28,35,37 Thus, when operating on patients with intrathoracic goiter and dysphonia, the surgeon should identify the nerve and free it from surrounding fibrosis and adjacent compressive structures. Occasionally, however, nerve injury during a previous procedure or infiltration by an adjacent malignancy makes the recovery of vocal cord function impossible. Lateral and posterior displacement of the esophagus causes dysphagia in about one fourth of patients being operated on for bulky intrathoracic goiters. However, these symptoms do not severely interfere with swallowing; aspirative complications and malnutrition have not been reported. Esophagograms show esophageal compressions and displacement by the thyroid mass but add little information to the management of these patients. Less frequently (10% of cases), obstruction of venous return gives rise to a fully or partially developed superior vena cava syndrome. This can be obvious with cyanosis, dilation of superficial

facial and neck veins, and descending collateral venous circulation (Fig. 33-2). Subclinical venous compression can be diagnosed by having the patient raising the arms (Marafion's maneuver or Pemberton's sign) and observing distention of the external jugular and superficial neck veins. Collateral circulation may rarely involve the upper esophagus with "downhill" varices developingtv'" and causing an upper gastrointestinal hemorrhage. Superior vena cava syndrome is reversed by thyroidectomy and is considered to be an absolute indication for surgery." Gross multinodular goiters, whether in the neck or mediastinum, tend to develop autonomous nodules, particularly in patients with a prolonged history.15,25 Although in some reports no patients with hyperthyroidism were observed,24.33,36 in others biochemical or clinical evidence of thyroid hyperfunction was found in a significant (15 % to 40%) proportion of patients. 34,35,40 Hyperthyroidism is more common in elderly patients. In Cougard and colleagues' series of 218 intrathoracic goiters.'? hyperthyroidism developed in 35% of patients 70 years or older and in only 17% of those younger than 70 years, Hyperthyroidism in elderly patients can have potentially lethal cardiac complications such as congestive heart failure, arrhythmias, and worsening of

Surgical Management of Recurrent and Intrathoracic Goiters - -

311

FIGURE 33-2. A and B, Superior vena cava syndrome in a patient with intrathoracic goiter. A pyramid-shaped bilateral intrathoracic goiter could not be retrieved through a collar incision, and thyroidectomy through a combined cervicomediastinal approach was carried out, with complete relief of caval compression.

ischemic heart disease. Thyrotoxicosis may develop simultaneously as a result of hyperfunctioning "hot" nodules (Plummer's disease), after administration of iodinated contrast medium, or after T 4 is given in an attempt to inhibit further growth of the goiter. Thus, it is important to identify patients with hyperthyroidism because they should receive definitive treatment, preferably surgical, as soon as possible. Radioactive iodine has been used to control hyperthyroidism in multinodular goiters, but it is often ineffective, repeated doses are required, and long periods of time elapse before obtaining the desired effects. Furthermore, radiation thyroiditis may occur soon after the administration of iodine 131 and may precipitate an emergency situation in the patient with airway obstruction.t' In several series, the prevalence of cancer in intrathoracic goiters ranged from 3% to 17% (Table 33-4), including both overt malignancies and occult papillary carcinomas. It is difficult to make an accurate preoperative diagnosis of carcinoma because the intrathoracic component cannot be reached by a fine needle. Furthermore, the exact location of the malignant nodule is difficult to ascertain. A relatively high proportion of thyroid lymphomas (6 of 102 substernal goiters) has been observed in the two series with the highest prevalence of malignancy.v-" Advanced intrathoracic thyroid carcinoma

may pose significant surgical problems if infiltrating surrounding structures; biopsy plus tracheostomy, palliative resection, and total thyroidectomy with or without laryngeal or segmental tracheal resection have all been performed in these circumstances. Review of unusual clinical presentations of intrathoracic goiters reveals a fair number of severe, albeit rare, complications. The following cases were collected from the literature by Lawson and Biller38: hematemesis from downhill esophageal varices, abscess formation, Homer's syndrome, chylothorax from thoracic duct occlusion, and transient ischemic attacks resulting from a "thyroid steal syndrome." Fatal hematemesis has been described in a patient with fullthickness ulceration of the esophagus by a posterior substernal goiter." Axillosubclavian vein thrombosis was found in one patient with substernal goiter compressing the innominate vein."? Injury to the membranous portion of the trachea at intubation for general anesthesia has occurred in at least two patients as a result of the trachea being angulated anteriorly by a posterior intrathoracic goiter" (1. M. Rodriguez, personal communication); thyroidectomy and tracheal repair were performed through sternotomy in both cases.

Preoperative Imaging and Assessment Various reports have emphasized the usefulness of chest radiographs and airway films in assessing the extent of tracheal displacement and obstruction caused by intrathoracic goiters. 4 1,42 Chest radiographs were abnormal in 60% to 90% of patients included in four studies.33.35-37 Lateral chest radiographs should also be taken to demonstrate any anterior displacement of the trachea, which may render orotracheal intubation dangerous (Fig. 33-3). Occasionally, lung metastasis from a thyroid carcinoma can be observed.P''? Extrinsic pressure on mediastinal structures is best shown by CT scanning, which is the most sensitive imaging technique for diagnosing intrathoracic goiter extension. 36,38-40,42 It should be obtained in patients with a history suggesting

312 - - Thyroid Gland

Iodine 131 scintigraphy should always precede CT scanning because intravenous iodine administered for vascular enhancement blocks iodine uptake by the goiter. Technetium 99m scintigraphy does not depend on iodine uptake by

FIGURE 33-3. Lateral cervicothoracic radiographic projection showing marked anteriordisplacement of the trachea, widening of the tracheovertebral space, and airway compression against the sternal manubrium by a large (580 g) intrathoracic goiter.

compression symptoms and in those with nonpalpable lower thyroid borders, particularly if chest radiographs show an abnormal mediastinal outline or marked tracheal deviation. CT scanning gives important information to the surgeon regarding (I) the precise location of the intrathoracic extension; (2) the presence, extent, and situation of the continuity between the cervical and the thoracic components of the goiter; (3) definition of the limits of the lesion; (4) areas of calcification; (5) degree of heterogeneity and cystification of the intrathoracic portion; and (6) level and degree of tracheal lumen reduction. Nuclear magnetic resonance imaging may be superior" because, in addition to the information provided by CT scanning, it has two advantages: it offers sagittal and coronal tomographic cuts, which further clarify the anatomy of the intrathoracic goiter, and it delineates more precisely the relations among the goiter, the whole length of the trachea, and the mediastinal vessels. Vascular invasion by a thyroid malignancy may also be detected. Thyroid scintigraphy has limited value in the preoperative assessment of intrathoracic goiters. Iodine 131 scintigraphy often fails to show the mediastinal prolongation24•36,38,40 and adds little to the management of intrathoracic goiter. In patients with subclinical or overt hyperthyroidism, it may show hot hyperfunctioning nodules. The most useful indication for 131I scintigraphy is to clarify the nature of an isolated mediastinal mass, and it should be ordered for patients in whom CT scanning does not show mass continuity between the mediastinum and the neck. The following is an example.

FIGURE 33-4. Chest radiograph (A) and iodine 131 scmtigram

(B) in a case of recurrent intrathoracic goiter independent of the neck approached through a median sternotomy. Subtotal thyroidectomy was performed 22 years before. The mass was situated behind the ascending aorta.

Surgical Management of Recurrent and Intrathoracic Goiters - - 313

the goiter, but because of the proximity of the goiter to the thoracic cardiovascular blood pool, the findings may be difficult to interpret. Its sensitivity has been reported to be only 33%.49 Laryngoscopy should be carried out in patients presenting with hoarseness or dysphonia and in those who have had prior neck surgery. Vocal cord paralysis may result from (1) previous surgery, (2) compartmental syndrome, or (3) invasion of the recurrent laryngeal nerve by a thyroid malignancy. These different possibilities should be borne in mind during operation. Thyroid function tests must be performed before surgery because hyper- or hypothyroidism may be associated with large intrathoracic goiters. Hyperthyroid patients should be treated with antithyroid drugs before surgery. Some authors" add steroids to the antithyroid drugs to prevent worsening of compartmental syndromes resulting from goiter inflammation. This practice, however, is not widespread, and most surgeons would prefer to operate on patients not receiving steroids. Failure to measure a recent thyroid hormone concentration may precipitate perioperative metabolic problems. One of our patients experienced postoperative acute myxedema despite a near-normal hormone concentration 1 month before surgery.

Surgical Treatment Thyroidectomy is the preferred treatment for intrathoracic goiter (Table 33-5). T4 treatment has repeatedly proved ineffective in reducing goiter volume" and may result in hyperthyroidism. A clinical trial using suppressive doses of L-thyroxine(2.5 ug/kg per day) to reduce the size of sporadic nontoxic goiters has shown that after 9 months of continued treatment 58% of the patients responded (as determined by ultrasonography). The mean reduction of goiter size was 25%. This benefit, however, was short lasting; 9 months after

the treatment was discontinued, the goiter volume regained its basal value" Evidence supports a growing consensus against the use of L-thyroxine treatment for goiter size reduction or goiter growth prevention." CERVICAL APPROACH

More than 90% of intrathoracic goiters can be removed through a standard collar incision. Several maneuvers facilitate approaching, dissecting, and delivering huge goiters into the cervical wound. These are summarized in the following description of a "standard" bilateral resection for multinodular intrathoracic goiter. The best position of the patient on the operating table is the semisitting Kocher position with hyperextension of the neck. This reduces venous pressure in the upper trunk and helps to minimize blood loss. To reduce further the pressure in the neck, it may be helpful to divide the sternal head of the sternocleidomastoid muscle and the strap muscles. This maneuver also gives a wide exposure for approaching the upper pole and the laterodorsal aspects of the goiter. Before any attempt is made to mobilize the intrathoracic extension, the upper thyroid vessels and lateral middle veins should be divided on both sides. The surgeon then decides which is the smaller of the two lobes and rotates it medially to identify and encircle its inferior thyroid artery. The posterolateral surface of the lower pole should be carefully inspected to detect any subcapsular parathyroid gland that may require autotransplantation in the sternocleidomastoid muscle. During mobilization of bulky thyroid lobes, we have found it useful to apply a small bulldog vascular clamp to the trunk of the inferior thyroid artery. Perithyroid and hilar dissection can then be carried out with a minimal blood supply to the thyroid; the clamp is released after lobectomy is finished. Pressure in the neck is greatly relieved at this stage, and resection of the mobilized lobe can be accomplished. Tracheal attachments of the dorsum of the thyroid are severed as completely as possible without endangering the contralateral recurrent laryngeal nerve. Having freed as many cervical attachments as possible, the surgeon now approaches the lobe with a major intrathoracic component. Access to the hilum may be difficult before the intrathoracic extension has been brought up. If this is the case, no heroic efforts should be

314 - - Thyroid Gland made to identify the recurrent nerve at this stage; attention is focused instead on delivering the thoracic goiter extension into the neck. This is done by gently pulling up the thyroid lobe while the surgeon frees loose adhesions surrounding the mediastinal portion of the goiter with the index finger and applies caudal to cephalad pressure onto it. If this proves difficult, two additional maneuvers may be helpful: (l) the finger of the surgeon can be replaced by. a sterile "soup spoon," which breaks negative intrathoracic pressure, reaches lower, and occupies less space th~n the surgeon's finger 34•52 ; and (2) intracapsular fragmentation of the thyroid (morcellation) was proposed by Lahey to reduce the size and soften the intrathoracic goiter extension and facilitate its removal through the neck. This technique has two drawbacks: major bleeding and tumor spillage. When the goiter is obviously cystic and no fear of malignancy exists, Allo and Thompson" occasionally used a variation of this technique by introducing a metal suction device through small capsular incisions. Katlic and colleagues-' also used morcellation, aspiration, or both, in 5 of their 80 operations for intrathoracic goiter, with good results. After the intrathoracic portion has been delivered into the neck, the operation proceeds in a standard manner, identifying the recurrent laryngeal nerve and the upper parathyroid gland. Use of closed suction drains is advisable to evacuate blood from the large remaining mediastinal cavity. If the intrathoracic part is very difficult to mobilize before the recurrent nerve is identified and the tracheal attachments of the thyroid lobe are severed, the surgeon may identify the nerve close to the inferior hom of the thyroid cartilage where it enters the larynx and dissect it downward. This is followed by section of the tracheal attachments. By so doing, the cervical part is completely free and more efficient upward traction, without fear of injuring the nerve, can be exerted on the thoracic part of the goiter. Identification of the recurrent nerve at the level of the cricoid cartilage, however, is technically demanding and should not be attempted by the less experienced surgeon.

STERNOTOMY AND COMBINED MEDIASTINAL APPROACH

The anterior chest wall should be prepared and draped in all patients undergoing thyroidectomy for large intrathoracic goiters should sternotomy be required. Sternoto.my can be carried out as a last resort or maneuver, or, better, It should be planned electively for patients in whom preoperative imaging demonstrates very bulky, low-lying, solid goiters with complex anatomic relations. Between 2% and 11% of intrathoracic goiters have required removal through a combined cervical and sternotomy approach. 32-42,49.53 Indications for this combined approach include a large discrepancy between the diameter of the thoracic inlet and that of the goiter (pyramidal or pearshaped intrathoracic extensions; see Fig. 33-5), superior vena cava syndrome, retroesophageal extension, deepseated tumors reaching the carina, invasive carcinoma, and acute respiratory distress. The specific reasons for performing sternotomy given in a number of studies are su~m~zed in Table 33-6. The main advantage of sternotomy IS Widening of the thoracic inlet. Widening facilitates deeper blunt dissection and exteriorization of large thyroid masses that otherwise would require fragmentation. It may also help to control bleeding in the occasional case in which mediastinal vessels to the goiter are identified. If a carcinoma is present, invading the lower trachea, sternotomy may be required to achieve a radical resection.lv" If sternotomy is used, the cervical part of the operation is done first to control the major thyroid vessels. Leaving sternotomy to the end of the operation also has the advantage of shortening the wound exposure time, thus reducing the risk of infection. In cases of superior vena cava syndrome, however, early sternotomy may be required to decompress the large neck veins effectively. Partial or full median sternotomy is carried out. Partial sternotomy has the advantage of being more cosmetic. It can be done by raising the lower skin flap over the sternal manubrium, thus sparing a presternal skin wound.

Surgical Management of Recurrent and Intrathoracic Goiters - - 315

The following case history represents a good example of a patient with recurrent giant intrathoracic solid goiter who underwent total thyroidectomy through a combined cervicomediastinal approach.

Widening the thoracic outlet by sternum splitting may decrease the risk of recurrent laryngeal nerve injury in difficult cases. In a study by Cougard and colleagues/" no permanent nerve palsy was observed in 16 patients who had sternotomy, whereas a 6.8% palsy rate was noted in patients operated on through only a cervical incision.

THORACOTOMY A half-century ago, there was uncertainty as to the best route for resecting large intrathoracic goiters when access to the chest was required.> Thoracotomy (usually right) was proposed mainly by thoracic surgeons such as Clagett, Sweet, and Ellis in the belief that most intrathoracic goiters represented isolated thoracic masses and that posterior goiters could not be safely removed through a neck incision. Since then, experience has shown that approaching the intrathoracic goiter through posterolateral thoracotomy should be discouraged. There are several reasons for this. Posterior thoracic goiters are no longer per se an indication for thoracotomy because they can usually be delivered through collar incision or median sternotomy. Major thyroid vessels cannot be appropriately controlled from the thorax, and the cervical extension of the goiter cannot be dissected free from the adjacent structures. It is because of these

FIGURE 33-5. Recurrent goiter

witha largeintrathoracic extension of the right lobe. A, Chest radiograph film shows lateral displacement of the trachea by a large mediastinal mass. B, Computed tomography scan shows downward prolongation of the goiter past the aortic arch. C. Sagittal section in a nuclear magnetic resonance scan showsthe relationshipof the intrathoracic goiterwith the venous innominate trunk, the spine, and the right mainbronchus. D. Coronal section shows tracheal compression, pleural thickening around the goiter, and relationship withthecarina. Median sternotomy was performed to allow blunt finger dissection of the lower pole of the right lobe lying behind the vena cava on the right main bronchus.

316 - - Thyroid Gland technical difficulties that thoracotomy is associated with substantial risk of recurrent laryngeal nerve injury.37,55.56 If a thoracotomy is carried out because an incorrect diagnosis of purely posterior mediastinal "tumor" has been made, it often requires conversion to a neck incision.'? Shahian and Rossi'? made the case for exceptional circumstances that may require thoracotomy: at the Lahey Clinic, two patients had a cervical and thoracotomy approach in a 20-year period. Both presented with a right posterosuperior mediastinal goiter extending from a left thyroid lobe passing behind the trachea and the esophagus. In our experience, however, these "corkscrew goiters" can also be approached by a full median sternotomy and opening of the right pleural cavity. Gentle pressure on the posterior thyroid mass helps to untwist the goiter around the tracheoesophageal axis. SUMMARY

It is usually difficult to foresee which patients will require a thoracic approach when operating on an intrathoracic goiter. It is therefore advisable to prepare the surgical field for sternotomy in cases of huge thoracic thyroid masses, especially if they are posterior, suspicious of being malignant, or recurrent." Further studies based on preoperative imaging techniques, anatomic landmarks, and volumetric studies may serve to delineate further the subset of patients who require a thoracic approach.

Postoperative Complications The morbidity rate after surgery for intrathoracic goiters ranges between 4% and 12% in various series from referral institutions. The most common significant complications are listed in Table 33-7. Patients with the highest complication rates are those with thyroid malignancies and those undergoing a combined cervicomediastinal approach. Despite the extensive perithyroidal dissection required to resect these large goiters, permanent hypoparathyroidism is unusual in the hands of experienced surgeons. To achieve these results, knowledge of the altered anatomy is essential, as is proper identification and eventually autotransplantation of any parathyroid gland in the surface of the thyroid whose blood supply cannot be guaranteed. Recurrent laryngeal nerve paralysis results from not identifying the nerve and inadvertent injury or from stretching during blunt dissection of large intrathoracic masses. As previously stated, efforts to identify the nerve before the

intrathoracic goiter is fully mobilized may result in inadvertent injury. If the nerve is not transected, vocal cord paralysis is usually (75%) temporary. Tracheal softening leading to tracheal collapse and respiratory failure (tracheomalacia) is being reported exceptionally, even in series of patients operated on for airway compression. In several major studies 32-3M1,42 encompassing 298 patients (including two series of patients operated on for respiratory distress), only 2 patients were diagnosed with tracheomalacia and required postoperative tracheostomy.3M2 Of the seven patients with tracheomalacia reported by Geelhoed.l? three had recurrent goiters and one had a longstanding multinodular goiter. Methods for management of tracheomalacia are extensively reviewed in this study. External splinting by custom-made rings or Marlex mesh has also been tried.59 Tracheostomy, however, remains the standard treatment whenever tracheal softening is identified at surgery.

Summary Operations on recurrent and intrathoracic goiters are associated with increased intraoperative technical difficulties and permanent sequelae. Because compression symptoms are common or may develop with time, surgery becomes the only rational therapy. An appropriate preoperative assessment, including laryngoscopy, CT scanning, and thyroid function tests, and an experienced surgeon are essential for minimizing perioperative complications. Safe thyroid resection is the aim, and the incidence of permanent vocal cord paralysis and hypocalcemia should be near zero when treating these benign conditions.

REFERENCES I. Burman KD. Is long-term levothyroxine therapy safe? Arch Intern Med 1990;15:2010. 2, Miccoli P, Antonelli A, Iaconi P, et al. Prospective, randomized, double-blind study about effectiveness of levothyroxine suppressive therapy in prevention of recurrence after operation: Result at the third year of follow-up. Surgery 1993;114: 1097. 3. Cohen-Kerem R, Schachter P, Sheinfeld M, et al. Multinodular goiter: The surgical procedure of choice. Otolaryngol Head Neck Surg 2000;122:848. 4. Welbourn R. The History of Endocrine Surgery. New York, Praeger, 1990, p 44. 5. Bistrup C, Nielsen JD, Gregersen G, Franch P. Preventive effect of levothyroxine in patients operated for non-toxic goitre: A randomized trial of one hundred patients with nine year follow-up. Clin Endocrinol (Oxf) 1994;40:323. 6. Anderson PE, Hurley PR, Rosswick P. Conservative treatment and long-term prophylactic thyroxine in the prevention of recurrence of multinodular goiter. Surg Gynecol Obstet 1990;171:309. 7. Berglund J, Bondesson L, Christensen SB, et al. Indications for thyroxine therapy after surgery for nontoxic benign goitre. Acta Chir Scand 1990;156:433. 8. Kraimps JL, Marechaud R, Gineste D, et al. Analysis and prevention of recurrent goiter. Surg Gynecol Obstet 1993;176:319. 9. Berghout A, Wiersinga WM, Drexhage HA, et al. The long-term outcome of thyroidectomy for sporadic nontoxic goiter. Clin Endocrinol (Oxf) 1989;31: 193. 10. Reeve TS, Delbridge L, Cohen A, et al. Total thyroidectomy: The preferred option for multinodular goiter. Ann Surg 1987;206:782. I I. Delbridge L, Guinea AI, Reeve TS. Total thyroidectomy for bilateral benign multinodular goiter: Effect of changing practice. Arch Surg 1999;134:1389.

Surgical Management of Recurrent and Intrathoracic Goiters - 12. Duh QY, Clark OH. Factors influencing the growth of normal and neoplastic thyroid tissue. Surg Clin NorthAm 1987;67:281. 13. Geerdsen JP, Frolund L. Recurrence of nontoxic goitre with and without postoperativethyroxine medication. Clin Endocrinol (Oxf) 1984;21:221. 14. Goretzki P, Roeher HD, Horeyseck G. Prophylaxis of recurrent goiter by high-dose L-thyroxine. World 1 Surg 1981;5:855. 15. Roeher HD, Goretzki PE. Management of goiter and thyroid nodules in an area of endemic goiter. Surg Clin North Am 1987;67:233. 16. Goretzki PE, Clark OH. Thyroid-stimulating hormone receptor studies. Prog Surg 1988;19:181. 17. Stall GM, Harris S, Sokoll U, et al. Accelerated bone loss in hypothyroid patients overtreated with L-thyroxine. Ann Intern Med 1990;113:265. 18. Adlin EV, Maurer AH, Marks AD, et al. Bone mineral density in postmenopausal women treated with L-thyroxine. Am 1 Med 1991;90:360. 19. Ross DS. Subclinical thyrotoxicosis. In: Mazzaferri EL, Bar RS, Kreisberg RA (eds), Advances in Endocrinology and Metabolism. St. Louis, CV Mosby, 1991. 20. Smith SA, Gharib H. Thyroid nodule suppression. In: Mazzaferri EL, Bar RS, Kreisberg RA (eds), Advances in Endocrinology and Metabolism. St. Louis, CV Mosby, 1991. 21. Martina B, Staub JJ, Gemsenjager E. Long-term follow-up after thyroidectomy: Incidence of recurrent goiter and functional results. Schweiz Med Wochenschr 1992;122:1753. 22. Steiner H, Zimmermann G. Reinterventions an der Schilddriise. Cited in Roeher HD, Goretzki PE. Management of goiter and thyroid nodules in an area of endemic goiter. Surg Clin North Am 1987;67:233. 23. Harrer P, Broecker M, Zint A, et al. Thyroid nodules in recurrent multinodular goiters are predominantly polyclonal. 1 Endocrinol Invest 1998;21:380. 24. Cho HT, Cohen IP, Som ML. Management of substernal and intrathoracic goiters. Otolaryngol Head Neck Surg 1986;94:282. 25. Dorbach M, Schicha H. Frequency and temporal occurrence of a functional autonomy in recurring goiter. Nuklearmedizin 1993;32:316. 26. Levin KE, Clark AH, Duh QY, et al. Reoperative thyroid surgery. Surgery 1992;III :604. 27. Beahrs OH, Sakulsky SB. Surgical thyroidectomy in management of exophthalmic goiter. Arch Surg 1968;96:512. 28. AI-Suliman NN, Graversen HP, Blicher-Toft M. Surgical treatment of benign recurrent goiter: Technique, complications and permanent sequelae. Ugeskr Laeger 1994;156:165. 29. latzko GR, Lisborg PH, Miiller MG, Welle VM. Recurrent nerve palsy after thyroid operations: Principal nerve identification and a literature review. Surgery 1994;115:139. 30. Menegaux F, Turpin G, Dahman M, et aI. Secondary thyroidectomy in patients with prior thyroid surgery for benign disease: A study of 203 cases. Surgery 1999;126:479. 31. Weitensfelder W, Lexer G, Aigner H, et aI. Long-term laryngoscopic follow-up in vocal cord paralysis following struma surgery. Chirurgie 1989;60:29. 32. Shahian DM. Surgical treatment of intrathoracic goiter. In: Cady B, Rossi RL (eds), Surgery of the Thyroid and Parathyroid Glands. Philadelphia, WB Saunders, 1991, p 215. 33. Katlic MR, Grillo HC, Wang Cc. Substernal goiter. Am 1 Surg 1985;149:283. 34. Allo MD, Thompson NW. Rationale for the operative management of substernal goiters. Surgery 1983;94:969.

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35. Michel LA, Bradpiece HA. Surgical management of substernal goitre. Br 1 Surg 1988;75:565. 36. Sanders LE, Rossi RL, Shahian DM, Williamson WA. Mediastinal goiters: The need for an aggressive surgical approach. Arch Surg 1992;127:609. 37. Maruotti RA, Zannini P,Viani MP, et aI. Surgical treatment of substernal goiters. Int Surg 1991;76:12. 38. Lawson W, Biller HF. Management of substernal thyroid disease. In: Falk SA (ed), Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine, and Radiotherapy. New York, Raven Press, 1990, p 389. 39. Rodriguez 1M, Hernandez Q, Pinero A, et aI. Substernal goiter: Clinical experience of 72 cases. Ann Otol Rhinol LaryngoI1999;108:501. 40. Cougard P, Matet P, Goudet P, et al. Substernal goiters: 218 operated cases. Ann Endocrinol (Paris) 1992;53:230. 41. Melliere D, Saada F, Etienne G, et al. Goiter with severe respiratory compromise: Evaluation and treatment. Surgery 1988;I03:367. 42. Shaha A, Alfonso A, laffe BM. Acute airway distress due to thyroid pathology. Surgery 1987;102:1068. 43. Stephenson BM, Shandall AA, Griffith GH. Peak expiratory flow in the detection ofretrosternal goiter. Ann R Coli Surg Engl 1991;73:215. 44. Kelly TR, Mayors Dl, Bontsicaris RS. "Downhill" varices: A cause of upper gastrointestinal hemorrhage. Am Surg 1982;48:35. 45. Sorokin JJ, Levine SM, Moss EG, Biddle CM. "Downhill" varices: Report of a case 29 years after resection of a substernal thyroid gland. Gastroenterology 1977;73:345. 46. Parker DR, el-Shaboury AH. Fatal haematemesis due to benign retrosternal goiter. Postgrad Med 11992;68:756. 47. Santos GH, Ghalili K. Axillosubclavian vein thrombosis produced by retrosternal thyroid. Chest 1990;98: 1281. 48. Dubost C, D' Acremont B, Potter C, et al. Tracheal injury caused by intubation for compressive endothoracic goiter. 1 Chir (Paris) 1991;128:109. 49. Al-Suliman NN, Graversen HP, Blicher-Toft M. Intrathoracic goiter: Diagnostic aspects, surgical complications and permanent sequelae. Ugeskr Laeger 1994;156:1646. 50. Berghout A, Wiersienga WM, Drexhage HA, et al. Comparison of placebo with L-thyroxine alone or carbimazole for treatment of sporadic goiter. Lancet 1990;336: 193. 51. Gharib H, Mazzaferri EL. Thyroxine suppressive therapy in patients with nodular thyroid disease. Ann Intern Med 1998;128:386. 52. Landreneau RI, Nawarawong W, Boley TM, et al. Intrathoracic goiter: Approaching the posterior mediastinal mass. Ann Thorac Surg 1991;52:134. 53. Mussi A, Ambrogi MC, Iacconi P, et al. Mediastinal goitres: When the transthoracic approach? Acta Chir Belg 2000;100:259. 54. Daou R. Substernal goitre. Chirurgie 1991;117:43. 55. ludd ES, Beahrs OH, Bowes DE. A consideration of the proper surgical approach for substernal goiters. Surg Gynecol Obstet 1960;110:90. 56. Ellis FH lr, Good CA, Seybold WD. Intrathoracic goiter. Ann Surg 1952;135:79. 57. Shahian DM, Rossi RL. Posterior mediastinal goiter. Chest 1988;94:599. 58. Monchik 1M, Materazzi G. The necessity for a thoracic approach in thyroid surgery. Arch Surg 2000;135:467. 59. Geelhoed GW. Tracheomalacia from compressing goiter: Management after thyroidectomy. Surgery 1988;I04: 1100.

Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract H. Dralle, MD • M. Brauckhoff, MD • A. Machens, MD • O. Gimm, MD

Thyroid cancer invading the aerodigestive tract is uncommon (Table 34-1). Apart from distant metastases, extrathyroid invasion is the dominating risk factor for tumor recurrence and mortality in thyroid cancer. [-3 Among the patients with extrathyroid extension of thyroid cancer, those with tracheal or esophageal invasion have a worse prognosis in terms of survival than those with invasion of other extrathyroid structures." Apart from tumor extension, the extent of primary surgery as the mainstay of therapy in differentiated and medullary thyroid carcinoma significantly affects tumor recurrence and survival.v' In an investigation regarding cancer-specific cause of death in thyroid cancer, local complications from tumor growth accounted for 35% of fatalities, distant metastases for 34%, local and metastatic disease jointly for 28%, and complications related to therapy for 4%.7 By direct tumor extension, thyroid cancer may take three main directions of spread: (1) the central route, involving the paratracheallymph nodes, the recurrent laryngeal nerve, and the aerodigestive axis; (2) the lateral route, involving lymph nodes of the lateral compartment, the carotid sheath; and the lateral nerves; and (3) the mediastinal route, involving the upper mediastinal lymph nodes, the great vessels, the thymus, and other mediastinal organs. The four main types of thyroid cancer, papillary, follicular, medullary, and undifferentiated thyroid carcinoma, differ with regard to tumor biology and disease progression not only from each other but also from squamous cell carcinoma of the head and neck. Consequently, the efficacy of adjuvant treatment modalities such as radioiodine therapy and percutaneous irradiation varies significantly according to the tumor entity. Unlike involvement of the lateral neck and mediastinum, invasion of the aerodigestive tract has stirred considerable controversy concerning indications, technique, and extent of resection. Because patients with aerodigestive tract invasion are generally older than patients without aerodigestive tract

318

invasiont'? and the aerodigestive tract is vitally important, surgery in this setting poses a real challenge for both the surgeon and the patient. Prevention and elimination of airway obstruction are the primary objectives of surgical therapy, while striving at the same time to preserve the patient's voice capacity and quality of life. As in other complex diseases, optimal selection of patients and outcome for thyroid cancer invading the aerodigestive tract can be accomplished only in a multidisciplinary approach. The preoperative work-up for local and distant tumors relies on joint radiologic and nuclear medicine expertise. The surgical resectability depends on the cooperation of surgeons with anesthesiologists; ear, nose, and throat specialists; and plastic, vascular, and thoracic surgeons. Postoperative care requires the combined expert knowledge from fields as diverse as radiology and nuclear medicine (radioiodine therapy, percutaneous irradiation) and advanced endoscopy (e.g., intraluminal stenting, laser ablation). During the past 4 decades, sophisticated surgical techniques of laryngotracheal resection have been developed and have become the prerequisite to perform extended resections with minimal morbidity and mortality. Optimal survival can be achieved by radical resection of the primary tumor at the first operation.' Hence, a thorough preoperative ascertainment of tumor spread and a speedy referral of patients to specialized centers for primary surgery are the mainstay of therapy for thyroid cancer invading the aerodigestive tract.

Preoperative Assessment of Local and Distant Disease As invasion of the aerodigestive tract by thyroid cancer remains asymptomatic for a long time, the diagnosis of visceral infiltration is often not made preoperatively.

Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - - 319

A heightened index of suspicion is warranted in patients who have either sonographic evidence of airway invasion or clinical symptoms of extrathyroid tumor growth such as hoarseness, hemoptysis, and dysphagia. These patients should undergo a thorough work-Up, including fine-needle aspiration cytology, computed tomography, and/or magnetic resonance imaging. In this setting, flexible laryngotracheobronchoscopy, pharyngoesophagoscopy, and endolurninal biopsy are helpful in verifying full-thickness invasion of the aerodigestive tract and mapping the longitudinal and circumferential extension of tumor involvement. In the absence of transmural involvement radiologically, endoscopy is unlikely to yield additional information. Indirect laryngoscopy and direct laryngoscopy provide information on preoperative vocal cord function (Fig. 34-1). Every patient with locally advanced thyroid cancer should be evaluated for his or her cardiovascular and pulmonary performance and also undergo intensive imaging to identify or exclude distant metastases (Fig. 34-2). Lung and bone are the most common sites of distant metastases in thyroid carcinoma.P Remarkably, only half of patients with pulmonary metastases die because of respiratory insufficiency.' Bone metastases account for 30% to 40%7.14,15 and brain metastases for 3% to 20%7,16-18 of cancer-specific fatalities.

FIGURE 34-1. Radiologic and endoscopic diagnosis of intramural and intraluminal invasion of upper airway in advanced thyroid cancer. A and B. A 62-year-old woman with follicular thyroid carcinoma, insular type, invading the left wall of the cricoid and trachea (MRI). C and D, A 35-year-old woman with recurrent follicular thyroid cancer with intraluminal invasion of the right lateral part and pars membranacea of the upper trachea (MRI). E and F, A 61-year-old woman with recurrent papillary thyroid cancer invading the posterior part of the larynx and upper trachea, endoscopy (E) and MRI (F).

320 - - Thyroid Gland Resectability:

Clinical check Cervical US

assessment of tumor type and local extension

FNAC

Tracheal, esophageal wall invasion

Operability: assessment of physical condition and systemic tumor extension

Complete medical evaluation of physical condition

FIGURE 34-2. Preoperative evalu-

ation of resectability and operability in thyroid cancer patients with aerodigestive invasion (ADI). CT = computed tomography; FNAC = fine-needle aspiration cytology; MRI = magnetic resonance imaging; PET = positron emission tomography; US = ultrasonography.

Imaging of lung, liver, bone, brain (CT/MRI,

PET)

MUltiple progressive lung and/or other distant, mets Walt and see

or palliation

Evidence suggests that fluorodeoxyglucose (FOG) positron emission tomography (PET) may be suitable to detect metastatic deposits from differentiated thyroid cancer in patients who have elevated thyroglobulin levels but negative radioiodine scans. The detection rate of FOG-PET in this setting was 70% to 80%. False-negative results were obtained in patients who displayed low serum thyroglobulin levels and/or minimal cervical lymph node enlargement. 19.20 On multivariate analysis, patients with a metastatic FDGPET volume of more than 125 mL had a significantly reduced survival." FDG-PET may also be useful to detect metastatic deposits from medullary thyroid carcinoma"

Selection of Patients For patients with locally advanced thyroid cancer, especially when it invades the aerodigestive tract, the key to success is the selection of the best operation for the individual patient. This allocation of the best operation must incorporate aspects as diverse as technical resectability of the tumor, progression of disease, and the patient's physical condition and social background.

Local Resectability Modem imaging techniques are highly accurate in determining the extent of local disease, not only in respect to soft tissue and vascular invasion but also in terms of laryngeal, tracheal, or esophageal invasion.23•24 Therefore, not only must palliative versus curative interventions be balanced against each other but also various types of resection (see Fig. 34-2). In contrast to primary squamous carcinoma, which requires wide excisions, resectability of invasive thyroid carcinoma can often be achieved, leaving only small margins of normal tissue. When resection margins are involved histologically, the microscopic tumor deposits can sometimes be ablated subsequently with radioiodine therapy provided the residual tumor takes up iodine. Irresectability from a technical point of view is ill defined but mostly present in patients with mediastinal involvement of the great vessels, including the innominate artery, trachea, and esophagus. With widespread neck involvement, extensive surgical procedures on the visceral axis are of limited value, especially when tumor widely invades the carotid sheath. In general, multiple distant metastases, undifferentiated carcinoma, or non-Hodgkin's lymphoma precludes extensive

Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - - 321

surgery on the aerodigestive tract. There are only a few reports of successful resections on the aerodigestive tract for undifferentiated thyroid carcinomas, associated with a long-term palliation of 3 to 7 years. 12.25

Progression of the Disease In patients with recurrent disease and poorly differentiated carcinoma, progression of the disease should be considered. This may be difficult because reliable biomarkers for tumor progression are nonexisting. The role of distant metastases is hard to evaluate. Patients with metastases confined to the lung have an improved survival rate compared with those with multiple-organ involvement, bone metastases only, or other single-organ involvement.Fv" Only half of the patients in the first group succumb to their pulmonary metastases." Accordingly, most authors do not recommend excluding surgery on the aerodigestive tract when the metastatic disease is stable or only slowly progressing and confined to the lung. 9,IO,28-31 Except for clinical risk factors such as disease progression or local or distant tumor spread, there is only limited knowledge about biologic or molecular markers indicative of a dire prognosis in thyroid cancer. Poorly differentiated tumors.F an aneuploid DNA pattern," and nuclear atypia!' have been encountered more frequently in patients with than without tracheal invasion. The prognostic suitability of these and others parameters such as p53,32 CD97,33 or E-cadherin34-36 remains to be elucidated. Owing to the lack of suitable prognostic biomarkers, clinical decision making continues to be based on the presence or absence of clinical risk factors.

Physical and Mental Condition of the Patient Aerodigestive tract invasion is often associated with two major pro~lems: poorly differentiated thyroid cancers and elderly patients. Although papillary thyroid carcinoma prevails in all published series on aerodigestive invasion (Table 34-2), ~oorly differentiated thyroid carcinomas may be more susceptible to laryngotracheal invasion than their well-differentiated counterparts. 8,II,12,37,38 In addition, patients with aerodigestive invasion are on average 5 to 10 years older than those without aerodigestive invasion. 9,10-12 These increments in patients' age require a careful evaluation of the patient's cardiovascular and pulmonary performance and physical condition, all of which tend to deteriorate with increasing age (see Fig. 34-2). . In inoperable cases, a "wait and see" policy may be supenor to tracheostomy when the obstruction of the airway is tolerable. In patients with progressive airway obstruction and local irresectability, construction of a tracheostomy should be avoided because of the associated decline in the patient's quality of life. Instead, intraluminal stenting and tumor ablation (e.g., by laser surgery) should be attempted before resorting to permanent tracheostomy.

Surgical Approach The first surgical attempts at trachea resections were reported at the end of the 19th century by Gluck and Zeller (1881 )39 and Colley (1895).40 These authors used dogs for their experiments on segmental resections of the neck trachea.

322 - - Thyroid Gland Reconstruction was performed using either circular anastomoses in a three-stage operation'? or a bayonet-shaped anastomosis in a one-stage operation." V. Eiselsberg, in 1896, was the first to publish a circular tracheal resection with primary anastomosis that was successful; the patient was a 46-year-old man. Before that period, tracheal stenoses were treated only with tracheal dilatation, longitudinal tracheal splitting, and/or placement of tracheal tubes." The milestones on the road toward a systematic approach to tracheal resections were the development of intubation anesthesia in the 1940s and 1950s42-44 and the technique of tracheal release described in 1946.45

Preparation of the Patient The patient is prepared for a cervical or cervicomediastinal procedure. When a cervical evisceration is envisaged, the preparation also involves the upper abdomen for a median abdominal incision to harvest the intestinal graft. Intubation is achieved either orally or through a preexisting tracheostomy. In the latter instance, the indwelling tracheal cannula is exchanged for an oral endotracheal tube when there is no proximal obstruction. For most extended cervical operations, a low U-shaped collar incision is preferred, which can be extended down to the xiphoid for complete median sternotomy and mediastinal dissection. The cervical cutaneous flap is developed upward to reach the cranial larynx.

Cervical Exploration The aim of cervical exploration is to determine resectability and, when the tumor is resectable, to mobilize the tumor in a centripetal direction, a procedure referred to as "encircling the enemy." This technique affords an en bloc resection of the whole surgical specimen, thus avoiding piecemeal resection of the tumor. Usually, the dissection starts at the anterior and medial aspect of the jugular vein and carotid artery on the side with the most tumor. Precluding extensive visceral resections, invasion of the carotid artery is a rare phenomenon (Table 34-3), often indicative of poorly differentiated cancer. Combining carotid artery resection with

cervicovisceral resection carries a high risk of lethal complications, notably carotid rupture, and thus should be avoided. Concomitant lateral lymph node metastases should be dissected appropriately. Prophylactic dissections are not recommended in order to preserve the soft tissues.

Surgical Technique of Radical Resection of Aerodigestive Invasion Tracheoesophageal invasion is often the result of direct invasion from the primary tumor but rarely arises from lymph node metastases.v'" According to pathoanatomic studies of Shin and coworkers" and Salassa and colleagues, this mode of visceral invasion may be due to (1) the proximity of the posterior thyroid capsule and the pretracheal fascia, (2) the paucity of lymphatics and lymphatic invasion by thyroid cancers of the posterior thyroid fascia, and (3) the presence of potential lines of weakness in the tracheal wall where the vessels penetrate perpendicular to the lumen (Fig. 34-3), opening avenues for tumor invasion. Considering these preformed pathways of tumor invasion, Shin and coworkers devised an anatomic staging system according to the depths of tracheal invasion. This system may be relevant not only for surgical decisions on the extent of resection but also for estimating the prognosis for the individual patient (Fig. 34-4). In their series, the prognosis for patients with stages 1 to 3 (invasion of tracheal wall without infiltration of the entire thickness of the mucosa) was significantly better than that for patients with stage 4 disease (invasion of tracheal wall with complete mucosal invasion)." The human arterial blood supply of the tracheoesophageal axis is organized in a segmental fashion and substantially differs from that in mammals, especially dogs. It has been extensively studied by Miura and Grillo (1966) and Salassa and coworkers (1977). From their studies, it can be concluded that the vascular pedicles of the lateral trachea, which are essential for the nutrition of the tracheal cartilages, arise from branches of the inferior thyroid, supreme intercostal, subclavian, internal mammary, innominate, and bronchial arteries (see Fig. 34-3). These vessels interconnect along the lateral tracheal wall, forming a longitudinal anastomosis that

34-3. Macro- and microarchitecture of arterial blood supply of the tracheoesophageal tract. A. Left anterior view. B, Right anterior view. C, Microscopic blood supply. (From Salassa JR, Pearson BW, Payne WS. Gross and microscopical blood supply of the trachea. Ann Thorac Surg 1977;24:100.) FIGURE

324 - - Thyroid Gland

FIGURE 34-4. Staging system for thyroid carcinoma invading the trachea. (From Shin DH, Mark EJ, Suen He, Grillo He. Pathologic

staging of papillary carcinoma of the thyroid with airway invasion based on the anatomic mannerof extension to the trachea: A clinicopathologic study basedon 22 patients who underwent thyroidectomy and airway resection. Hum Pathol 1993;24:866.)

gives rise to the transverse intercartilaginous arteries of each tracheal segment. The submucosal capillary plexus that is fed by the transverse intercartilaginous arteries supplies the posterior tracheal wall. Therefore, preservation of the lateral vascular pedicles is of utmost importance when performing tracheoesophageal resection. Unlike anterior dissection, vascular division close to the lateral wall is not recommended. Only the vessels that supply the segment to be resected may be ligated in order to maintain a sufficient blood supply. It should also be noted that the removal of the thyroid gland, although indicated in most patients with advanced thyroid cancer, may be detrimental in some instances, because the inferior thyroid artery largely contributes to the tracheal blood supply. The esophagus can safely be separated from the posterior tracheal wall without compromising arterial blood supply when the lateral pedicle is preserved. Technically, the extent and type of laryngotracheal resection depend on (I) localization of the invading cancer (larynx, cricoid, or cervical trachea), (2) tumor extension in longitudinal and horizontal directions, and (3) tumor extension through

the tracheal wall (Shin grades I to 3 versus grade 4). Considering the rates of involved structures in advanced thyroid cancer without and, in particular, with aerodigestive invasion, unilateral tracheal invasion with ipsilateral involvement of the recurrent laryngeal nerve is by far the most prevalent form of aerodigestive tract invasion from thyroid cancer (see Table 34-3). Laryngeal and/or esophageal invasion is less frequent. In contrast, invasion of the strap muscles and the internal jugular vein in isolation is rather common. Depending on the respective combination of the aforementioned resection criteria, six principal types ofstage- and localization-oriented laryngotracheal tumor resections with or without reconstruction can be distinguished (Fig. 34-5, Table 34-4): Type 1: Unilateral circumscribed tumor invasion at the laryngotracheal angle, often associated with involvement of the ipsilateral recurrent laryngeal nerve. Tumor invasion should not exceed more than 2 em in the longitudinal direction and no more than one third of the laryngotracheal circumference. This type of resection

Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - -

325

FIGURE 34-5. Types of laryngotracheal resection and reconstruction in invasive thyroid cancer.

("window" resection) can be reconstructed with a sternocleidomastoid flap covering the laryngotracheal wall defect. A suprahyoidallaryngeal release is not necessary. Type 2: Extent of tumor invasion is comparable to that in type 1 but localizedinferiorto the laryngocricoidregion.

Reconstruction is similar to that in type 1 except for the higher division of the sternocleidomastoid muscle. In both types of reconstruction, a circular, airtight, rnusculotracheal anastomosis is fashioned, suturing the external muscular fascia onto the anastomosis. To this

326 - - Thyroid Gland end, a monofilic absorbable thread (3-0) and fullthickness running sutures are used. Type 3: Unilateral tumor invasion involving more than 2 em in length and/or more than one third of the laryngotracheal circumference is best treated with a circular laryngotracheal (type 3) or tracheal resection (type 4). Because preservation of at least one recurrent laryngeal nerve is of paramount importance, type 3 requires an oblique, sometimes S-shaped transection of the trachea above and below the tumor, allowing congruent approximation of the resection margins.29.30.38.52.53 The tracheal anastomosis is usually constructed with a monofilic absorbable thread (3-0) and full-thickness interrupted sutures. Because of the proximity of resection anastomosis to the contralateral vocal cord, a transient protective (mini)tracheotomy with sufficient distance to the anastomosis'" is fashioned (Fig. 34-6). Type 4: Tumor invasion of the cervical trachea that extends more than 2 em in length and more than one third of the tracheal circumference to one or both sides of the trachea is best dealt with by circumferential trachea resection and primary tracheal reconstruction. Types 3 and 4 require to some extent careful tracheal mobilization and, in most cases, a suprahyoidal release of the larynx. 55.56 We and others suggest avoiding extensive mediastinal mobilization to facilitate construction of the cervical anastomosis so as not to disrupt the vascular blood supply of the trachea.57 By a combination of anteflexion and mobilization of

both trachea and larynx, about 7 cm of resectional length can be gained. 58,59 In type 4, routine tracheostomy is frequently unnecessary provided that at least one recurrent laryngeal nerve is intact. To verify recurrent laryngeal nerve integrity, we routinely monitor the recurrent laryngeal and vagal nerves intraoperatively using an electromyographic neuromonitoring device. In both types of circumferential tracheal resection, we routinely protect the tracheal anastomosis with a sternocleidomastoid muscle flap. Covering the tracheal suture lines with a protective muscle flap is crucially important in combined tracheoesophageal resections, where the esophageal anastomosis directly adjoins the tracheotracheal anastomosis, to decrease the risk of esophagotracheal fistula formation. Type 5: In types 5 and 6, the airway cannot be reconstructed because of extensive bilateral tumor invasion of the laryngocricoid area. When the pharyngoesophageal segment is not involved, laryngectomy without cervical esophagectomy is adequate. A terminal suprajugular tracheostomy is constructed. Type 6: In bilateral laryngocricoid and transmural pharyngoesophageal tumor invasion, total laryngotracheoesophagectomy and construction of a terminal tracheostomy are inevitable. When only the cervical digestive tract is involved, a free jejunal flap seems to be the reconstruction of choice. 6o- 64 In this instance, we prefer to connect the mesenteric artery of the graft to the ipsilateral external carotid artery and the mesenteric

FIGURE 34-6. Oblique sleeve resection of the trachea with primary anastomosis (type 3). This 50-year-old woman had recurrent papillary thyroid carcinoma (PTC) invading the left cricoid portion and the trachea. A, Preoperative magnetic resonance imaging scan. B, Tumor invasion of the left cricoid and upper trachea with infiltration of the left recurrent laryngeal nerve. C, View of the right portion of larynx and trachea that shows no tumor invasion; the right recurrent laryngeal nerve remained intact. D, Oblique sleeve resection of the left cricoid with resection of the cervical trachea. E, Primary anastomosis after laryngeal release. F, Resected specimen showing intraluminal tumor invasion.

Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - - 327

vein of the graft to the internal jugular vein. It is of utmost importance to free only very short vascular segments from the mesenteric fat pad to protect the vascular anastomosis from incidental kinking and ultimately graft ischemia. The microvascular anastomoses are fashioned using running sutures and a monofile, nonabsorbable thread (8-0) (Fig. 34-7). Only in the event of jejunal graft failure or mediastinal extension of esophageal resection would we opt for a gastric graft65.66 or colon graft67,68 supplied by the left colonic artery for digestive reconstruction. The general placement of a soft drainage is not recommended. Although some of the numerous surgical details may be controversial and subject to discussion, the following principles are of major importance.

Encircling the Front of Invasion at the Aerodigestive Level and En Bloc Resection. En bloc resection is the

cornerstone of oncologic surgery, because it minimizes tumor spillage and thus diminishes the risk of local recurrence. In contrast to primary aerodigestive malignancies, thyroid cancer invades the aerodigestive tract from the outside. Hence, the first step of en bloc resection consists of encircling the extraluminal specimen and dissecting it off adjacent structures in a centripetal fashion. The aerodigestive tract should be transected only after the extraluminal portions of the tumor have been freed, thus ensuring that the whole tumor is resected as a single specimen, with extraluminal and intraluminal tumor extensions in continuity. To accomplish this goal, the front of tumor invasion is narrowed down to the point where the tumor penetrates the aerodigestive axis. This crucial step of preparation is achieved by using optical magnification, as for the entire operation.

Protection of the Ipsilateral Recurrent Laryngeal and Vagal Nerve. The ipsilateral recurrent laryngeal nerve

is involved in up to 50% of advanced thyroid carcinomas (see Table 34-3). Therefore, preserving nerve integrity on at least one side is highly important to maintain postoperative speech and respiration. Intraoperative neuromonitoring helps to identify and preserve the nerve,69,70 especially at its point of entry at the laryngotracheal angle. Most experts agree that perineural tumor infiltration in differentiated thyroid cancer does not warrant resection of the nerve, in particular when the nerve is still functioning.P'P Minimal residual disease at the nerve can be treated with postoperative radioiodine ablation without incurring higher rates of recurrence or poorer surviva1.9.10.72 Nonfunctioning nerves, however, should be resected, because nerve function will not recover postoperatively when the nerve is infiltrated. This situation is different from that in the nerve palsies encountered in benign goiter, which may recover when the nerve is released. When bilateral palsy of the recurrent laryngeal nerve cannot be avoided, we and others recommend medialization of one vocal cord, which can be performed during the same session or in the early postoperative period." Window Resection. Window resection, as opposed to circumferential (sleeve, circular) resection, denotes a fullthickness wedge resection leaving intact the continuity of the residual trachea. Although most experts in tracheal resection have incorporated window resections into their armamentarium (Table 34-5), this type of resection continues to spark controversial debates. The main disadvantages of this type of

resection may be insufficient tracheal stability and a higher risk of residual disease at the tracheal margins. Several techniques have been developed to prevent instability of the residual trachea: coverage of the resectional defect with fascia lata, either in isolation or supported by a muscle flap,74-76 a myoperiosteal flap from the sternocleidomastoid muscle," or autologous grafts from distant sites,?8-81 Window resection may be indicated for small, circumscribed, invading tumors, especially when located at the laryngotracheal angle, that do not exceed more than 2 em in length and one third of the tracheal circumference. More extensive tumor invasions should be treated with sleeve resection with circular reconstruction. Shaving Procedures. Shaving procedures summarize all resectional techniques on the aerodigestive tract that preserve wall continuity while risking leaving residual cancer. Shaving procedures are contraindicated in patients with intraluminal invasion when the intent is curative but may be adequate in terms of long-term survival in patients who have only superficial tracheal wall infiltration,4.9.10,25.37,71,73.82-86 The drawbacks of shaving procedures are the impossibility to assess reliably the extent of tracheal invasion and the risk of producing tracheal ischemia, a disastrous complication that can emerge when the trachea is too vigorously shaved, In an era of growing expertise in laryngotracheal resections, the need to shave should be limited to patients who either are unable to tolerate transmural resections or have extensive local or distant disease precluding extended resections from an oncologic point of view, Another subgroup who might benefit from shaving are patients who have only superficial but not intraluminal laryngeal invasion that otherwise would require laryngectomy. Intraoperative Frozen Section, Safety Margins. The purpose of obtaining frozen sections in thyroid cancers invading the aerodigestive tract is to better define the tumor type and to ensure that all surgical margins of the resectional specimen are free of tumor. Although it should be possible in most instances to discriminate at least between differentiated, medullary, and undifferentiated thyroid cancers, it may not always be feasible on frozen section to exclude reliably minimal invasive disease at the margins, which may become apparent only on conventional histopathology. In the study of Nishida and colleagues (1997), 11 of 40 patients who had negative margins on frozen section were eventually found to have positive margins on postoperative histopathology. At least some of those patients who have positive margins develop local recurrences. 31.87,88 Despite the lack of systematic studies, minimal margins of normal tissue seem to be adequate in differentiated and poorly differentiated thyroid cancers from an oncologic standpoint. This is in contrast to squamous cell and anaplastic carcinomas of the upper aerodigestive tract. Mediastinal Tracheal Resection. Mediastinal tracheal resection in thyroid cancer is rarely indicated. Tracheal invasion below the offspring of the innominate artery is often associated with involvement of the great mediastinal vessels, a constellation that frequently precludes radical resection on oncologic grounds. The rare exceptions where resection of the mediastinal trachea may be warranted include short-distance invasions related to local recurrence or lymph node metastases. In addition to a complete sternal split, resections on

328 - - Thyroid Gland

FIGURE 34-7. Cervical evisceration (type 6). This 69-year-old woman had recurrent follicular cancer. The patient came to operation with tracheostomy and feeding tube via gastrostomy. A, Cervical exploration with assessment of resectability. E, Resection of larynx, cervical trachea, and esophagus. C, Resected specimen showing tumor invasion of laryngotracheal (left) and pharyngoesophageal (right) areas.

D, First step of jejunal free graft transplantation: jejunoesophagostomy (end to end). E, Second step: hypopharyngojejunostomy (end to end). F, Third step: arterial anastomosis with mesenteric artery and external carotid artery (end to end). G, Fourth step: venous anastomosis with mesenteric vein and internal jugular vein (end to side). H, Gastrografin demonstration of intact digestive anastomoses at the seventh postoperative day.

Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - - 329

the mediastinal trachea necessitate a complete release of the cervical and mediastinal trachea. This resection is fraught with an increased risk of anastomotic leakage when the cuff of the endotracheal tube is positioned over the tracheotracheal anastomosis. Pharyngoesophageal Invasion. Pharyngoesophageal invasion only is less frequent (see Tables 34-3 and 34-5) and usually does not require reconstructions as complex as invasions of the upper airway. Because of its position behind the trachea, transmural invasionof the esophagus mainly occurs in combination with extensive laryngotracheal or tracheal invasion. In most instances, however, extramucosal esophageal resection eradicates the tumor. The esophageal defect is closed by simple approximation and primary suture of the extramucous esophageal wall. When a transmural esophageal resection is necessary, the remaining distance between the margins after esophageal release determines whether simple approximation and primary suture are adequate or whether a jejunal free graft is required for reconstruction. Postoperative Care. Apart from the complexity of the procedures themselves, the association between old age and aerodigestive tract invasion demands the dedication of surgeons, surgical residents, nurses, and ancillary staff involved in postoperative care. Except for rare patients in whom prolonged intubation and mechanical ventilation are required for other reasons, patients with tracheal anastomoses should be extubated immediately after the operation. Because of the inevitable contamination with the flora of the upper aerodigestive tract, antibiotics should be routinely administered preoperativelyfor prophylaxis. In laryngocricoid resections, the moderate use of systemic steroids may reduce

laryngeal edema. When patients undergo prolonged intubation, both cuff pressure and cuff position relative to the tracheal anastomosis must be repeatedly checked to avoid local tracheal ischemia. After reconstructions using a free jejunal graft, the jejunal graft must be closely inspected for mucosal ischemia as an indicator of compromised graft perfusion, especially in the immediate postoperative period. Vascular complications are exceptional after the second postoperative day. Parenteral feeding can be resumed 6 days after the jejunal transfer when anastomotic leakage has been ruled out by a diatrizoate meglumine (Gastrografin) swallow. Complications. After such complex procedures, serious early and late complications may ensue. The management of these complications requires extensive experience and skills. In 317 cervicovisceral resections reported on during the last 3 decades, hospital mortality was approximately 4% (see Table 34-5). The impact of the learning curve on morbidity was demonstrated in a multi-institutional study from Japan." In this series, the complication rate of tracheoplasty that was performed for a variety of conditions (l 0% of which involved thyroid cancer) progressively declined since the 1960s. The complication rate increased significantly with the extent of tracheal resection and was excessive after resection of more than eight tracheal rings. Tracheal anastomosis with resorbable sutures tended to involve less complications than that with nonresorbable sutures. Surgical experience obviously mattered more than the type of suture used. Anastomotic dehiscence was the second most common complication (33% of complicated cases), associated with a 48% death rate.

330 - -

Thyroid Gland

Apart from the high lethality of anastomotic dehiscence, arterial rupture of the right common carotid artery or innominate artery, albeit rare, may emerge after tracheal resection, typically during the second half of the first postoperative week. First published by Korte" (1879) after simple tracheostomy, this disastrous complication can develop after tracheal resection, mediastinal tracheostomy, cervical reoperation, and after external irradiation with or without preceding cervical operation.P" Risk factors predisposing to arterial rupture include lymphatic fistula, hematoma, and wound infection.46-50 In some wound infections, Staphylococcus aureus was identified as the infectious agent. Arterial rupture is a highly dramatic and life-threatening event that necessitates immediate intervention to save the patient from instant exsanguination. Median sternotomy must be performed to obtain control of the proximal innominate and subclavian arteries. The arterial defect can be resected and then reconstructed, using, for instance, a saphenous vein autograft.v" Palliative Local Procedures. Palliative local procedures are reserved for end-stage disease in patients with thyroid cancer invading the aerodigestive tract when radical surgery is not feasible or is contraindicated. With the advent of interventional techniques, in particular intraluminal stenting and laser ablation,46-5o,96 extensive although not radical resections that leave gross tumor at the resection margin are rarely indicated. Moreover, these new techniques relegate permanent tracheostomy to a last-resort procedure reserved for desperate situations. Tracheostomy may not be a simple procedure in patients who have extensive involvement of the aerodigestive tract and, thus, patients are at an increased risk for major complications such as bleeding, infection, obstruction, or tracheoesophageal flstula.97,98 Therefore, tracheostomy should no longer be portrayed as the one and only palliative alternative to radical surgery. Additive Treatment (Radioiodine Therapy. External Irradiation). Radioiodine treatment and external irradiation are recommended as additive therapies for thyroid cancer patients who reveal bulky or minimal residual disease. However, the efficacy of both modalities in achieving local control of tumor is doubtful and unproved in this setting. Radioiodine treatment in differentiated thyroid cancer responsive to radioiodine may be an effective adjunct to shaving procedures when the residual tracheal invasion is minimal. Conversely, some suggest that radioiodine treatment is not effective for local tumor control after nonradical surgery.82 Some tumors also fail to recur after subtotal resection despite positive surgical margins and the failure to initiate postoperative radioiodine ablation,87.88 Likewise, external irradiation for aggressive thyroid cancers has not always improved survival. 99-102 Nevertheless, there are also proponents of external radiotherapy in differentiated thyroid carcinoma with extrathyroidal growth. 103-105 In most of these studies, the benefit was limited to local recurrence only, but survival was not improved,I06-108 Considering these data, radioiodine treatment seems to be useful in minimal residual disease after shaving procedures or tracheal resections and for patients with distant metastases that take up 131I. Whether external irradiation has a role in patients with major aerodigestive tract invasion is still to be elucidated. When gross residual tumor remains after partial resection,

external radiotherapy may be unable to prevent local recurrence." Therefore, external radiotherapy should be reserved for patients who have irresectable progressive local disease and patients who have positive tumor margins after extensive resection.

Long-Term Results after Surgery In aerodigestive tract invasion, the type of thyroid cancer, the presence of nonpulmonary distant metastases at initial resection, the extent of local tumor invasion, and the patient's age are the four universally recognized determinants of survival. 5,8,12,29,3o Unfortunately, all clinical studies comparing different surgical strategies, such as shaving procedures, radical, incomplete, and palliative resections,4.9,IO,12,25,7I,73,8287,109,110 are retrospective and uncontrolled. In addition, the populations studied are not comparable with regard to the biologic determinants of survival (Table 34-6). None of the studies excluded patients with intraluminal airway invasion, whose survival is much lower. 5I For cure, these patients would require complete resection of the involved part of the airway. Given the rarity of thyroid cancer in general and of aerodigestive tract invasion in particular (see Table 34-1), it is virtually impossible to set up a controlled prospective trail large enough to yield unbiased results for different types of treatment. Summarizing the data shown in Table 34-6, the following conclusions can be drawn: at present, there are only eight studies available that compare different surgical strategies for thyroid cancers invading the aerodigestive tract. All studies are retrospective and fail to specify known determinants of survival such as patients' age, extent of tumor invasion, type and differentiation of thyroid cancer, or presence or absence of distant metastases. Keeping these shortcomings in mind, shaving procedures, complete resections, or both clearly fared better than incomplete resections in all seven pertinent studies. 4,25,82,83,87,109,111 This finding was significant in three studies,83,I09,l11 Comparing shaving and complete resections, four of six studies found no difference in terms of surviva1.4,83,109,11O In only one of these six studies, survival was significantly better in the complete resection group than in the shaving group. III In conclusion, incomplete resections are associated with local recurrence and decreased survival. Nevertheless, some patients may enjoy a remarkably long life after palliative resection. With the exception of one study, complete resection and shaving procedures produced comparable results in terms of survival. Although incomplete or shaving resections are not indicated in patients with intraluminal invasion of thyroid cancer, shaving resections may be beneficial in case of superficial laryngotracheal invasion. In experienced hands, deep wall invasion of the aerodigestive tract may be treated by radical resection. In addition, owing to the lack of controlled and unbiased data, the decision about the extent of resection has to be based on individual factors such as patient's age, type of tumor, progressive distant disease, and physical and mental condition. Given the tremendous challenge posed by aerodigestive involvement, every effort must be undertaken to prevent this disastrous condition by detecting

Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - - 331

and eliminating thyroid cancer before it invades the aerodigestive tract.

Summary Aerodigestive tract invasion by thyroid cancer affects approximately 6% of patients with thyroid cancer, representing one of the most demanding disease-related complications in endocrine surgical oncology. Two thirds of patients with advanced thyroid cancer suffer from invasion of the upper airway, whereas pharyngoesophageal involvement accounts for only approximately 20% to 25%. Because of the more aggressive biology of the tumors and older age of the patients, aerodigestive tract involvement signifies a "negatively" selected group of thyroid cancer patients. Aerodigestive invasion poses a real challenge to both surgeon and patient. Because the aerodigestive tract is located at the crossroads of various medical disciplines, a joint interdisciplinary effort is essential for the best outcome in these patients with advanced thyroid cancer. When combined, modem diagnostic

technologies can often differentiate among extramural, intramural, and intraluminal as well as local and distant tumor invasion. Preoperative work-up of the patient is directed at determining technical resectability and operability, both of which are prerequisites for surgery. The surgical approach to the upper aerodigestive tract is dependent on the extent of wall invasion and, for visceral resection, on the anatomy and adequacy of the arterial blood supply to the larynx, trachea, and esophagus. Accordingly, there are six types of upper airway resection: type 1, window resection at the laryngocricoid level; type 2, window resection of the trachea; type 3, oblique sleeve resection of the laryngocricoid; type 4, horizontal sleeve resection of the trachea; type 5, laryngectomy; and type 6, cervical evisceration. Resection with curative intent aims at removing the extraluminal, intramural, and intraluminal portions of the tumor in a single surgical specimen. As in other solid cancers, centripetal preparation and en bloc resection are the principles of oncologic surgery in thyroid cancer. Shaving procedures violate these basic rules of surgical oncology. Nonetheless, shaving procedures may be indicated in

332 - - Thyroid Gland elderly patients with partial-thickness invasion and/or progressive multiple distant metastases that are not amenable to resection.

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84. Fujimoto Y, Obara T, Ito Y, et al. Aggressive surgical approach for locally invasive papillary carcinoma of the thyroid in patients over forty-five years of age. Surgery 1986;100:1098. 85. Musholt TJ, Musholt PB, Behrend M, et aI. Invasive differentiated thyroid carcinoma: Tracheal resection and reconstruction procedures in the hands of the endocrine surgeon. Surgery 1999; 126: 1078. 86. Park CS, Suh KW, Min JS. Cartilage-shaving procedure for the control of tracheal cartilage invasion by thyroid carcinoma. Head Neck 1993;15:289. 87. Ishihara T, Kobayashi K, Kikuchi K, et al. Surgical treatment of advanced thyroid carcinoma invading the trachea. J Thorac Cardiovasc Surg 1991;102:717. 88. Ozaki 0, Sugino K, Mimura T, Ito K. Surgery for patients with thyroid carcinoma invading the trachea: Circumferential sleeve resection followed by end-to-end anastomosis. Surgery 1995; 117:268. 89. Dickmann PS, Nussbaum E, Finkelstein JZ. Arteriotracheal fistula in patients treated for lymphoma. Pediatric Pathol 1989;9:329. 90. Iannuzzi R, Metson R, Lofgren R. Carotid artery rupture after twice-aday radiation therapy. Arch Otolaryngol Head Neck Surg 1989;100:621. 91. Ishihara T, Yamazaki S, Kobayashi K, et al. Resection of the trachea infiltrated by thyroid carcinoma. Ann Surg 1982; 195:496. 92. Neville WE. Reconstruction of the trachea and stem bronchi with Neville prosthesis. Int Surg 1982;67:229. 93. Orringer MB. Anterior mediastinal tracheostomy with and without cervical exenteration. Ann Thorac Surg 1992;54:628. 94. Reiter D, Piccone BR, Littman P, Lisker S. Tracheoinnominate artery fistula as a complication of radiation therapy. Otolaryngol Head Neck Surg 1979;87:185. 95. Scheumann GFW, Maschek HJ, Dralle H. Arteriotracheal fistula as a fatal complication after tracheal resection and twice-a-day-irradiation for thyroid carcinoma. Acta Chir Aust 1993;4:278. 96. Grillo HC, Zannini P, Michelassi F. Complications of tracheal reconstruction. J Thorac Cardiovasc Surg 1986;91:322. 97. Djalilian M, Beahrs OH, Devine KD, et al. Intraluminal involvement of the larynx and trachea by thyroid cancer. Am J Surg 1974; 128:500. 98. Holting T, Meybier H, Buhr HJ. Probleme der Tracheotomie beim organiiberschreitenden anaplastischen Carcinom. Langenbecks Arch Chir 1989;374:72. 99. Benker G, Oblricht T, Reinwein D, et al. Survival rates in patients with differentiated thyroid carcinoma. Influence of postoperative external radiotherapy. Cancer 1990;65:1517. 100. Lerch H, Schober 0, Kuwert T, Saur HB. Survival of differentiated thyroid carcinoma studied in 500 patients. J Clin Oncol 1997;15:2067. 101. Mazzaferri EL, Young RL. Papillary thyroid carcinoma: A 10 year follow-up report of the impact of therapy in 576 patients. Am J Med 1981;70:511. 102. Staunton MD. Thyroid cancer: A multivariate analysis on influence of treatment on long-term survival. Eur J Surg Oncol 1994;20:613. 103. Tsang RW, Brierley JD, Simpson WJ, et al. The effects of surgery, radioiodine, and external radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma. Cancer 1998;82:375. 104. Tubiana M, Schlumberger M, Rougier P, et al. Long-term results and prognostic factors in patients with differentiated thyroid carcinoma. Cancer 1985;55:794. 105. Farahati J, Reiners C, Stuschke M, et al. Differentiated thyroid cancer-Impact of adjuvant external radiotherapy in patients with perithyroidal tumor infiltration (stage pT4). Cancer 1996;77:172. 106. Mueller Gaertner HW, Brzac HT, Rehpenning W. Prognostic indices for tumor relapse and tumor mortality in follicular thyroid carcinoma. Cancer 1991;67:1903. 107. Phlips P, Hanzen C, Andry G, et aI. Postoperative irradiation for thyroid cancer. Eur J Surg OncoI1993;19:399. 108. Lipton RJ, McCaffrey T, van Heerden J. Surgical treatment of invasion of the upper aerodigestive tract by well-differentiated thyroid carcinoma. Am J Surg 1987;154:363. 109. Simpson WJ, Panzarella T, Carruthers JS, et al. Papillary and follicular thyroid cancer: Impact of treatment in 1578 patients. Int J Radiat Oncol BioI Phys 1988;14:479. 110. Segal K, Abraham A, Levy R, Schindel J. Carcinomas of the thyroid gland invading larynx and trachea. Clin OtolaryngoI1984;9:21. III. Friedmann M, Danielzadeh JA, Caldarelli DD. Treatment of patients with carcinoma of the thyroid invading the airway. Arch Otolaryngol Head Neck Surg 1994;120:1377.

Potentially New Therapies in Thyroid Cancer Jin-Woo Park, MD • Quan-Yang Duh, MD • Orlo H. Clark, MD

Differentiated thyroid cancer (DTC) of follicular cell origin is a fascinating tumor because of its varying aggressiveness. Fortunately, most patients with these cancers, despite regional metastasis, can be cured by surgical resection, radioiodine ablation, and thyroid-stimulating hormone (TSH) suppression therapy. Unfortunately, patients with poorly differentiated thyroid cancers or anaplastic thyroid cancers usually fail to respond to this combined therapy. These tumors usually grow rapidly, invade adjacent structures, and spread to other parts of the body. During the dedifferentiation process, they lose thyroid-specific gene expressions, including the ability to take up and organify radioiodine and to make thyroglobulin (TG). The methods used to treat patients with DTC are therefore usually not effective in these patients. These tumors also usually fail to respond to alternative treatment with external radiation or systemic cancer chemotherapy. Medullary thyroid carcinomas are also highly aggressive, and there is no alternative if patients do not respond to surgical treatment. We therefore need to develop novel treatments for these unfortunate patients. Advances in molecular and cellular biology make it possible to develop new therapeutic approaches to thyroid cancer. These approaches can be divided largely into two categories regarding treatment targets. Redifferentiation therapy targets thyroid-specific genes to restore thyroid-specific differentiated function and to make the tumors respond to conventional therapy. The other possible category of treatment targets several cancer-related genes or their products that do not depend on thyroid-specific genes but depend on altered characteristics of thyroid cancer cells during tumorigenesis (Fig. 35-1). Therapeutic approaches described in this chapter have established effects in vitro, but the majority of them are not ready for medical practice yet. Careful clinical trials and analyses should be performed.

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Restoration of Differentiated Thyroid Function Redifferentiating Agents DTCs of follicular cell origin (papillary and follicular cancers) are usually well differentiated and behave in a nonaggressive manner. However, some lose differentiated functions (dedifferentiation) and behave more aggressively. These cancers become refractory to thyroid-specific therapies that are based on differentiated thyroid function such as radioiodine therapy and thyrotropin (TSH)-suppressive therapy. Restoring differentiated functions in these tumors may not only slow tumor growth but also resensitize tumors to thyroid-specific therapy such as treatment with radioactive iodine. Redifferentiating therapies are tissue specific and generally less toxic than nonspecific chemotherapy. There are several redifferentiating agents for thyroid cancers: (1) retinoids, (2) aromatic fatty acids, (3) peroxisome proliferator-activated receptor y (PPARy) agonists, and (4) histone deacetylase inhibitors. RETINOIDS

Retinoids have been shown to modulate cell growth and differentiation by binding to their receptors' The mechanism of action of retinoids is not completely understood. There are two classes of receptors: retinoic acid receptor (RAR) and retinoid X receptor (RXR). Each class has three subtypes, o, ~' and y.Although RAR and RXR function as either homodimers or heterodimers, RAR-RXR heterodimers and RXR-RXR homodimers are predominant. To activate transcriptional activity, RAR-RXR heterodimers bind to RA response element (RARE) and RXR homodimers bind to retinoid X response element (RXRE) (Fig. 35-2).2,3 RXRs also heterodimerize with the vitamin D receptor (VDR), thyroid hormone receptor (T3R), and PPAR.4

Potentially New Therapies in Thyroid Cancer - LOH 3p, 7q21.1-7q31.1, 10q, 17p, T(2;3)(q13;p25)

Functioning follicular adenoma

Follicular carcinoma

Follicular adenoma FIGURE 35-1. Proposed multistep tumorigenesis model for thyroid carcinoma. LOH = loss of heterozygosity; TSH-R =TSH receptor. (Modified from Learoyd DL, Messina M, Zedenius J, et al. Molecular genetics of thyroid tumors and surgical decision-making. World J Surg 2000;24:923.)

335

Poorly differentiated carcinoma

Thyrocyte

p53

Anaplastic carcinoma

RET/PTe, trk met, res, gsp Braf

There are several natural retinoids or ligands such as alltrans-retinoic acid (all-trans-RA), 13-cis-RA, and 9-cis-RA. All-trans-RA binds only with RAR, but 9-cis-RA binds with both RAR and RXR. 13-cis-RA converts to all-trans-RA in vivo. There are also synthetic ligands such as LGD1550 (RAR a1~/y agonist), tazarotene (RAR ~/y agonist), AM80 (RAR ex agonist), and LGDl069 (RXR agonist). The antiproliferative and redifferentiating effects of retinoids have been demonstrated in many human cancers, including thyroid cancer.5 ,6 RA induces cell cycle arrest in

FIGURE 35-2. Basic mechanisms of action of retinoids and peroxisome proliferatoractivated receptor y (PPARy). The retinoid receptors are activated by specific ligands: retinoic acid receptor (RAR) by all-transretinoic acid (all-trans-RA) or 9-cis-retinoic acid (9-cis-RA); retinoid X receptor (RXR) by 9-cis-RA. The PPARy is activated by specific ligands such as thiazolidinedione (TZD) derivatives or aromatic fatty acids. Activated receptors bind with each other and form homo- or heterodimers. These in turn bind to specific response elements to promote the transcription of target genes: retinoic acid response element (RARE), retinoid X response element (RXRE), and PPAR response element (PPRE). The transcription of these genes then induces growth inhibition and redifferentiation.

the Gon phase with a reduced level of cyclin D1 and cyclindependent kinase 2 (CDK-2) messenger RNA (mRNA) and protein, which leads to reduced phosphorylation of the retinoblastoma protein." RA treatment increased mRNA for the sodium-iodide symporter (NIS) and radioactive iodine uptake in vitro in human thyroid cancer cells."!" In clinical trials, about 40% of patients treated with RA have had increased radioiodine uptake. 11 Although these effects are generally reversible and usually do not result in a dramatic clinical response, some patients

336 - - Thyroid Gland are helped by this treatment and combined treatment with other drugs may improve the effect of this therapy. AROMATIC FATTY ACIDS: PHENYLACETATE, PHENYLBUTYRATE

There is increasing evidence that aromatic fatty acids such as phenylacetate and phenylbutyrate induce tumor growth inhibition and redifferentiation in vitro, in vivo, and also in some clinical trials. 12-15 Aromatic fatty acids act through multiple mechanisms. They can block the tumor cell access to free glutamine and also block the isoprenylation of ras family proteins. 16 Histone deacetylase inhibition and PPARy activation are other suggested mechanisms of action. 17-19 Phenylacetate is a metabolite of phenylalanine. It accumulates in phenylketonuria and is associated with brain damage. It has been used to treat children who have urea cycle disorders. Phenylbutyrate metabolizes to phenylacetate in humans. Phenylacetate often induces differentiation and apoptosis in human cancer cell lines at concentrations that have been safely used in humans. Phenylbutyrate seems to be more potent in inducing apoptosis than phenylacetate." It is also reported that aromatic fatty acids can modulate sensitivity to chemotherapy when combined with chemotherapeutic drugS.21-23 Kebebewand colleagues reported that phenylacetate induced cytostasis in the GOII cell phase and induced radioiodine uptake in thyroid carcinoma cell lines.24 They also reported that phenylacetate decreased the TSH growth response, TG secretion, and the secretion of vascular endothelial growth factor (VEGF) in the thyroid cancer cell lines. Differentiating agents can be synergistic or additive in combination with other differentiating agents acting by other mechanisms. A combination of RA and phenyl acetate had synergistic antiproliferative effects in follicular thyroid cancer cell lines," Phenylbutyrate also seems to induce more apoptosis than phenylacetate at the same concentration in thyroid cancer cell lines. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR YAGONIST

PPAR belongs to the nuclear hormone receptor superfamily implicated in inhibition of cell proliferation and induction of cell redifferentiation-" PPAR has three isoforms, ex, 8, and y. They are ligand-dependent transcription factors that must form heterodimers with the RXR receptor in order to bind to their response elements (PPREs) and activate transcription (see Fig. 35-2).27 Among numerous PPARy agonists, thiazolidinedione (TZD) derivative antidiabetic drugs such as troglitazone, pioglitazone, and rosiglitazone are newly discovered potent PPARy agonists.P-" Investigations have shown that TZD derivatives are not only insulin sensitizers but also inhibit proliferation of human breast, prostate, bladder. colon, lung, and gastric cancer cells in vitro. in vivo, or both. 30-35 In thyroid carcinogenesis, PPARyappears to play an important role, especially in follicular thyroid cancer. A chromosomal translocation creating a fusion protein of PAX8-PPARyl was found in five of eight follicular thyroid carcinomas but not in follicular thyroid adenomas or papillary thyroid carcinomas, and this abnormal fusion protein is a dominant negative suppressor of wild-type PPARyactivity.36

Ohta and colleagues reported antiproliferative effects in vitro and growth inhibition in vivo of troglitazone in papillary thyroid cancer cell lines.37 In our investigations, human thyroid cancer cell lines express PPARy variably, and chromosomal translocations involving PPARy are uncommon. Troglitazone induced antiproliferation in papillary, follicular, Hilrthle cell, and anaplastic thyroid cancer cell lines. Its action can be explained in part by cell cycle arrest in the GOII phase and apoptotic cell death. We also demonstrated downregulation of CD97, a thyroid dedifferentiation marker, in thyroid cancer cell lines treated with troglitazone." Treatment with PPARy agonists might be a useful new medical therapy for patients who have poorly differentiated thyroid cancers by inducing growth inhibition and redifferentiation. HISTONE DEACETYLASE INHIBITOR

Histone acetylation and deacetylation can modulate chromatin structure and regulate gene expression related to DNA replication, transcription, differentiation, and apoptosis." Reversible acetylation of s-amino groups of lysine residues in the aminoterminus of histone is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs) (Fig. 35-3). HATs lead to the relaxation of chromatin structure and transcriptional activation, whereas HDACs lead to chromatin condensation and transcriptional repression of target genes.'? There is increasing evidence that a disorder in equilibrium of histone acetylation can be associated with tumor development." HDAC inhibitors such as depsipeptide (FR901228), trichostatin A, and suberoylanilide hydroxarnic acid (SAHA) are promising new anticancer agents. HDAC inhibitors induce hyperacetylation of chromatin and activate genes that are related to differentiation and apoptosis in cancer cells. 42,43 Depsipeptide (FR901228) is currently in phase I clinical studies and the results of treatments are promising.r' In thyroid cancer cells, HDAC inhibitors inhibit cell proliferation by inducing apoptosis through activation of the caspase cascade and cell cycle arrest at G[ and G 2/M by a reduction in cdk2- and cdkl-associated kinase activities." In addition to the antiproliferative effects, HDAC inhibitors can modulate expression of several genes. Thyroid-specific genes can be transcriptional targets controlled by the acetylation status of histones. In particular, Kitazono and coauthors reported that depsipeptide markedly increased the mRNA level of NIS and resultant radioiodine uptake in low concentrations." Zarnegar and colleagues demonstrated NIS expression in different thyroid diseases. They also demonstrated that trichostatin A dramatically increases NIS expression and resultant radioiodine uptake in low concentrations. Trichostatin A inhibits cell proliferation by inducing apoptosis and cell cycle arrest at the G 2/M phase in a dose-dependent manner," Methylation is another mechanism of transcriptional repression of certain genes. Combinations of inhibitors for these processes might be synergistic because these two epigenetic processes are closely linked."

Gene Therapy Cancer gene therapy is the transfer of nucleic acids that can replace defective genes or introduce suicide genes or immune modulator genes. During the past several years, there have

Potentially New Therapies in Thyroid Cancer - -

337

FIGURE 35-3. Reversible acetylation of histones by histone acetyltransferase (HAT) and histone deacetylase (HDAC). Acetylation status can affect transcriptional activity of the specific gene by transcriptional factor (TF).

been remarkable technical advances in terms of transfection efficiency and tissue specificity, Gene therapy for cancer has moved from success in laboratory practice to clinical trials. Several genes have been considered as candidates for gene therapy in thyroid cancer, Differentiation-related genes such as p53, 1TF-l, PAX-S, and NIS were introduced to retard cancer cell growth or induce redifferentiation. Thyroidspecific promoter and HDAC inhibitors have been used to increase transcriptional activity and tissue specificity in thyroid cancer cell lines.49,50 Currently, many investigators are trying to improve the efficiency of tissue-specific, multigene, transfection therapy.

differentiation-related genes or other effective genes might be needed, In addition to the role of wild-type p53 in dedifferentiation of thyroid cancers, thyroid-specific transcriptional factors, such as TTF-l, TTF-2, and PAX-8, are closely related to thyroid-specific differentiated functions such as radioiodine uptake. 58-6o It was reported that overexpression of TTF-l and PAX-8 restored TG gene promoter activity in thyroid cancer cell Iines."' Further investigations are necessary to determine whether cotransfection of wild-type p53 and thyroid-specific genes is more effective in inducing redifferentiation.

P53, TTF-l, PAX-B

After surgical resection of the thyroid gland and tumor in patients with DTC of follicular cell origin, regional or distant metastases are often effectively treated with radioiodine, Iodide uptake by thyrocytes is mediated by NIS. Most differentiated thyroid carcinomas express NIS, and NIS expression correlates with clinical radioiodine uptake.f However, some differentiated and most undifferentiated thyroid carcinomas fail to express NIS, These tumors lack the ability to take up iodide and are thereby refractory to radioiodine therapy.63.64 Many investigators have tried to restore NIS expression in thyroid cancer cells. 10,24,58 There are two remarkable advances in this field: HDAC inhibitors and gene therapy using the NIS gene. Cloning and characterization of the NIS gene made it possible to try gene therapy using this gene in both thyroid and nonthyroid malignancies. Several clinical trials using NIS gene transfection for triggering significant iodide uptake in nonthyroid tumors are under way.65-67 In thyroid cancer, transduction of human NIS (hNIS) in a follicular thyroid cancer cell line (FfC-133) induced high uptake of radioiodine in vitro and also in vivo in a xenograft model/" Although the transduction of the hNIS gene can induce radioiodine influx, it is followed by rapid efflux.

Most DTCs do not have p53 gene mutations, whereas some poorly differentiated thyroid cancers, most anaplastic thyroid cancers, and established thyroid cancer cell lines have p53 mutations.?' Several investigations suggest that undifferentiated thyroid carcinomas originate from differentiated ones, It therefore appears that p53 mutations occur as a late genetic event associated with dedifferentiation of thyroid tumor cells and immortalization of cell lines. Gene therapy with wild-type p53 in thyroid carcinoma cells in culture that had a p53 mutation showed that it (1) induced growth arrest (not apoptosisj.P (2) increased thyroid-specific gene expression" (3) enhanced the response to chemotherapy and radiation therapy,54,55 and (4) downregulated expression of thrombospondin (TSP) 1 (not VEGF),56,57 However, it seems unlikely that gene therapy with wild-type p53 gene alone will become an effective treatment in patients who have poorly differentiated thyroid cancer or anaplastic thyroid cancer. It induced growth arrest rather than apoptotic cell death in most studies and it rarely induced thyroid-specific gene expression, especially for radioiodine uptake. For it to be an effective treatment, cotransfection of

SODIUM-IODIDE SYMPORTER (NIS) GENE

338 - - Thyroid Gland Inhibition of iodide efflux has to be added for a therapeutic application of the hNIS gene. Iodide efflux could be inhibited by cotransfection of the thyroperoxidase gene (TPO), decreasing pendrin (PDS) gene activity, or combination with lithium treatment. 69,70 For transcriptionally targeted gene therapy, the TG promoter can be used. Thyroid-specific transcription factors such as TIF-l, TTF-2, or PAX-8 closely interact with the TG promoter. TG promoter activity, however, may not be enough in poorly differentiated and anaplastic thyroid cancer cells that also have defects in these transcriptional factors. Cotransfection of these genes may enhance TG promoter activity."

Treatments Independent of Differentiated Thyroid Function Cytotoxic Drugs GEMCITABINE

Gemcitabine is a new antimetabolite drug. Gemcitabine is a deoxycytidine analog and induces antiproliferative activity by phase-specific killing of cells undergoing DNA synthesis and blocking the cell cycle progression through the GI/S phase. Gemcitabine has dose-dependent synergistic activity with cisplatin. Data from two randomized clinical studies support the use of combined treatment with gemcitabine and cisplatin for treatment of patients with locally advanced or metastatic cancers including non-small cell lung cancer and prostatic cancer. n ,73 Combination of gemcitabine and other cytotoxic drugs such as vinorelbine, cyclophosphamide, or paclitaxel is also currently under clinical study. Antitumor activity of gemcitabine is also observed in thyroid cancer cells in vitro. Gemcitabine induced apoptosis, cell cycle arrest in the S phase, and upregulation of Fas in poorly differentiated or anaplastic thyroid cancer cell lines.r'-" A multimeric form of gemcitabine appears to be more potent for inhibition of tumor cell growth than the monomeric form in thyroid cancer cells in vitro." In a medullary thyroid cancer cell line, IT, gemcitabine also induced an antiproliferative effect and decreased neuroendocrine activity." Gemcitabine and cisplatin in combined treatment are also synergistic in thyroid cancer cell lines. Voigt and colleagues reported that combined treatment is schedule dependent and effective only when gemcitabine is followed by cisplatin, not vice versa, in anaplastic thyroid cancer cell lines." Although small numbers of patients with thyroid cancer were included in phase I clinical trials using gemcitabine, further clinical studies are required to confirm the safety and effectiveness of regimens including gemcitabine." GELDANAMYCIN

Geldanamycin is a specific inhibitor of heat shock protein 90 (Hsp90). Hsp90 is one of the most abundant chaperone proteins in the cytosol of eukaryotic cells. It helps newly synthesized proteins make stable conformations (maturation) or helps translocate them to their ultimate locations."? It plays an important role in stress such as heat shock, and it is associated with the mitogen-activated signal cascade.

It is also an essential component for fundamental cellular processes such as hormone signaling, cell cycle control, proliferation, and differentiation under physiologic conditions.P Although Hsp90 is essential for eukaryotic cells and its inhibition may cause significant toxicity, cancer cells appear to be more sensitive to inhibition of this chaperone's activity, Hsp90 expression can be upregulated by mitogen or growth factor stimulation, and it is higher in tumors than in normal tissues." Hsp90 may therefore playa critical role in tumor cell growth or survival, or both. Several oncoproteins, such as Raf-l, erbB family receptors, and mutant p53 proteins, are reported to be substrates for Hsp90, and they can change their conformation and be stabilized by Hsp90. 82-84 The National Cancer Institute screened drug sensitivity to geldanamycin in 60 tumor cell lines in vitro and reported that geldanamycin is a promising anticancer drug effective at nanomolar concentrations." Our investigations using human thyroid cancer cell lines demonstrated that geldanamycin inhibited cell proliferation, downregulated oncoproteins, and inhibited epidermal growth factor (EGF)-induced invasion. 86 Although geldanamycin is a novel anticancer drug based on differential dependence on Hsp90 between cancer cells and normal cells, significant side effects related to inhibition of diverse substrates for Hsp90 are inevitable and may limit its clinical usefulness, However, continued characterization of the ansamycin binding site on Hsp90 will make it possible to develop more substrate- or tissue-specific Hsp90 inhibitors. The results of a phase I clinical trial using the geldanamycin analog 17-allylamino-17-dernethoxygeldanamycin (l7-AAG) were reported by Memorial SloanKettering Cancer Center.s? They suggested that clinically achievable concentrations of 17-AAG exceed those that were effective in preclinical models. Structurally different Hsp90 binding drugs such as radicicol have also been introduced as a second class of Hsp90 inhibitors.

Gene Therapy Gene therapy in thyroid cancer can be designed to kill cancer cells independent of thyroid-specific function. Suicide gene therapy was designed to kill the thyroid cancer cells by chemosensitization. Immune modulatory genes such as interleukin 2 (IL-2) and IL-12 have been studied for immunotherapy. A thyroid-specific promoter such as TG promoter can make the gene therapy more tissue specific, and multigene transduction can make the gene therapy more effective. SUICIDE GENE

Suicide gene therapy is the transduction of chemosensitization genes that can transform a nontoxic form of a drug (prodrug) into a toxic substance. A classic example of this therapy is transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene with nucleoside analogs, such as acyclovir or ganciclovir. It is, however, difficult to transfect all of the target cells. A bystander effect is therefore an important aspect of suicide gene therapy.V With a bystander effect, this strategy has been evaluated for possible treatment of localized tumors. Suicide gene therapy is currently in clinical trials for several human cancers including melanoma, glioblastoma, and breast cancer.":"

Potentially New Therapies in Thyroid Cancer - - 339

HSV-tk and prodrug therapy has been reported to induce antitumor activity in thyroid cancer cell lines in vitro and in vivo/? A thyroid-specific promoter such as TG promoter with or without the Cre-IoxP system (site-specific recombination system) increased tissue specificity and decreased toxicity.93-95 INTERLEUKIN 2 AND INTERLEUKIN 12

IL-2 is associated with augmentation of antitumor T-cell and natural killer cell activity; IL-12 also plays an important role in the development of cellular immunity. Although systemic administration of recombinant interleukins has demonstrated antitumor activity, systemic toxicity with increasing dosage and longer exposure has been observed. 96.97 Appropriate local production of interleukins without systemic toxicity can be achieved by gene therapy. Gene therapy using IL-2 or IL-12 has been well studied in medullary thyroid cancer models. In rat and mouse medullary thyroid cancer models, transduction of IL-2 or IL-12 resulted in tumor regression and loss of tumorigenicity without significant toxicity.98-IOO Gene therapies in these models also induced regression of an established tumor at a distant site and longlasting tumor-specific immunity. Furthermore, combining suicide and immunoregulatory gene therapies (IL-2) enhanced tumor growth inhibition and immune reaction in a rat xenograft model.'?' Immunoregulatory genes can be added in multigene therapy in combination with a thyroid-specific promoter.

ErbB Family of Tyrosine Kinase Receptors The tyrosine kinase receptors of the ErbB family are important receptors involved in cellular proliferation, differentiation, and survival and are widely expressed in malignant tissue. Overexpression of EGF receptor (EGFR) has been associated with cell proliferation, invasion, angiogenesis, and both chemoresistance and radioresistance. It is therefore natural to target these receptors in cancer therapy. EGFR and ErbB2 are frequently expressed in papillary thyroid cancer and are reported to be associated with lymph node metastases and recurrence. 102-105 Haugen and colleagues suggested autocrine stimulation of EGFR by transforming growth factor a (TGF-a) in papillary thyroid cancers.l'" EGF and TGF-a enhanced invasion and growth of DTC cells in vitro and in vivo by binding to the EGF receptors. EGF- and TGF-a-mediated effects were blocked by a monoclonal antibody to EGF receptor (Mab528) or genistein, a tyrosine kinase inhibitor.l'" However, treatment with anti-EGFR antibody alone failed to induce growth inhibition. 108 Anti-EGFR antibody treatment may be effective for therapeutic use in combination with other chemotherapeutic agents or conjugation with radioiodine. Transduction of a normal human ErbB2 gene changed the growth property of rat thyrocytes. Thyroid cells transformed with ErbB2 can grow in the absence of thyrotropin and do not respond to the growth-inhibitory effect of TGF_~.109 Ligand binding of both thyroid hormone (T3) and RA receptors inhibited the transcriptional activity of EGF receptor and ErbB2 prornoter.!'? Several compounds targeting the ErbB family or its downstream cascade are in clinical studies and demonstrate promising results (Fig. 35-4). IMC-225 (cetuximab,

anti-EGFR) and trastuzumab (Herceptin, anti-HER2/neu) are monoclonal antibodies, and ZD1839 (Iressa) and OSI-774 (Tarceva) are selective EGFR-tyrosine kinase inhibitors.Ul-l'? To our knowledge, the therapeutic utility of these drugs in patients with thyroid cancer has not been evaluated.

Metalloproteinase Inhibitor Matrix metalloproteinases (MMPs) and the plasmin activation system are proteolytic enzymes that play a crucial role in extracellular matrix (ECM) degradation in many cancers. This degradation is very important in tumor growth, invasion, and metastasis. Angiogenesis requires MMPs that degrade ECM for endothelial cell invasion. On the other hand, MMPs also produce anti angiogenic protein fragments. I13 MMP activity depends on interaction between MMPs, membrane-type MMPs (MT-MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), and ECM metalloproteinase inducer (EMMPRIN). Stromal cells make most MMPs in cancers. Cancer cells induce synthesis of MMPs by stromal cells through EMMPRIN and cytokine stimulatory mechanisms. 114 Thyroid cancer cells overexpress MMP-l, MMP-2 (or increase the proMMP-2 activation ratio), MMP-9, and MTlMMP. Overexpression usually correlates with more aggressive behavior such as advanced stage, tumor invasion, and lymph node metastases.I'>!'? Cytokines, growth factors, and hormones can stimulate cancer cell invasion in vitro. This stimulation occurs in part through MMP activity. The modulation of MMPs appears to depend on the cell lines and stimulator.Us!'? Thyroid cancer cell invasion can be

FIGURE 35-4. Strategies for ErbB family inhibition. mAb = monoclonal antibody.

340 - - Thyroid Gland stimulated by IL-l, tumor necrosis factor a (TNF-a), EGF, and TSH.I17,120.121.122 MMP-9 was induced by IL-l, TNF-a, and phorbol esters but MMP-2 was not.'!? Growth factors generally upregulate expression of MMP-2 and MMP-9, but EGF stimulation appears to increase invasion in part through MMP-l in thyroid cancer cell lines.P' The effects of TSH on growth, migration, and invasion of thyroid cancer cells were biphasic, with an increase at low and a decrease at high concentrations.120 TSH induced invasion of thyroid cancer cells through the activation of urokinase-like plasminogen activator (uPA) and basement membrane type IV collagenase.P? but TSH inhibited EGF-induced MMP-l expression.'!' Interaction between thyroid cancer cells and tumor-derived fibroblasts also appears to be important in the balance of MMP activity.'!" Inhibition ofMMP activity has been studied as a new anticancer therapy. TlMPs are important in the homeostasis of ECM by regulating the activity of MMPs. However, there is increasing evidence that TlMPs are also involved in cell proliferation, apoptosis, proMMP-2 activation, and angiogenesis through MMP-dependent or MMP-independent pathways. A treatment strategy using TlMPs is not appropriate because of their paradoxical role in tumorigenesis.F'P" Several orally active MMP inhibitors (MMPIs) have been developed: marimastat (BB-25l6), prinomastat (AG3340), BAY 12-9566, CGS-27023A, and Col-3 (6-deoxy-6-demethyl4-dedimethylamino tetracycline). These drugs have demonstrated anti-invasive, antimetastatic, and antiangiogenic effects in preclinical studies. 125- 127 Among doxycycline and modified tetracyclines, Col-3 (metastat) is the most potent MMPI. Col-3 induced cell cycle arrest at the GOIl phase, apoptosis, and necrosis in vitro. Col-3 also decreased MMP-2, TIMP-l, and TIMP-2 secretion in vitro and inhibit cancer invasion in vitro.P? In clinical studies, COL-3 demonstrated antitumor activity in several human cancers. The most common adverse event was dose-related photosensitivity.F'P? Yeh and coworkers demonstrated that Col-3 effectively inhibited thyroid cancer cell invasion in vitro at the clinically achievable concentration with no significant apoptotic cell death.!" Some clinical trials using orally active MMPIs, however, failed to achieve survival gain in phase III trials, although results of these studies are incomplete.P" MMP activity appears to be more important in early local invasion or micrometastasis than established metastasis.'!' It is therefore still possible that MMPI treatment may be helpful in early-stage cancer, after chemotherapy or radiation therapy, or both. Further studies are needed in thyroid cancers.

Vascular Endothelial Growth Factor Inhibitors VEGF is a potent stimulator of endothelial cell proliferation in vitro, promotes neoangiogenesis in vivo, and increases vascular permeability. VEGF is overexpressed in most human malignancies in which elevated VEGF expression is associated with a more aggressive cancer. High expression of VEGF was found in both chronic lymphocytic thyroiditis and DTCs but not in poorly differentiated cancers. 131.132 Although it is controversial, there is considerable evidence that VEGF overexpression in DTCs is associated with aggressive clinical features, such as a larger

tumor and local and distant metastases. 133-135 Endothelial cells lining tumor-embedded microvasculature express VEGF receptors. 136 Transduction of VEGF to a thyroid cancer cell line in vitro demonstrated that VEGF indirectly promotes the growth of thyroid tumors by stimulating angiogenesis. 137 TSH can promote growth of thyroid cancer cells in part by stimulating VEGF secretion, but short-term TSH stimulation with recombinant human TSH (rhTSH) did not increase serum VEGF levels significantly. 138.139 Redifferentiating agents such as phenylacetate inhibit VEGF secretion in human thyroid carcinoma cells." The neutralization of VEGF by anti- VEGF monoclonal antibody inhibited tumor growth and neovascularization markedly in the dermal matrix angiogenesis model in vivo.140 Manumycin (a famesyltransferase inhibitor) also decreased VEGF and inhibited endothelial cell proliferation. These effects were enhanced by a combination of manumycin and paclitaxel (a microtubule inhibitor) in an anaplastic thyroid carcinoma mouse xenograft model. 141 A VEGF inhibitor appears to be attractive treatment for thyroid cancers.

Conclusion There are many potentially new medical treatments that appear promising in vitro, in vivo, and in preclinical studies. Clinical trials and more basic scientific research are necessary, but there is optimism about their effectiveness. We hope that these new therapies and clinical trials will result in their use for patients who do not respond to conventional therapy and open the way to investigating novel treatment targets based on newly extended molecular and cytogenetic understanding of cancer.

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122. Packman KS, Demeure MJ, Doffek KM, et al. Increased plasminogen activator and type IV collagenase activity in invasive follicular thyroid carcinoma cells. Surgery 1995; 118:1011. 123. Jiang Y, Goldberg ID, Shi YEo Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 2002;21:2245. 124. Yoshizaki T, Sato H, Furukawa M. Recent advances in the regulation of matrix metalloproteinase 2 activation: From basic research to clinical implication [Review]. Oncol Rep 2002;9:607. 125. Bonomi P. Matrix metalloproteinases and matrix metalloproteinase inhibitors in lung cancer. Semin OncoI2002;29(1 SuppI4):78. 126. Tonn JC, Kerkau S, Hanke A, et al. Effect of synthetic matrixmetalloproteinase inhibitors on invasive capacity and proliferation of human malignant gliomas in vitro. Int J Cancer 1999;80:764. 127. Lokeshwar BL, Selzer MG, Zhu BQ, et al. Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral nonantimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model. Int J Cancer 2002;98:297. 128. Cianfrocca M, Cooley TP, Lee JY, et al. Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi's sarcoma: A phase I AIDS malignancy consortium study. J Clin Oncol 2002;20:153. 129. Rudek MA, Figg WD, Dyer V, et al. Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer. J Clin OncoI2001;19:584. 130. Yeh MW, Rougier JP, Park JW, et al. Invasion by thyroid cancer cells is regulated by signaling through the EGF receptor and effected by activated gelatinases. Submitted to Cancer Res. 131. Soh EY, Duh QY, Sobhi SA, et al. Vascular endothelial growth factor expression is higher in differentiated thyroid cancer than in normal or benign thyroid. J Clin Endocrinol Metab 1997;82:3741. 132. Klein M, Picard E, Vignaud JM, et al. Vascular endothelial growth factor gene and protein: Strong expression in thyroiditis and thyroid carcinoma. J EndocrinoI1999;161:41. 133. Fenton C, Patel A, Dinauer C, et al. The expression of vascular endothelial growth factor and the type I vascular endothelial growth factor receptor correlate with the size of papillary thyroid carcinoma in children and young adults. Thyroid 2000;10:349. 134. Lennard CM, Patel A, Wilson J, et al. Intensity of vascular endothelial growth factor expression is associated with increased risk of recurrence and decreased disease-free survival in papillary thyroid cancer. Surgery 2001;129:552. 135. Klein M, Vignaud JM, Hennequin V, et al. Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma. J Clin Endocrinol Metab 2001;86:656. 136. Viglietto G, Maglione D, Rambaldi M, et al. Vpregulation of vascular endothelial growth factor (VEGF) and downregulation of placenta growth factor (PIGF) associated with malignancy in human thyroid tumors and cell lines. Oncogene 1995;11:1569. 137. Belletti B, Ferraro P, Arra C, et al. Modulation of in vivo growth of thyroid tumor-derived cell lines by sense and antisense vascular endothelial growth factor gene. Oncogene 1999;18:4860. 138. Soh EY, Sobhi SA, Wong MG, et al. Thyroid-stimulating hormone promotes the secretion of vascular endothelial growth factor in thyroid cancer cell lines. Surgery 1996; 120:944. 139. Tuttle RM, Fleisher M, Francis GL, et al. Serum vascular endothelial growth factor levels are elevated in metastatic differentiated thyroid cancer but not increased by short-term TSH stimulation. J Clin Endocrinol Metab 2002;87:1737. 140. Soh EY, Eigelberger MS, Kim KJ, et al. Neutralizing vascular endothelial growth factor activity inhibits thyroid cancer growth in vivo. Surgery 2000;128:1059. 141. Xu G, Pan J, Martin C, Yeung Sc. Angiogenesis inhibition in the in vivo antineoplastic effect of manumycin and paclitaxel against anaplastic thyroid carcinoma. J Clin Endocrinol Metab 2001; 86:1769.

Comparative Genomic Hybridization in Thyroid Neoplasms Daishu Miura, MD • Nobuyuki Wada, MD • Laurent Brunaud, MD

Thyroid tumors of follicular cell origin serve as a good model for studying possible genetic events in tumor initiation, transformation, and progression. Fagin 1 and WynfordThornas-? proposed the multistep model of genetic alterations for thyroid tumors that arise from follicular cells (Fig. 36-1). They proposed a model with two main pathways: from follicular adenoma to follicular carcinoma and from low-risk papillary carcinoma to high-risk papillary carcinoma. Subsequently, these differentiated thyroid carcinomas may transform to anaplastic thyroid carcinoma. The latter change, from differentiated to anaplastic, is associated with p53 mutations.F' Comparative genomic hybridization (CGH) is a genome scanning technique that allows identification of changes in a relative copy number of DNA sequences (gains or losses), using DNA extracted from clinical tumor samples or cell lines (Fig. 36-2).6 The fluorescence in situ hybridization (FISH) reaction can also be used to detect gains and losses. FISH, however, is restricted to the analysis of metaphase nuclei only, whereas CGH is able to analyze interphase nuclei from cells that are not actively proliferating. In cancer cells, gains and losses of oncogenes and tumor suppressor genes can be mirrored by chromosomal abnormalities such as chromosomal deletions, monosomies, duplication, polysomies, and gene amplifications such as homogenously staining regions or double-minute chromosomes.'

Methods DNA Extraction High-molecular-weight whole genomic DNA (>4 kb) was obtained for reference DNA from healthy female and male donors and also for test DNA from samples. The normal reference DNA was prepared from peripheral lymphocytes, and the test DNA was from tissue samples. DNA was extracted after overnight proteinase K digestion followed by the phenol chloroform isoamyl method and alcohol precipitation. 344

The concentration of reference and test DNA were measured with a fluorometer.

Preparation of Metaphase Spreads The quality of the normal metaphase spreads, to which reference and test DNA were hybridized, strongly influence the reliability and sensitivity of CGH analyses. Metaphase spreads were prepared from synchronized cultures of peripheral blood cells from a healthy male donor (Fig. 36-3). T lymphocytes in RPMI 1640 medium were stimulated with phytohemagglutinin and cultured for 72 hours. The cells were then synchronized by treatment with 10-7 M methotrexate (MTX) for 15 hours to inhibit DNA replication, followed by 10-5 M thymidine for 5 hours to release the cells synchronously from the MTX-induced block. Colcemid (l ug/ml.) was added during the final 30 minutes of thymidine release. Lymphocytes were fixed in a 3:1 solution of methanol and acetic acid and dropped on precleaned microscope slides. The slides were air-dried using a Thermotron environmental chamber.

Comparative Genomic Hybridization CGH was performed according to the protocol described by Kallioniemi and associates," with slight modifications using fluorochromes conjugated to dUTP for standard nick translation (see Fig. 36-2).8 Test and reference DNA were labeled using the nick translation reaction with fluorescein-12 (FITC)-dUTP and Alexa Fluor 568-5-dUTP, respectively. The size of DNA fragments was adjusted from 500 to 1500 bp for hybridization, depending on the amount of DNA polymerases and incubation time. Approximately 200 ng each of FITC-labeled test and Alexa-568-labeled reference DNA samples were hybridized to the normal metaphase spreads. Twenty micrograms of unlabeled Cot-l DNA was used to block the binding of repeated DNA sequences. The DNA was denatured for 5 minutes at 73°C in hybridization solution (50% formamide, 10% dextran

Comparative Genomic Hybridization in Thyroid Neoplasms - - 345

FIGURE 36-1. Carcinogenesis in thyroid tumors.

sulfate, and 2X SSC, pH 7.0). Metaphase slides were also denatured in a denaturing solution (70% formarnide, 2X SSe. pH 7.0) for 3 to 5 minutes at 73°C and dehydrated with ethanol.Hybridizationwas performed in a chamber at 37°C for 2 or 3 days. Posthybridization slides were washed three times in washing solutions (50% formarnide, 2X sse, pH 7.0), once in 2X SSC at 45°C, once in 2X sse at room temperature, twice in a PN buffer (0.1 M NazHP04, 0.1 M NaHzP04, 0.1% NP-40, pH 8.0), and once in distilled water at room temperature. The slides were counterstained with 10 ul, of 0.4 I-1M 4',6-diarnidino-2-phenylindole (DAPI) in an antifade solution.

Digital Image Acquisition and Analysis The three-color images-blue (DAPI), green (FITC), and red (Alexa-568)-with appropriate light source and filters were acquired using several different image acquisition systems (Figs. 36-4 and 36-5). At least 10 images of metaphase

FIGURE 36-2. Technique of comparative genomic hybridization. Equal amounts of the fluorochrome-labeled test and reference DNA were hybridized to normal metaphase spreads with unlabeled Cot-l DNA to block the binding of repeated DNA sequences.

FIGURE 36-3. Schema of cell cycle.

spreads were used for each hybridization. These three-color images were analyzed to determine the ratio of green and red fluorescence intensity along each chromosome. Image analysis typically involved normalizing the intensity of green and red images, chromosome segmentation, background subtraction, medial axis calculation, integration of fluorescence intensity in bands perpendicular to the medial axis across each chromosome, and calculation of green-tored ratios along each medial axis. The green-to-red ratio indicated the relative DNA sequence copy number at each point in the test genome. At least six metaphase spreads were analyzed per hybridization and the results were averaged. The regions with a green-to-red ratio of more than 1.20 were interpreted as gains and those with a ratio less than 0.80 as losses. However, the results were dependent on the cutoff values. Cot-l DNA inhibited binding of the labeled DNA to the centromeric and heterochromatic regions, so that the centromeric areas of chromosome 1, 9, 16, and Y and the

346 - - Thyroid Gland Normal metamorphosis chromosomes

FIGURE 36-4. Schema in digital image acquisition and analysis.

p arm of acrocentric chromosomes (chromosomes 13-15, 21, and 22) could not be analyzed in this study. A positive control with known chromosomal abnormalities and a negative control using normal human male and female DNA were used in each hybridization as controls to verify the reliability of this method.

Papillary Thyroid Carcinoma DNA copy number changes are uncommon in papillary thyroid carcinomas as compared with other poorly differentiated and well-differentiated thyroid carcinomas. Papillary thyroid

carcinomas in CGH studies have variable rates of genetic aberrations and specific sites of aberrations. Nonetheless, several common aberrations have been identified, including gains on chromosomes lq, 5q, 6q 9q 13q, 19q, 2lq, 4 and 7, and losses on chromosomes lp, 9q, 16q, 17, 19, and 22.9- 11 Hemmer and associates 10 found genetic aberrations in only 3 (12%) of 26 papillary thyroid carcinomas and reported a positive correlation between the presence of aberrations and older age (>70 years) and cervical lymph node metastasis. Singh and colleagues!' identified genetic aberrations in 10 (48%) of 21 papillary thyroid carcinoma cases. They reported that the loss of chromosome 22 was found only in younger patients «45 years) and was associated

FIGURE 36-5. Comparative genomic hybridization image. The high intensity of green and red images demonstrates gains and losses on chromosomes, respectively.

Comparative Genomic Hybridization in Thyroid Neoplasms - - 347

with a higher rate of regional lymph node metastasis. In our study, no chromosomal aberration was found in 6 welldifferentiated papillary thyroid carcinomas, but 3 (43%) of 7 poorly differentiated papillary thyroid carcinomas had chromosomal aberration. The most common chromosomal site was a gain on lq in 2 (29%) of the 7 poorly differentiated papillary thyroid carcinomas (Table 36-1). This region of lq abnormalities harbors a gene that encodes one of the receptors for the nerve growth factor (NTRKl), which is activated in about 15% of papillary thyroid carcinomas.'? Clonal chromosomal aberrations have been identified in almost half of the cytogenetically examined papillary thyroid carcinomas by other methods than CGH. The most frequent alteration has been an intrachromosomal rearrangement, a paracentric inversion in lOq (RET/PTC). This site is frequently the only change, and it is not detectable by CGH.IO.13-21

Follicular Thyroid Tumor Thyroid tumors of follicular cell origin serve as a good model for studying possible genetic events regarding tumor origin, transformation, and progression. Multiple genetic events appear to be responsible for the progression from adenoma to carcinoma in some tumors (see Fig. 36-1).1.2.22.23 Follicular adenomas have close cytologic and morphologic similarity to follicular carcinomas; the defining difference is the presence of capsular invasion and/or vascular invasion in carcinomas. Because of this similarity, it has been proposed that follicular carcinomas originate from preexisting adenomas. Follicular adenomas could represent premalignant tumors that could transform into carcinomas, through copy number changes in critical genes controlling invasion, angiogenesis, and metastasis. Clinical evidence that follicular carcinomas are obviously larger than follicular adenomas supports this theory. Hemmer and coworkers>'found that copy number changes were more frequent in follicular carcinomas (9 [69%] of 13) than in histologically benign follicular adenomas (14 [48%] of 29) using CGH. However, the average number of copy number changes was less in follicular carcinoma (1.6 changes

per case, range 0 to 6) than in follicular adenoma (2.5 changes, range 0 to 12). On the other hand, Frisk and associates-" subsequently described that the frequency of aberrations was similar in follicular adenomas (8 adenomas, 1.9 changes/mean) and follicular carcinomas (13 carcinomas, 1.5 changes/mean), as well as in 8 minimally invasive follicular carcinomas (1.5 changes/mean) and 5 widely invasive follicular carcinomas (1.6 changes/mean). Hemmer and colleagues" reported that a loss of chromosome 22 or 22q was particularly common in carcinomas (6 [46%] of 13) whereas a loss of chromosome 22 was found in only 2 (7%) of 29 adenomas. Moreover, loss of the chromosome 22 was present in 7 (54%) of the 13 widely invasive follicular carcinomas but in none of the 7 minimally invasive carcinomas (P = 0.04).10 Loss of chromosome 22 was also common in older than in younger patients (P =0.01). A loss of lp was frequent in follicular carcinomas (20%), whereas gains in chromosomes 5, 7, 12, 14, and X were common in follicular adenomas but not found in follicular carcinomas.s' A DNA copy number loss was also common in l3q in follicular carcinomas (25%).10 The common regions for DNA copy number gain were in lq (25%) and in l7q (20%) for follicular carcinomas. Papillary carcinomas that also arise from follicular cells have fewer chromosomal aberrations, especially losses, than follicular carcinomas. 10 One candidate for the tumor suppressor gene in chromosome 22q is neurofibromatosis type 2 (NF2) located at 22q 12, and there may be another putative suppressor gene distal to NF2. The significance of these and other suppressor genes located in 22q in the genesis of follicular carcinoma is currently unknown. Although formation of fusion genes PAX8-PPARyl caused by a t(2;3)(q13;p25) has been observed in several cases of follicular carcinomas." unfortunately it is difficult to identify these chromosomal translocations using CGH.

Hurthle Cell Thyroid Tumor Hiirthle cell thyroid tumors comprise 1% to 5% of all thyroid neoplasms and have been classified as variants of follicular thyroid tumors. They differ from follicular thyroid carcinomas by their inability to trap radioiodine and by

348 - - Thyroid Gland

HOrlhle cell adenomas

Left: losses Right: gains

FIGURE 36-6. Summary of chromosomal aberrations analyzed by comparative genomic hybridization in 15 Hiirthle cell adenomas and 13 Hiirthle cell carcinomas.

HOrlhle cell carcinomas

the accumulation of mitochondria and eosinophilic cytoplasm on histology. They are also more likely to be multifocal, have nodal metastasis, and appear to be clinically aggressive. Hiirthle cell carcinomas are similar to follicular thyroid carcinomas in that they usually cannot be diagnosed by fine-needle aspiration biopsy or frozen section. It is also difficult to distinguish Hiirthle cell adenomas from carcinomas preoperatively or intraoperatively. Some investigators previously recommended that all Hiirthle cell tumors should be considered as malignant and be treated aggressively because of their malignant potential. 27.28 Others suggested that Hiirthle cell tumors are separated into adenomas (which have no capsular and vascular invasion) and carcinomas, using similar criteria as used for follicular tumors. 29-32 Some studies have suggested that patients with Hiirthle cell carcinoma do not necessarily have a worse prognosis than patients with follicular thyroid carcinorna.Pr" Hemmer and coworkers/" reported 3 of 4 Hiirthle cell adenomas had chromosomal aberrations. Frisk and associates"

also reported that 2 of 3 Hiirthle cell adenomas had chromosomal aberrations, as did 3 of 4 Hiirthle cell carcinomas. Similarly, Tallini and colleagues-' documented that 6 of 7 adenomas and 3 of 4 carcinomas had chromosomal aberrations. We found chromosomal aberrations in 9 of 15 Hiirthle cell adenomas and in 8 of 13 Hiirthle cell carcinomas." The mean number of chromosomal gains and losses were 2.1 and 0.7 in 15 adenomas versus 4.2 and 0.8 in 13 carcinomas. Although Hiirthle cell adenomas were more likely to have fewer chromosomal aberrations than Hiirthle cell carcinomas, in our study, this difference was not significant (P > 0.05) (Fig. 36-6 and Table 36-2). Our investigations have found that whole or focal chromosomal gains are relatively common in chromosomes 5, 7, 12, 17, 19, and 20 and losses are in chromosomes 2 and 9 in both Hiirthle cell adenomas and carcinomas (see Fig. 36-6).36 Frisk and colleagues'" reported that loss of 9q 13-q21.3 was a specific aberration in Hiirthle cell carcinomas. In our study, gains in chromosome 12 were more common in Hiirthle cell

Comparative Genomic Hybridization in Thyroid Neoplasms - - 349

carcinomas than in Hiirthle cell adenomas and, in particular, gains in l2q occurred more frequently in patients with Hiirthle cell carcinomas who developed recurrent disease (P < 0.001).36 Roque and coworkers'? have reported an increased frequency of gains in chromosome 7 and 12 among different thyroid tumors (e.g., goiters, follicular adenomas, and follicular carcinomas). These findings support the concept that some thyroid neoplasms develop in a multistep process. We also found that gains in 5p, 7, 19p, 19q, and 20p were associated with a higher risk of tumor recurrence as well as l2q in patients with Hiirthle cell carcinoma (Table 36-4).36 The presence of these chromosomal aberrations in primary Hiirthle cell carcinoma may predict developing recurrent disease. Erickson and associates'" reported

that loss of chromosome 22, by FISH, was associated with deaths due to Hiirthle cell carcinoma.

Anaplastic Thyroid Carcinoma Anaplastic thyroid carcinoma is an extremely aggressive cancer, with a median survival after diagnosis of just a few months.l? The outcome is so poor that the American Joint Committee on Cancer (AJCC) classifies all patients with this tumor as having stage 4 thyroid cancer. Fortunately, anaplastic thyroid carcinoma accounts for less than 2% of all thyroid carcinomas in the United States and has been decreasing in incidence.f'-"

350 - - Thyroid Gland

Hemmer and colleagues, to as previously mentioned, reported that more chromosomal aberrations occurred in follicular thyroid carcinomas than in papillary thyroid carcinomas. They studied DNA copy number changes by CGH in 69 patients with thyroid carcinoma. Among the 20 follicular thyroid carcinomas, there were 22 deletions and 26 gains (median changes 2, range 0 to 8, for one sample). In contrast, among the 26 papillary thyroid carcinomas, there were no deletions and 6 gains (median changes 0, range 0 to 4, for one sample). Among the 13 anaplastic thyroid carcinomas, there were 5 deletions and 27 gains (median changes 2, range 0 to 13, for one sample). Their documentation of more gains than losses in anaplastic thyroid carcinomas is similar to our results. By CGH analysis of 10 anaplastic thyroid carcinomas, chromosomal aberrations were found in 5 of the 10 anaplastic thyroid carcinomas (Table 36-5).8 We identified 24 chromosomal aberrations, of which 22 were gains and 2 were losses (Fig. 36-7). The two anaplastic thyroid carcinomas (cases 9 and 10) that had the greatest number of chromosomal aberrations (6 and 13) were found histologically in association with follicular thyroid carcinoma. The others with no chromosomal abnormalities (cases 1, 2, and 6), or two or fewer chromosomal abnormalities (cases 3, 4, and 5) were histologically associated with papillary thyroid carcinoma. The median numbers of chromosomal aberrations were 9.5 for anaplastic thyroid carcinoma associated with follicular thyroid carcinoma versus 0.5 for those associated with papillary thyroid carcinoma; this difference was significant (P = 0.046). Two of the anaplastic thyroid carcinomas without known association with follicular or papillary thyroid

carcinoma had no chromosomal aberrations. We found that DNA copy number changes in anaplastic thyroid carcinomas appear to parallel those of the associated follicular or papillary thyroid carcinomas. Thus, after transformation from follicular thyroid carcinoma or papillary thyroid carcinoma to anaplastic thyroid carcinoma, the cells appear to retain their cytogenetic profile. We found no significant correlation between the presence of chromosomal aberrations and overall survival or other clinicopathologic characteristics in our investigation (see Table 36-5).8 The most common chromosomal aberrations were gains in chromosome lq2l-qter in 3 of 10 anaplastic thyroid carcinomas and gains in chromosome lOp and Xp in 2 of 10 anaplastic thyroid carcinomas (see Fig. 36-7). Two of 3 anaplastic thyroid carcinomas that had a gain in lq were associated with papillary thyroid carcinoma (see Table 36-5), but neither had a known history of radiation exposure. The region of lq aberrations found in these 3 anaplastic thyroid carcinomas harbors a gene that encodes one of the receptors for the nerve growth factor (NTRKI), which is activated in about 15% of papillary thyroid carcinomas.P Activation of NTRKI has been reported to be present in papillary thyroid carcinomas that occur after exposure to radiation in children, as well as RET/PTe chromosomal rearrangements.P'v"? Human thyroid cancer cell lines had more chromosomal aberrations than did frozen thyroid cancer samples in our studies, consistent with other studies (Fig. 36-8 and Table 36_6).8,10.48.49 More alterations may be required to establish an immortalized cell line or that cultivating of cells leads to the selection of cells that have more chromosomal aberrations.P No common chromosomal aberrations by

Comparative Genomic Hybridization in Thyroid Neoplasms - -

351

FIGURE 36-7. Summary of chromosomal aberrations analyzed by comparative genomic hybridization in 10 anaplastic thyroid carcinomas.

CGH in anaplastic thyroid carcinoma were apparent when we compared our findings to those reported in the literature (see Table 36-6).

Medullary Thyroid Carcinoma Apart from the RET protooncogene (RET) point mutation of chromosome 10, no other genes have been found to be involved in the original growth of medullary thyroid carcinomas. Germline RET mutations have been identified in about 98% of patients with familial medullary thyroid carcinoma, and somatic RET mutations have been frequently detected in sporadic medullary thyroid carcinomas.t! In sporadic medullary thyroid carcinomas, the RET gene is mutated in codon 918, where a methionine is substituted to a threonine (M918T). Chromosomal aberrations have been detected by CGH in approximately 50% to 60% of the patients with medullary thyroid carcinoma.P>' The number of chromosomal aberrations in medullary thyroid carcinoma appears to be lower than in other thyroid carcinomas that arise from thyroid follicular cells.'? Frisk and coworkers>' reported that chromosomal regions 19q, 19p, 13q, and llq may be involved in medullary thyroid carcinogenesis but that medullary thyroid carcinoma is a relatively genetically stable tumor. Overall, the results of CGH investigations in medullary thyroid carcinomas have suggested a normal modal number of chromosomes with a marked tendency to random hypodiploidy.P Hypodiploidy has also been found in medullary thyroid carcinoma cell lines. 53

Limitations and Difficulties of Comparative Genomic Hybridization CGH only detects genomic aberrations that involve loss or gains of DNA sequences. Balanced translocations or inversions are therefore not detectable, nor are small intragenic rearrangements and point mutations. CGH also only detects DNA sequence copy number changes relative to the average copy number in the entire tumor sample. The relative green-to-red ratios can be transformed to indicate actual copy numbers if the absolute copy number in several loci are independently determined or if the ploidy is determined by DNA content analysis. 6•54 Pericentromeric and heterochromatic repeat regions, unfortunately, cannot be reliably evaluated by CGH because unlabeled Cot-I DNA blocks binding of the labeled DNA to the pericentromeric and heterochromatic regions. These DNA sequences are highly polymorphic in copy number between individuals. Thus, ratio changes at or near these regions should be interpreted cautiously, especially when the test and reference DNA samples come from different individuals.> CGH, unfortunately, cannot detect single-copy losses or gains unless the extent of the region in loss/gain is greater than about 10 Mb, Moreover, the CGH ratio may not be a quantitative measure of the number of copies lost or gained unless the involved region is much greater than 10 Mb in extent. Similar to other methods based on extracted DNA, CGH requires that the tumor specimens be relatively free from

352 - - Thyroid Gland

- - - FTC cell lines (FTC133, FTC236 , FTC238) •

• ATC cell line (AR081-1)

............ PTC cell line (TPC-1)

FIGURE 36-8. Summary of chromosomal aberrations analyzed by comparative genomic hybridization (CGH) in five thyroid cancer cell lines: (I) FfC-133 was derived from a primary follicular thyroid cancer (FfC); (2) FfC-236 was derived from a lymph node metastasis of FfC from the same patient as in FfC-133; (3) FfC-238 was derived from a lung metastasis ofFfC from the same patient as in FfC-133; (4) AR081-1 was derived from an anaplastic thyroid cancer (ATC); and (5) TPC-I was derived from a papillary thyroid cancer (PTC).

Comparative Genomic Hybridization in Thyroid Neoplasms - - 353

surrounding normal tissues that dilute the green-to-red ratio changes. If the normal tissue contribution is greater than 50% of the total DNA content, reliable detection of the ratio becomes increasingly difficult. In addition to normal cell contamination, intratumor genetic heterogeneity may also dilute the green-to-red ratio changes detected by CGH. This technique detects the average copy number of sequences in all cells included in the specimen, so those aberrations that are homogenously present (clonal) in the tumor cells are more readily detected. In most cases, this is an advantage, because the clonal changes are likely to represent the early and most important changes. However, in multiclonal tumors, the different genetic aberrations present in the individual clones may sometimes balance one another or exist at too Iowa frequency to be detected. 54

Conclusions Investigations using CGH have identified several regions of the genome with gains and losses that havepreviously not been suspected to be involved in thyroid carcinoma. These regions may contain important novel genes that are responsible for thyroid tumor development and progression. Further investigations using higher resolution CGH analysis and a larger series of tumors are required to validate and refine the locations of the common regions of loss and gain in each chromosome and to evaluate the significance of these genetic events in the multistep model of thyroid carcinogenesis.

REFERENCES 1. Fagin JA. Genetic basis of endocrine disease: III. Molecular defects in thyroid gland neoplasia. J Clin Endocrinol Metab 1992;75:1398. 2. Wynford-Thomas D. Molecular basis of epithelial tumorigenesis: The thyroid model. Crit Rev OncoI1993;4:1. 3. Wynford-Thomas D. Origin and progression of thyroid epithelial tumours: Cellular and molecular mechanisms. Horm Res 1997;47:145. 4. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal tumor development. N Engl J Med 1988;319:525. 5. Fagin JA, Matsuo K, Karmakar A, et al. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest 1993;91:179. 6. Kallioniemi A, Kallioniemi OP, Sudar D, et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 1992;258:818. 7. Ried T, Heselmeyer-Haddad K, Blegen H, et al. Genomic changes defining the genesis, progression, and malignancy potential in solid human tumors: A phenotype/genotype correlation. Genes Chromosomes Cancer 1999;25:195. 8. Miura D, Wada N, Chin K, et al. Anaplastic thyroid cancer: Cytogenetic patterns by comparative genomic hybridization. Thyroid 2003;13:283. 9. Chen X, Knauf JA, Gonsky R, et al. From amplification to gene in thyroid cancer: A high-resolution mapped bacterial-artificial chromosome resource for cancer chromosome aberrations guides gene discovery after comparative genome hybridization. Am J Hum Genet 1998;63:625. 10. Hemmer S, Wasenius VM, Knuutila S, et al. DNA copy number changes in thyroid carcinoma. Am J Pathol 1999;154:1539. 11. Singh B, Lim D, Cigudosa JC, et al. Screening for genetic aberrations in papillary thyroid cancer by using comparative genomic hybridization. Surgery 2000;128:888. 12. Said S, Schlumberger M, Suarez HG. Oncogenes and anti-oncogenes in human epithelial thyroid tumors. J Endocrinol Invest 1994; 17:371. 13. Antonini P, Venuat AM, Linares G, et al. A translocation (7;10) (q35;q21) in a differentiated papillary carcinoma of the thyroid. Cancer Genet Cytogenet 1989;41:139.

14. Bondeson L, Bengtsson A, Bondeson AG, et al. Chromosome studies in thyroid neoplasia. Cancer 1989;64:680. 15. Jenkins RB, Hay ill, Herath JF, et al. Frequent occurrence of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma. Cancer 1990;66:1213. 16. 01ah E, Balogh E, Bojan F, et al. Cytogenetic analyses of three papillary carcinomas and a follicular adenoma of the thyroid. Cancer Genet Cytogenet 1990;44:119. 17. Teyssier JR, Liautaud-Roger F, Ferre D, et al. Chromosomal changes in thyroid tumors: Relation with DNA content, karyotypic features, and clinical data. Cancer Genet Cytogenet 1990;50:249. 18. Herrmann ME, Mohamed A, Talpos G, Wolman SR. Cytogenetic study of a papillary thyroid carcinoma with a rearranged chromosome 10. Cancer Genet Cytogenet 1991;57:209. 19. Herrmann MA, Hay ill, Bartelt DH Jr, et al. Cytogenetic and molecular genetic studies of follicular and papillary thyroid cancers. J Clin Invest 1991;88:1596. 20. Sozzi G, Bongarzone I, Miozzo M, et al. Cytogenetic and molecular genetic characterization of papillary thyroid carcinomas. Genes Chromosomes Cancer 1992;5:212. 21. Sozzi G, Bongarzone I, Miozzo M, et al. A t(10;17) translocation creates the RET/PTC2 chimeric transforming sequence in papillary thyroid carcinoma. Genes Chromosomes Cancer 1994;9:244. 22. Farid NR, Shi Y,Zou M. Molecular basis of thyroid cancer. Endocr Rev 1994;15:202. 23. Learoyd DL, Twigg SM, Zedenius JV, Robinson BG. The molecular genetics of endocrine tumours. J Pediatr Endocrinol Metab 1998; 11:195. 24. Hemmer S, Wasenius VM, Knuutila S, et al. Comparison of benign and malignant follicular thyroid tumours by comparative genomic hybridization. Br J Cancer 1998;78:1012. 25. Frisk T, Kytola S, Wallin G, et al. Low frequency of numerical chromosomal aberrations in follicular thyroid tumors detected by comparative genomic hybridization. Genes Chromosomes Cancer 1999; 25:349. 26. Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARyl fusion oncogene in human thyroid carcinoma [corrected]. Science 2000;289: 1357. 27. Thompson NW, Dunn EL, Batsakis JG, Nishiyama RH. Hiirthle cell lesions of the thyroid gland. Surg Gynecol Obstet 1974;139:555. 28. Gundry SR, Burney RE, Thompson NW, Lloyd R. Total thyroidectomy for Hiirthle cell neoplasm of the thyroid. Arch Surg 1983;118:529. 29. Gosain AK, Clark OH. Hurthle cell neoplasms: Malignant potential. Arch Surg 1984;119:515. 30. Grossman RF, Clark OH. Hiirthle cell carcinoma. Cancer Control 1997;4:13. 31. DeGroot U, Kaplan EL, Shukla MS, et al. Morbidity and mortality in follicular thyroid cancer. J Clin Endocrinol Metab 1995;80:2946. 32. Arganini M, Behar R, Wu TC, et al. Hiirthle cell tumors: A twenty-fiveyear experience. Surgery 1986; I00: 1108. 33. Sanders LE, Silverman M. Follicular and Hiirthle cell carcinoma: Predicting outcome and directing therapy. Surgery 1998;124:967. 34. Sugino K, Ito K, Mimura T, et al. Hiirthle cell tumor of the thyroid: Analysis of 188 cases. World J Surg 2001;25:1160. 35. Tallini G, Hsueh A, Liu S, et al. Frequent chromosomal DNA unbalance in thyroid oncocytic (Hiirthle cell) neoplasms detected by comparative genomic hybridization. Lab Invest 1999;79:547. 36. Wada N, Duh QY, Miura D, et al. Chromosomal aberrations by comparative genomic hybridization in Hiirthle cell thyroid carcinomas are associated with tumor recurrence. J Clin Endocrinol Metab 2002;87:4595. 37. Roque L, Serpa A, Clode A, et al. Significance of trisomy 7 and 12 in thyroid lesions with follicular differentiation: A cytogenetic and in situ hybridization study. Lab Invest 1999;79:369. 38. Erickson LA, Jalal SM, Goellner JR, et al. Analysis of Hiirthle cell neoplasms of the thyroid by interphase fluorescence in situ hybridization. Am J Surg Pathol 2001;25:911. 39. Haigh PI, ltuarte PH, Wu HS, et al. Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival. Cancer 2001;91:2335. 40. Hundahl SA, Cady B, Cunningham MP, et al. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996: U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study. Cancer 2000;89:202.

354 - - Thyroid Gland 41. Clark OH. Predictors of thyroid tumor aggressiveness. West J Med 1996;165: 131. 42. Greco A, Miranda C, Pagliardini S, et al. Chromosome I rearrangements involving the genes TPR and NTRKI produce structurally different thyroid-specific TRK oncogenes. Genes Chromosomes Cancer 1997;19:112. 43. Pierotti MA, Bongarzone I, Borello MG, et al. Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells. Genes Chromosomes Cancer 1996;16:1. 44. Ron E, Modan B, Preston D, et al. Thyroid neoplasia following lowdose radiation in childhood. Radiat Res 1989;120:516. 45. Shore RE, Woodard E, Hildreth N, et al. Thyroid tumors following thymus irradiation. J Nat! Cancer Inst 1985;74:1177. 46. Schneider AB, Ron E, Lubin J, et al. Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: Evidence for the prolonged effects of radiation on the thyroid. J Clin Endocrinol Metab 1993;77:362. 47. Perkel VS, Gail MH, Lubin J, et al. Radiation-induced thyroid neoplasms: Evidence for familial susceptibility factors. J Clin Endocrinol Metab 1988;66:1316. 48. Komoike Y, Tamaki Y, Sakita I, et al. Comparative genomic hybridization defines frequent loss on 16p in human anaplastic thyroid carcinoma. IntJ OncoI1999;14:l157.

49. Wilkens L, Benten D, Tchinda J, et al. Aberrations of chromosomes 5 and 8 as recurrent cytogenetic events in anaplastic carcinoma of the thyroid as detected by fluorescence in situ hybridisation and comparative genomic hybridisation. Virchows Arch 2000;436:312. 50. Mark J, Ekedahl C, Dahlenfors R, Westermark B. Cytogenetical observations in five human anaplastic thyroid carcinomas. Hereditas 1987;107:163. 51. Frisk T, Zedenius J, Lundberg J, et al. CGH alterations in medullary thyroid carcinomas in relation to the RET M918T mutation and clinical outcome. Int J OncoI2001;18:1219. 52. Wurster-Hill DH, Pettengill OS, Noll WW, et al. Hypodiploid, pseudodiploid, and normal karyotypes prevail in cytogenetic studies of medullary carcinomas of the thyroid and metastatic tissues. Cancer Genet Cytogenet 1990;47:227. 53. Tanaka K, Baylin SB, Nelkin BD, Testa JR. Cytogenetic studies of a human medullary thyroid carcinoma cell line. Cancer Genet Cytogenet 1987;25:27. 54. Kallioniemi OP, Kallioniemi A, Piper J, et al. Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosomes Cancer 1994; 10:231.

Sodium-Iodide Symporter and Radioactive Iodine Therapy Rasa Zarnegar, MD

The treatment of patients with well-differentiated thyroid cancer (WDTC) includes three modalities: thyroidectomy, radioiodine (1311) ablation, and thyrotropin (thyroid-stimulating hormone, TSH) suppression. Unfortunately about 25% of WDTCs are initially resistant to 131 1, and about 50% of recurrent thyroid cancers are also resistant to 131 1 treatment. These patients have a worse prognosis, and several investigators have attempted to enhance radioiodine uptake in thyroid cancer cells of follicular cell origin.P Thyroid iodide uptake plays a critical role in the diagnosis and treatment of a variety of thyroid disorders. Since the cloning of the sodium-iodide symporter (NIS), research has been focused on methods of enhancing the uptake of iodide in thyrocytes. NIS is an intrinsic plasma membrane glycoprotein located on the basolateral membrane of thyroid follicular cells and is responsible for iodine uptake into thyroid cells (Fig. 37-1).3,4 It plays a critical role in the active transport of iodide from the blood stream into thyrocytes and in a number of nonthyroid tissues, including the mammary glands during lactation, stomach, kidneys, and salivary glands. Functional NIS expression on thyroid tissue is essential for the concentration of iodide in thyrocytes against a concentration gradient. Iodide is a component of the thyroid hormones triiodothyronine (T 3) and thyroxine (T 4), which playa role in the metabolism, growth, and maturation of a variety of organ systems.! When thyroid cells transform into cancer cells, their ability for iodine uptake is decreased." This is true for both papillary and follicular thyroid carcinomas. Most Hurthle cell carcinomas fail to take up enough 1311 for treatment to be effective. Three mechanisms have been proposed for poor iodide uptake in thyroid carcinoma: (I) NIS gene mutations, (2) suppression of NIS gene expression, and (3) posttranscriptional modifications of the NIS protein. Therefore, research is focused on increasing NIS symporter function in a variety of tumors using specific drugs or gene therapy followed by radioactive iodine ablation.

Molecular Characterization of the NIS Gene The molecular characterization of NIS was accomplished in 1996 when Dai and colleagues cloned the transporter' from Xenopus laevis oocytes, using the complementary DNA (eDNA) libraries derived from FRTL-5 cells (functional rat thyroid-derived cell line). The eDNA encoding the human NIS (hNIS) gene was identified on the expectation that hNIS would be highly homologous to rat NIS'? The hNIS gene is located on chromosome 19p12-13.2. It comprises 1929 base pairs encoding a 643-amino acid glycoprotein with a molecular weight of 70 to 90 kd. The variable molecular weight depends on the level of glycosylation of the protein. The coding region of hNIS contains 15 exons and 14 introns and codes for a 3.9-kb messenger RNA (mRNA).8 NIS is a membrane protein with 13 transmembrane domains with an extracellular NHz terminus and an intracellular COOH terminus (Fig. 37-2). The configuration of the NH z and COOH termini have been confirmed by immunohistochemistry." There are three potential asparagine (ASN) glycosylation sites at positions 225, 485, and 497. 10 However, glycosylation has not been shown to affect the functionality, targeting, or stability of the NIS protein." Findings derived from NIS mutations that cause congenital iodide transport deficiency (lTD) show that a spontaneous single amino acid substitution of proline (Pro) instead of threonine (Thr) at position 354 (T354P) is the cause of congenital lack of iodide transport in several patients.U'" This suggests that a hydroxyl group at the ~ carbon position (Thr-354) is essential for NIS function.14 In the same patients, a mutation from valine-59 to glutamate has also been discovered.P Subsequent to the cloning of hNIS, cDNAs encoding NIS have also been isolated from two other species, pig" and mouse." Mouse NISI6 and rat NIS3 contain 618 amino acid residues, whereas human NIS7 and pig NISI5 contain 643. A highly conserved homologue among all isolated NIS proteins exists.

355

356 - - Thyroid Gland Colloid

FIGURE 37-1. Schematic representation of the iodide uptake and

biosynthetic pathways of thyroidhormones in thyrocytes. Iodine is actively accumulated across the basolateral plasma membrane of the thyrocyte in a processcatalyzed by the sodium-iodide symporter (NIS). This transportis driven by the Na" gradientgenerated under adenosine triphosphate (ATP) hydrolysis by Na+,K+-ATPase. The iodideis passively translocated across the apical membrane of the thyrocyte by the pendrin (PDS)proteininto the colloid, where it is used to iodinate thyroglobulin (Tg). Iodine organification is catalyzed by thyroid peroxidase (TPO) and requires H202• The iodinated Tg, containing thyroid hormones, is stored in the colloid. Thyroid hormones, thyroxine (T4 ) and triiodothyronine (T3) , are released from Tg and secretedin the blood.All steps in the thyroid hormone biosynthetic pathway are stimulated by thyroid-stimulating hormone (TSH).TSH-R = TSH receptor. NIS gene expression is high in thyroid, gastric, and lactating mammary glands, and lower levels are present in other tissues including brain, small intestines, testes, skin, spleen, ovary, and prostate."

Regulation of NIS Gene Expression and Function It has been known for decades that pituitary-derived TSH increases iodide transport into the thyroid cells by way of an adenylate cyclase-cyclic adenosine monophosphate (cAMP)-mediated pathway.' Thyrotropin-releasing hormone from the hypothalamus stimulates the release of TSH, whereas T 3 and T 4 inhibit it. TSH binds the TSH receptor (TSHR) on the basolateral membrane of the follicular cells, causing the accumulation of iodide through the cAMP-mediated increase of NIS transporter synthesis (see Fig. 37-1).17 Upregulation of thyroid NIS expression and iodide uptake activity by TSH have been shown in in vitro and

animal modelsp-2o After withdrawal, a reduction in both intracellular cAMP and iodide uptake activity is observed. TSH stimulation has also been shown to affect cell polarization and spatial organization, leading to redistribution of the NIS transporter from the cytoplasm to the cell membrane. Therefore, TSH not only stimulates NIS transcription and biosynthesis but also is required for NIS targeting to the plasma membrane. The NIS protein is targeted to the basolateral membrane of follicular cells. Although the mechanism of this targeting is not fully elucidated, several sorting signals in the COOH terminus have been identified including the PDZ, dileucine, and acid-based motifs. 21-23 Localization of NIS at the basolateral plasma membrane is important not only for iodide transport in the thyroid gland but also for effective treatment of thyroid disease with radioactive iodine. Impaired targeting is one mechanism by which thyroid cancers have decreased iodide uptake. 24.25 Therefore, it is important for the treatment of thyroid cancer to determine the mechanisms that regulate the subcellular distribution of NIS. Phosphorylation, a common cellular mechanism for modulating protein activity, subcellular localization, and degradation, has been shown to playa role in the post-transcriptional stabilization of the NIS protein. In the presence and absence of TSH, the phosphorylation pattern of the NIS protein is different." Although studies have not shown a role of phosphorylation in the targeting and stability of the NIS protein, its role has been shown in the function of other transporters. Iodide has also been shown to be a major regulator of iodide uptake by the thyroid gland. In 1923, Plummer" noted that high doses of iodide block thyroid function in patients with hyperactive thyroid disease. However, it was Wolff and Chaikoff who, in 1948, reported that the binding of iodide in the rat thyroid in vivo was blocked when iodide plasma levels reached a critical high threshold, a phenomenon known as the acute Wolff-Chaikoff effect.28 Raben showed that the acute inhibition of organic iodide binding is dependent on intrathyroid rather than plasma concentrations of iodide by blocking iodide transport with thiocyanate." Studies went on to show that the inhibitory effects of iodide on the organification of iodine last 2 days, after which there is an adaptation or escape from the effect" The Wolff-Chaikoff effect and the ensuing escape constitute a highly specialized autoregulatory system that protects the thyroid from iodide overload but at the same time ensures adequate iodide uptake for thyroid hormone synthesis. The regulatory role of iodide in NIS function has been explored with studies indicating that NIS transcription is inhibited by iodide. 31.32 Eng and colleagues.P>' however, showed that iodide does not affect NIS gene transcription but rather increases the rate of turnover of the NIS protein. However, it is more likely that iodide affects NIS transporter protein at multiple levels, inhibiting transcription and also increasing turnover of the protein. Although the major regulators of the NIS transporter are TSH and iodide, there are associations between NIS regulation and cytokines including tumor necrosis factor a. (TNF-a.), TNF-~, interferon-y, interleukin-l a. (IL-l o), IL-I~, IL-6, and transforming growth factor ~2' All these cytokines have been shown to play an inhibitory role in NIS protein expression and iodide uptake through decreased NIS gene transcription.31.35.36

Sodium-Iodide Symporter and Radioactive Iodine Therapy - - 357

FIGURE 37-2. Schematic model of the human sodium-iodide symporter, which represents an intrinsic membrane protein with 13 transmembrane and 14 extramembranous domains and 3 potential N-linked glycosylation sites. ExM = Extramembranous domains.

NIS and Thyroid Cancer As previously mentioned, the treatment of patients with WDTC includes three modalities: thyroidectomy, radioiodine (1311) ablation, and TSH suppression. Unfortunately, about 25% ofWDTCs are initially resistant and about 50% of recurrent thyroid cancers are resistant to 1311 treatment. These patients have a worse prognosis, and many studies have attempted to enhance radioiodine uptake in thyroid cancer cells in such patients. 1•2,34,37,38 Since the discovery of the NIS gene, much attention has been focused on the symporter because it is a marker for differentiation and also the mechanism by which radioactive iodide therapy works. Thyroid diseases directly affect the function of the NIS symporter. Three mechanisms, as previously stated, have been proposed for poor iodide uptake in thyroid carcinoma: (I) NIS gene mutations.t? (2) suppression of the NIS gene expression,6.39-44 and (3) post-transcriptional modifications of the NIS protein. 24,26 Congenital lTD is an infrequent autosomal recessive condition caused by mutations in the NIS gene. The clinical picture consists of hypothyroidism, goiter, low thyroid iodide uptake, and low saliva-to-plasma iodide ratio. The incidence of lTD is 1 per 4000 neonates. It has an irreversible effect on the growth and development of the neonate, leading to cretinism. Mutations in thyroid-specific molecules such as thyroid peroxidase, thyroglobulin, and TSHR have been identified. 45-47 NIS mutations have also been reported in congenital hypothyroidism resulting in the absence of the functional NIS symporter. Kosugi and coworkers" reported that a T354P NIS gene mutation was found in seven Japanese

patients from five unrelated families. To date, approximately 60 cases of lTD belonging to 33 families have been reported. Twenty-seven cases from 13 families studied have been shown to have NIS gene mutations. 12.39,48-50 Thyroid cancer has not been shown to involve the mutations seen in congenital lTD. Russo and colleagues" performed direct sequencing of NIS cDNA from five papillary and two follicular thyroid cancers and found no mutations in the NIS gene. The proposed mechanism of reduced radioactive uptake in thyroid cancer has been associated with decreased expression of the NIS gene. Bidart and associates'? showed that NIS protein immunostaining is increased in Graves' disease and reduced in Hashimoto's and thyroid cancer. Our own studies have confirmed that NIS gene expression is increased in Graves' disease and hyperactive adenomas and reduced in Hashimoto's disease. Also, expression of the NIS symporter is reduced in papillary, medullary, and follicular thyroid cancers. Schmutzler'" found that the redifferentiation effect of retinoic acid in thyroid cancer cells is associated with increased NIS gene expression. NIS gene expression not only may be deceased in thyroid cancer but also may affect post-transcriptional targeting of the NIS protein. Saito and colleagues" showed that 7 of 17 papillary thyroid carcinomas overexpressed the NIS gene, but the NIS protein was located in the cytoplasm and not on the cell membrane. In contrast, NIS protein expression was barely detected in the paratumoral normal tissue. Contrary to the results of Saito and colleagues, several investigators have found absent or intermediate expression staining of the NIS protein in differentiated thyroid cancer. 54,55

358 - -

Thyroid Gland

Loss of polarization and impaired membrane targeting of other membrane proteins have been described in malignant thyroid cancer. The epidermal growth factor receptor, as detected by immunohistochemistry, was overexpressed and localized not only pericellularly but also intracellularly rather than exclusively localized on the basolateral membrane as in normal cells. NIS must be expressed, targeted, and retained in the appropriate plasma membrane surface in polarized epithelial cells for active iodide transport to occur. TSH regulates NIS distribution between the plasma membrane and intracellular membrane compartments. In thyroid cancer cells, iodide transport can still be present even in the absence of cell polarization, but targeting to and retention in the plasma membrane remain essential if active iodide transport is to take place. Therefore, elucidating the mechanisms involved in proper targeting and retention of NIS at the plasma membrane is essential to enhancing iodide uptake in thyroid cancer cells.

Enhancing NIS Gene Expression The NIS gene has become the focus of much attention in the past decade as new drugs have been developed that can enhance its expression. Retinoic acid (RA) was the first drug identified to enhance NIS gene expression. 1,53.56-60 9-cis-RA, a ligand for both retinoic acid receptor (RAR)/retinoic X receptor (RXR) heterodimers and RXRIRXR homodimers, markedly induced NIS mRNA expression in a dose- and time-dependent fashion, with maximal levels occurring at 12 hours. All-trans-RA, an RAR-specific ligand, had similar potency. Combining an RAR with an RXR-selective ligand enhanced both NIS mRNA expression and iodide uptake. Similarly, a ligand for peroxisome proliferator-activated receptor y (PPARy), when combined with 9-cis-RA, synergistically increased both NIS mRNA levels and iodide uptake. Schmutzler and colleagues" showed that RA increased radioiodine transport in two different follicular thyroid carcinoma cell lines (FTC-l33 and FTC-238), suggesting that RA may cause redifferentiation of advanced thyroid carcinoma. However, clinical trials with RA at our institution have not mirrored the results seen in cell studies. Histone deacetylase inhibitors are a group of anticancer agents that function through mechanisms that are not yet fully elucidated. Both hyperacetylation and hypoacetylation of histones appear to play important roles in carcinogenesis through gene regulation. Histone deacetylase inhibitors are a unique group of drugs that are under investigation for their role in the regulation of gene expression. Acetylation of lysine residues within the arninoterrninal domains of the core histones has been associated with the regulation of gene transcription/" Histone hyperacetylation correlates with increased gene transcription, whereas hypoacetylation correlates with decreased gene transcription. Although histone acetylation does not disrupt individual nucleosomes, moderate levels of acetylation can destabilize the higher order folding of arrays of nucleosomes. Thus, acetylation of specific lysine residues can regulate the chromatin binding or the enzymatic activity of other nonhistone proteins. 63,64

A number of investigations, however, determined that the up- or downregulation of genes by histone acetylation is not ubiquitous for all genes in a cell. 64 Indeed, a global increase in core histone acetylation did not induce widespread gene transcription. 65 Histone acetylation neutralizes electrical charges, separating DNA from the histones, thus allowing nucleosomal DNA to become more accessible to transcriptional activators or repressors. Histone acetylation is believed to stabilize local nucleosomal structures, thereby allowing transcription factors and the basal transcriptional machinery access to DNA. Hyperacetylation of histones has been shown to open chromatin markedly, and it is required for transcriptional activation." Histone acetylation is a reversible process. Histone acetyltransferases (HATs) transfer the acetyl moiety from acetyl coenzyme A to lysine, neutralizing the positive charge in the histones. Histone deacetylases (HDACs) remove the acetyl groups, re-establishing the positive charge in the histones. In studies at our institution, we found that trichostatin A (TSA) enhanced NIS gene expression in thyroid cancer cell lines with an associated increase in radioactive iodide uptake in these cell lines.s? Depsipeptide (FR901228), another HDAC inhibitor, has also be shown to increase NIS gene expression in well-differentiated thyroid carcinoma cell lines derived from follicular thyroid carcinomas (FTC-l33, FTC-236) and anaplastic carcinomas (SW-1736, KAT-4).68 At low concentrations, these drugs have minimal cytotoxic effects in cell lines (Fig. 37-3). Our studies with TSA showed that at low concentrations this drug caused cells to FTC 133

Hours

FIGURE 37-3. Colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-

diphenyl tetrazolium bromide (MIT) assay for FfC-l33 after treatment with trichostatin A (TSA), n = 3. TSA concentrations of 0, 10,50, 100,250,and 1000ng/mLwere usedin the cell line.Cell proliferation wasmeasured relative to day 0 andrepresents an average measurement. The measurements were taken at 24, 48, and 72 hours. FfC-133 cell proliferation occurred in the presence of TSA at concentrations up to 50 ng/mL, growth inhibition at 100, 250, and 1000ng/mL. FfC = follicular thyroid carcinoma.

Sodium-Iodide Symporter and Radioactive Iodine Therapy - - 359

The identification of drugs that can enhance the expression of the NIS gene does not have limited application to differentiated thyroid cancers. NIS gene expression was identified and characterized in the mammary gland by Tazebay and coworkers.s? A report by Kagai and coauthors'? showed induction of NIS gene expression and radioiodine uptake in breast cancer cells following treatment with RA. In the estrogen receptor-positive human breast cancer cell line MCF-7, all-trans-RA treatment stimulated iodide uptake in a time- and dose-dependent fashion up to approximately 9.4-fold. However, in estrogen receptor-negative human breast cancer, no induction of iodide uptake was observed after RA treatment. RA also did not induce increased iodide uptake in prostate cancer cells (LNCaP), choriocarcinoma cells (JEG-3), and lung cancer cells (A549, H460). Therefore, the effect of RA is cell specific. The effects of HDAC inhibitors in nonthyroidal carcinomas with respect to iodide uptake have yet to be elucidated. Cloning the NIS gene further allows the development of novel cytoreductive gene therapy by directing the transfer of the NIS gene into different tumor cells followed by radioiodine therapy. Early studies in transformed rat thyroid cells (FRTL-Tc) without iodide transport activity showed that transfection restores radioiodine accumulation activity in vitro and in vivo." Mandell and colleagues" demonstrated iodide accumulation in vitro and in vivo in several cancer cell lines, including melanoma, liver, colon, and ovarian carcinoma cell lines, after retrovirus-mediated transfection with the rat NIS gene. An in vitro clonogenic assay was used to demonstrate that rat NIS-transduced cancer cell lines could be killed selectively by the accumulated l3ll. Prostate cancer cells (LNCaP) were shown to be killed selectively by accumulation of radioiodine after tissue-specific iodide uptake by prostate-specific antigen promoter-directed NIS expression in vitro." In a study using adenovirus-mediated intratumoral NIS gene delivery, 3 mCi of 1311 intraperitoneally injected 4 days after transfection in LNCaP xenografts showed a clear therapeutic advantage with an 80% reduction in volume." Rhenium 188, a chemical analog of technetium, with the NIS transporter has been shown to deliver a radiation dose 4.5 times higher than 1311. The next crucial step toward clinical application of NIS gene delivery followed by radioiodine therapy will involve the generation and investigation of safe and efficient gene delivery with vectors that can be administered systemically, targeting specific tissue without severe side effects.

C FIGURE 37-4. Apoptosis assay by annexin V/PI staining and flow cytometryusing trichostatin A (TSA) at concentrations of 0,50, 100, and 500 ng/mL for 24, 48, and 72 hours. Cells are classifiedas viable, early apoptosis, and nonviable. Treatmentwith up to 100 nglmLTSA did not significantly affectthe numberof apoptotic cells.At 500 nglmL TSA, 68.7% of the cells were nonviableafter 72 hours.

redifferentiate with an associated transient Gz/M arrest and at higher concentrations caused cells to progress to apoptosis (Fig. 37-4). If these results can be confirmed in vivo, these drugs may be used clinicallyin the treatment of thyroid cancer in combination with radioactive iodine therapy. Depsipeptide is involved in several clinical trials for tumor redifferentiation in advanced cancers, including thyroid cancer.

Conclusion NIS research has become an exciting field with the cloning of the NIS gene and investigations into the trafficking of the symporter. NIS was used extensively in the management of thyroid disease even before its molecular characterization for radioiodine ablation. However, several thyroid cancers have decreased NIS expression, and therefore radioiodine therapy is less effective in the treatment of these tumors. The investigation of RA and histone deacetylating inhibitors such as depsipeptide and TSA, the possibility of enhancing NIS gene activity, and methods to increase the effectiveness of radioactive iodine therapy are entering clinical trials.

360 - - Thyroid Gland Treatment of nonthyroid tumors by transfecting tumor cells with the NIS gene followed by radioiodine ablation is also a field that requires further investigation. It has become evident that continued study of the mechanisms involved in NIS transporter synthesis and trafficking as well as study of drugs and vectors for systemic administration of the NIS gene will considerably affect the future of cancer therapy.

REFERENCES 1. Schmutzler C, Winzer R, Meissner-Weigl J, Kohrle J. Retinoic acid increases sodium/iodide symporter mRNA levels in human thyroid cancer cell lines and suppresses expression of functional symporter in nontransformed FRTL-5 rat thyroid cells. Biochem Biophys Res Commun 1997;240:832. 2. Lawrence JE, Emerson CH, Sullaway SL, Braverman LE. The effects of recombinant human TSH on the thyroid I23-iodide uptake in iodide treated normal subjects. J Clin Endocrinol Metab 2001;86:437. 3. Dai G, Levy 0, Carrasco N. Cloning and characterization of the thyroid iodide transporter. Nature 1996;379:458. 4. Dohan 0, De la Vieja A, Carrasco N. Molecular study of the sodiumiodide symporter (NIS): A new field in thyroidology. Trends Endocrinol Metab 2000; II :99. 5. Carrasco N. Iodide transport in the thyroid gland. Biochim Biophys Acta 1993;1154:65. 6. Min JJ, Chung JK, Lee YJ, et al. Relationship between expression of the sodium/iodide symporter and 131J uptake in recurrent lesions of differentiated thyroid carcinoma. Eur J Nucl Med 2001;28:639. 7. Smanik PA, Liu Q, Furminger TL, et al. Cloning of the human sodium iodide symporter. Biochem Biophys Res Commun 1996;226:339. 8. Smanik PA, Ryu KY, Theil KS, et al. Expression, exon-intron organization, and chromosome mapping of the human sodium iodide symporter. Endocrinology 1997;138:3555. 9. De la ViejaA, Ginter C, Carrasco N. Topology of the sodium/iodide symporter.Program of the 12th InternationalThyroid Congress, Kyoto, Japan, 2000;107. 10. Levy 0, De la Vieja A, Ginter CS, et al. N-linked glycosylation of the thyroid Na+/I-symporter (NIS). Implications for its secondary structure model. J BioI Chern 1998;273:22657. 11. Fujiwara H. Congenital hypothyroidism caused by a mutation in the Na+/I-symporter. Nat Genet 1997;17:122. 12. Fujiwara H, Tatsumi K, Moo K, et al. Recurrent T354P mutation of the Na+/I- symporter in patients with iodide transport defect. J Clin Endocrinol Metab 1998;83:2940. 13. Fujiwara H, Tatsumi K, Tanaka S, et al. A novel V59E missense mutation in the sodium iodide symporter gene in a family with iodide transport defect. Thyroid 2000;10:471. 14. Levy 0, Ginter CS, De la Vieja A, et al. Identification of a structural requirement for thyroid Na+/I-symporter (NIS) function from analysis of a mutation that causes human congenital hypothyroidism. FEBS Lett 1998;429:36. 15. Ruby S, Watrin C, Rousset B. Molecular cloning and functional analyses of the pig sodium iodide symporter: Evidence for three forms generated by alternatesplicing. Program of the 12thInternationalThyroid Congress, Kyoto, Japan 2000;107. 16. Perron B, Rodriguez AM, Leblanc G, Pourcher T. Cloning of the mouse sodium iodide symporter and its expression in the mammary gland and other tissues. J EndocrinoI2001;170:185. 17. Weiss SJ, Philip NJ, Ambesi-Impiombato FS, Grollman EF. Thyrotropin-stimulated iodide transport mediated by adenosine 3',5'monophosphate and dependent on protein synthesis. Endocrinology 1984;114:1099. 18. Levy 0, Dai G, Riedel C, et al. Characterization of the thyroid Na+/Isymporter with an anti-COOH terminus antibody. Proc Natl Acad Sci USA 1997;94:5568. 19. Kogai T, Curcio F, Hyman S, et al. Induction of follicle formation in long-term cultured normal human thyroid cells treated with thyrotropin stimulates iodide uptake but not sodium/iodide symporter messenger RNA and protein expression. J EndocrinoI2000;167:125.

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Sodium-Iodide Symporter and Radioactive Iodine Therapy - 43. Lin JD, Chan EC, Chao TC, et al. Expression of sodium iodide symporter in metastatic and follicular human thyroid tissues. Ann Oncol 2000; II :625. 44. Ryu KY, Senokozlieff ME, Smanik PA, et al. Development of reverse transcription-competitive polymerase chain reaction method to quantitate the expression levels of human sodium iodide symporter. Thyroid 1999;9:405. 45. Bikker H, Vulsma T, Baas F, de Vijlder 11M.Identification of five novel inactivating mutations in human thyroid peroxidase gene by denaturing gradient gel electrophoresis. Hum Mutat 1995;6:9. 46. Leiri T, Cochaux P, Targovnik HM, et al. A 3' splice site mutation in the thyroglobulin gene responsible for congenital goiter with hypothyroidism. J Clin Invest 1991;88:1901. 47. Sunthornthepvarukui T, Gottschalk ME, Hayashi Y, Refetoff S. Brief report: Resistance to thyrotropin caused by mutations in the thyrotropin receptor gene. N Engl J Med 1995;332:155. 48. Fujiwara H, Tatsumi K, Miki K, et al. Congenital hypothyroidism caused by a mutation in the Na+/I- symporter. Nat Genet 1997;16:124. 49. Matsuda A, Kosugi S. A homozygous missense mutation of the sodium/iodide symporter gene causing iodide transport defect. J Clin Endocrinol Metab 1997;82:3966. 50. Kosugi S, Inoue S, Matsuda A, Jhiang SM. Novel, missense and lossof-function mutations in the sodium/iodide symporter gene causing iodide transport defect in three Japanese patients. J Clin Endocrinol Metab 1998;83:3373. 51. Russo D, Manole D, Arturi F, et al. Absence of sodiumliodide symporter gene mutationsin differentiatedhuman thyroidcarcinomas.Thyroid 2001; 11:37. 52. Bidart lM, Mian C. Lazar V, et al. Expression of pendrin and the Pendred syndrome (PDS) gene in human thyroid tissues. J Clin Endocrinol Metab 2000;85:2028. 53. Schmutzler C. Regulation of the sodium/iodide symporter by retinoids-A review. Exp Clin Endocrinol Diabetes 200 I; I09:41. 54. Jhiang SM, Cho JY, Ryu KY, et al. An immunohistochemical study of Na+/I- symporter in human thyroid tissues and salivary gland tissues. Endocrinology 1998;139:4416. 55. Castro MR, Bergert ER, Beito TG, et al. Monoclonal antibodies against the human sodium iodide symporter: Utility for immunocytochemistry of thyroid cancer. J Endocrinol 1999;163:495. 56. Volume 240, Number 3 (1997), in Article No. RC977715, "Retinoic acid increases sodium/iodide symporter mRNA levels in human thyroid cancer cell lines and suppresses expression of functional symporter in nontransformed FRTL-5 rat thyroid cells," by C. Schmutzler, R. Winzer, J. Meissner-Weigl, and J. Kohrle, pages 832-838. Biochem Biophys Res Commun 1998;246:562. 57. Kogai T, Schultz 11, Johnson LS, et al. Retinoic acid induces sodium/ iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line. Proc Nat! Acad Sci USA 2000;97:8519. 58. Schmutzler C, Kohrle J. Retinoic acid redifferentiation therapy for thyroid cancer. Thyroid 2000;10:393.

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Parathyroid Embryology, Anatomy, and Pathology Miguel F. Herrera, MD • Armando Gamboa-Dominguez, MD

A small gland located in the vicinity of the thyroid gland was first described in 1880 by the Swedish anatomist Sandstrom, 1 who named it "glandula parathyroideae." The first anatomic descriptions of the parathyroid glands in humans were published by Welsh in 18982 and Halsted and Evans in 1907. 3 These authors demonstrated in their classic studies that there are typically four parathyroid glands (two on each side) with a relatively constant mutual location. It is essential for the surgeon dealing with endocrine surgery to be familiar with the embryology, anatomy, and histology of parathyroid glands to appreciate the rationale of certain surgical maneuvers and decisions.

Embryology The thyroid, the parathyroid glands, and the thymus originate from the embryonic pharyngeal region. The pharynx itself is initially an endodermally lined cul-de-sac that forms the cephalic extremity of the foregut. This is derived from a part of the yolk sac. The foregut diverticulum is divided into a more cranial pharynx and a more caudal proper foregut with the appearance of the primordium of the pulmonary apparatus as a small ventral outgrowth. When the embryo is approximately 26 days old, lateral walls of the pharynx show a nonuniform growth that forms five pairs of endodermally lined pouches." Only the first pouch persists as a large, hollow cavity to form at least the greater part of the middle ear cavity and the tympanic tube. The second pouch almost completely disappears. It is from the third and fourth pouches that the parathyroid and thymus glands develop, and they also contribute to the formation of the thyroid gland. The fate of the fifth pouch is uncertain. Each pair of parathyroid glands has a different origin. The inferior parathyroid glands originate from the third branchial pouch and, therefore, are designated as parathyroid III, whereas the superior parathyroid glands descend from the fourth branchial pouch and are referred to as parathyroid IV. Figure 38-1 schematically depicts the development and migration of the parathyroids.

Norris," basing his findings on a collection of 139 human embryos, fetuses, and newborn children, studied the morphogenesis of the parathyroid glands. He divided the developmental process into five stages, as described next.

Preprimordial Stage The preprimordial stage is represented by embryos from 4 to 8 mm in length. This stage makes up the embryonic development between the time of the formation of the pharynx (foregut) and the earliest appearance of a recognizable parathyroid anlage. The third and fourth pouches show slight dorsal extensions. The third pouch, which has the form of a tubelike lateral expansion from the embryonic pharynx, makes contact with the ectoderm of the branchial cleft and then continues its growth downward in the ventral direction.

Early Primordial Stage At this stage, the embryo is about 9 mm in length. The tissue destined to become the parathyroids can be recognized. Proliferation and differentiation of large, clear cells with sharply demarcated polygonal outlines occur in the third and four pouches. This proliferation results in a thickening of the third diverticulum wall. The early primordium of parathyroid IV adopts the form of a solid budlike nodule; the fourth pouch still exists as a tubular diverticulum from the pharynx.

Branchial Complex Stage At this stage, paired derivatives of the third and fourth pouches become separated from each other to take up independent positions. During the early stage, the branchial pouches are joined to the pharynx; subsequently, the pharyngobranchial ducts become drawn out, narrowed, and finally divided so that at each side of the midline there is a pair of lobulated bodies. One pair represents the thymus and parathyroid III (third branchial complex), and the other represents the lateral thyroid and parathyroid IV (fourth branchial complex).

365

366 - - Parathyroid Gland and parathyroid III is at about the level of the lower pole of the thyroid, parathyroid III increases in size and gradually becomes constricted at its base of attachment, and complete separation occurs. The two elements of the fourth complex also grow and become constricted until the interlobular stalk is divided. There is almost no descent of this complex, and the isolation of parathyroid IV occurs when the lateral and median thyroids become incorporated. The final position of parathyroid IV in relation to the thyroid gland is determined by the place at which the inclusion of the lateral thyroid body occurs. Isolation of the parathyroid glands is usually accomplished by the time the embryo is 20 mm in length.

Definitive Form Stage This stage is the period from the end of the stage of isolation to the time when the parathyroids assume their definitive form. Alteration in form from a spherical or globular body toward an ellipsoid shape occurs. The form of the parathyroid glands is ultimately determined by their relation to adjacent structures. This embryologic relationship of the parathyroids, the thyroid, and the thymus makes the location of most parathyroid glands predictable. FIGURE 38-1. Origin of parathyroid glands from the third and

fourth pharyngeal pouches.

The median thyroid, which descended in an earlier stage from a median diverticulum of the floor of the pharynx, begins to grow out laterally and cephalocaudally in the form of a flat plate that extends to both sides of the midline. This plate begins to bend dorsally at its lateral edges and extends more and more dorsally to intervene between the laterally placed third branchial complex and the more medially placed fourth branchial complex. At the beginning of the branchial complex stage, the thymus primordium and the parathyroid primordium are intimately joined; however, the thymus enters into a period of rapid ventral growth until it makes contact with the pericardium. Parathyroid III, on the other hand, does not grow as rapidly as the thymus and remains as a budlike projection from the upper end of the thymus cord. Finally, parathyroid III takes a spherical shape, intimately attached to the cephalic pole of the thymus cord. At the end of this stage, the third branchial complex migrates through the entire extent of the embryonic neck, and separation of the parathyroid from the thymus begins. The position of the fourth complex in relation to the median thyroid depends on changes in form, size, and position of the rapidly growing lateral lobe of the median thyroid. During this time, parathyroid IV is still attached to the lateral thyroid body. The brachial complex stage ends when the embryo is approximately 18 to 20 mm in length.

Isolation Stage This stage is characterized by separation of each branchial complex. When the thymus and parathyroids have descended

Anatomy Most humans have four parathyroid glands. The percentage of individuals with supernumerary glands varies from 2.5% to 22%. The presence of as many as eight parathyroid glands has been reported, and different series have determined that there is a wide variation in the number of individuals with fewer than four glands. The exact number of individuals with fewer than four glands may be impossible to determine because the surgeon or researcher may not be able to find one or more glands, and a missing gland could represent an unobserved rather than an absent gland. The parathyroid glands usually lie on the posterior surface of the thyroid gland, each with its own connective tissue capsule surrounded by lighter colored fat globules. Figures 38-2 and 38-3 depict the normal location of parathyroid glands with emphasis on their anatomic relations. The superior parathyroid gland is normally located on the posteromedial aspect of the thyroid gland near the tracheoesophageal groove. The majority of these glands are located within a circumscribed area 2 em in diameter, about 1 em above the intersection of the recurrent laryngeal nerve and the inferior thyroid artery. They may be either intimately associated with the cricothyroid junction or tucked behind the upper and middle thirds of the thyroid. When a gland is in intimate association with the cricothyroid junction, it is suspended by a small pedicle and enveloped by a pad of fatty tissue. When they are located on the posterior surface of the upper pole, parathyroid glands are invariably beneath a thyroid-investing fascial sheath. Superior parathyroid glands can be located farther down, sometimes obscured by the inferior thyroid artery or the recurrent laryngeal nerve. A rather unusual location is above the upper thyroid pole in the posterior aspect of the neck, the retropharyngeal or retroesophageal space. True superior intrathyroidal glands are rarely seen.

Parathyroid Embryology, Anatomy, and Pathology - - 367

FIGURE 38-2. Frontal view of the anatomic location of parathy-

roid glands.

The inferior parathyroid glands are more widely distributed. They are normally located on the posterolateral aspect of the inferior pole of the thyroid gland, below the inferior thyroid artery, although they may be located anterior, inferior, or lateral to the inferior thyroid pole. They are usually surrounded by fat and sometimes may be in a fatty

FIGURE 38-3. Lateral viewof the anatomic location of upperand

lower parathyroid glands. A, Right. B, Left.

appendage of the inferior thyroid pole. Some of these inferior glands can be found high up on the thyroid lobe. Another common location of the inferior parathyroids is the region inferior to the thyroid, close to the thyrothymic ligament or within the cervical part of the thymus. Inferior glands can also be located farther down in the thymus or in the fatty tissue of the anterior mediastinum, at the carotid bifurcation, or within the substance of the thyroid gland. Most anatomic studies have not involved serial sections of the thyroid gland, but Thompson and colleagues'' carefully sliced all thyroid lobectomy specimens during a 10-year period and found truly intrathyroid parathyroid glands in 3% of the cases. They were all located in the lower third of the thyroid and, therefore, were considered inferior parathyroid glands. Failure of an inferior parathyroid gland to descend during its embryonic development may result in a gland located higher up in the neck, even above the upper thyroid pole. These glands are usually surrounded by a remnant of thymic tissue. When supernumerary glands exist, the fifth gland is most often located in the thymus or in relation to the thyrothymic ligament."? Figure 38-4 graphically demonstrates the frequency of anatomic locations of both superior and inferior parathyroid glands as reported by Gilmour in a study on 527 autopsies. 10 As previously stated, parathyroid glands can be either extracapsular or intracapsular. When the gland is located underneath the fibrous capsule of the thyroid, it is designated intracapsular; whereas when it lies outside the capsule it is termed extracapsular. This anatomic feature has great surgical importance. When an intracapsular gland is diseased, it expands locally within the confines of the thyroid capsule and remains in its place. An enlarged extracapsular parathyroid gland, on the other hand, tends to be displaced to the area of least resistance. Thus, an extracapsular gland at the cricothyroid junction falls into the posterior mediastinum and an extracapsular gland within the thymus disappears behind the clavicle and falls into the superior anterior mediastinum. Symmetry of parathyroid glands varies for parathyroids III and IV. Symmetry of superior glands is found in approximately 80% of the cases, whereas approximately 70% of inferior glands are symmetrical. Relative symmetry of all four glands is noted in approximately 60% of the cases. It is important to note that symmetry is less marked when the glands are located in an unusual site.? When two parathyroid glands are intimately related to each other and appear to be fused, they are known as "kissing pairs." This is a rare finding. A kissing-paired parathyroid can be differentiated from a bilobular gland by the presence of a cleavage plane present in the kissing pair and an intact capsule in the bilobulated gland. The parathyroid glands vary in size, shape, and color. They are spherical, somewhat flattened, or ovoid bodies whose shapes are modeled by pressure from the surrounding structures. The size of parathyroid glands varies from 4 to 6 mm in length and 3 to 4 mm in width. The average parathyroid gland is about 5 x 3 x I mm. When they are long, they tend to be narrow and thin. Conversely, when they are short, they are wide and thick. The average weight of a parathyroid is 35 to 40 mg, but it ranges from 10 to 70 mg. The color of the glands varies with age. In the newborn. they are gray and semitransparent. They are light pink in children,

368 - - Parathyroid Gland

FIGURE 38-4. Frontal view of the anatomic location of upper and lower parathyroid glands as reported by Gilmour,"

turning yellow in adults as their fat content increases. In older adults, they become darker,"!' Parathyroid glands may conceivably be confused with small lobules of fat, with accessory nodules of thyroid tissue, or even with lymph nodes. Several physical characteristics may help to distinguish one from the other. The parathyroid glands are faintly globular or oblong structures that are softer in consistency than the adjacent thyroid or lymph nodes. Fat lobules are more friable than parathyroid glands and do not have the gland consistency or the lacework of blood vessels on the surface. Lymph nodes have a more rounded configuration and are more adherent to the surrounding tissues. Thyroid nodules are always harder, more reddish, and less homogeneous than parathyroid glands. Parathyroid tissue is quite vascular, and on biopsy a "blush" or diffuse bleeding can be seen on the cut surface. Neither fat nor lymph nodes exhibit such a blush. 6,l 2,l 3 At surgery, the typical appearance of a parathyroid gland is that of a small "body" that moves inside its own fat capsule when gentle pressure on the surface is applied with a fine surgical instrument.

Relation between the Parathyroid Glands and the Recurrent Laryngeal Nerve Emphasis has been placed on the relationship of the parathyroid glands and the recurrent laryngeal nerve. A predictable relation of both the superior and inferior parathyroid glands to the recurrent laryngeal nerve is noted within a rectangular area that can be imagined visually when the lobe of the thyroid is rotated medially. The superior boundary of this rectangle is the most cephalad portion of the thyroid lobe; the inferior boundary is a point on the trachea 4 em below the inferior pole of the thyroid gland; posteriorly, the esophagus; and anteriorly, the surface of the thyroid lobe and trachea. The usual course of the recurrent laryngeal nerve should divide this rectangle into two triangles, one lying ventral and the other dorsal to the nerve. After analyzing 100 autopsy specimens, Pyrtek and Painter" found that 93%

of parathyroid glands were situated in a predictable relation to the recurrent laryngeal nerve (i.e., superior glands lying posterior and superior to the nerve and inferior glands lying anterior to the nerve). This supports the reliability of the recurrent laryngeal nerve as a guide for locating the parathyroid glands.

Arterial Blood Supply to the Parathyroids On the basis of the study of 357 parathyroid gland pedicles, Flament and colleagues" found a single artery supplying the parathyroids in 80% of the cases. This artery was simple in 65% of the cases, bifurcated before its entry into the gland in 30%, and divided into three branches in 5%. In 15% of the total group, two distinct arteries were observed, in 4% three were seen, and in 1%, even four separate arteries were found. The length of the artery is variable, usually between 8 and 12 mm. When long, the arteries are commonly tortuous; when the pedicle is short, it holds the parathyroid hard against its vessel of origin. Generally, pedicles of the superior parathyroid are shorter than those of the inferior ones. Both the superior and inferior parathyroid glands most frequently borrow their blood supply from the inferior thyroid artery. In particular, superior parathyroid glands receive their arterial blood supply from this artery in approximately 80% of the cases. In 15%, the blood supply is provided by the superior thyroid artery, and in 5%, by anastomoses running between the two systems. When the superior thyroid artery supplies the superior parathyroid, the supply almost always comes from the posterior branch or from an artery arising from the posterior branch and destined for the esophagus or the larynx. In approximately 10% of the cases, inferior parathyroid glands are vascularized by the superior thyroid artery, anastomosis of both systems, or Neubauer's artery." This figure is intimately related to the frequency of agenesis of the inferior thyroid artery, which occurs in 1% to 6% of cases. In terms of parathyroid blood supply, certain practical observations are worthwhile. A special tiny parathyroid

Parathyroid Embryology, Anatomy. and Pathology - - 369 artery always supplies the gland and is considered terminal. Superior and inferior parathyroid arteries usually arise from the glandular branch of the thyroid artery but can often arise from the muscular or the esophageal branches. They can also originate from an anastomosing channel between the inferior and superior thyroid vessels. Very few, if any, vascular connections between the parathyroid glands and the adjacent connective tissue normally exist. The fine branches that the parathyroid arteries give off to the surrounding fat end in the fatty tissue, thus making it easier to enucleate the glands with their involved fat than to liberate them from it. 3,14

Adenoma

Parathyroid glands consist of chief and oxyphil cells, fibrovascular stroma, and adipose tissue. Chief cells are identified in children and adults; oxyphil cells are mainly observed in adults. Chief cells constitute almost all the parenchyma and measure 6 to 8 urn in diameter; their cytoplasm contains argyrophilic granules and lipids. Clear cells have an optically clear cytoplasm as a result of glycogen loss during histologic processing. The total number of oxyphil cells grows with increasing age; however, this kind of cell is also identified in pediatric populations. It is associated with secretory functions, contrary to the usual point of view that these are degenerated cells. 15 Parenchymal cells are arranged in solid sheets, cords, tubular structures, or, in 2% to 50%, microcystic formations. The admixture of stromal and adipose elements varies with age and function. The parenchyma-to-stroma ratio is used as an indicator of a normocellular or hypercellular gland; the median ratio is 50%, but the adipose tissue content varies from 40% to 70% (Fig. 38-5). Therefore, some authors consider the stromal-parenchymal index inadequate for separating normal from abnormal glands.l's'? Primary hyperparathyroidism can be produced by three different pathologic lesions: adenoma, hyperplasia, and carcinoma. The frequencies of these vary, mainly because of the use of different criteria for their diagnosis in the various series.

An adenoma is a benign neoplasm composed of chief cells, oncocytic cells, transitional oncocytic cells, or a mixture of these cell types. They are responsible for 80% to 90% of hyperparathyroidism cases and usually affect a single gland. Adenomas are more frequent in females than males, at a ratio of 3:1. Macroscopically, the affected gland is enlarged, tan-brown, ovoid, well limited or encapsulated, and occasionally with areas of hemorrhage or cystic spaces (Fig. 38-6). In smaller adenomas, a rim of normal glandular tissue is identified. The remaining glands are normal or atrophic. I? Histologically, adenomas are encapsulated tumors composed of cohesive sheets of cells surrounded by a fine capillary network. Occasionally, insular, tubular, trabecular, or acinar patterns are observed. Stromal fat is scant or absent, and the large, thick-walled veins typical of normal parathyroid glands are lacking. However, these two criteria, classically considered diagnostic of adenoma, have been regarded as less relevant.F:" A rim of normal glandular tissue is always identified in small lesions but is sometimes absent in large adenomas even if serial sections are made. On the other hand, adenomas are occasionally confused with hyperplastic nodules admixed with normal glandular tissue in cases of parathyroid hyperplasia. Because of the poor reproducibility of histologic criteria to differentiate parathyroid adenoma from hyperplasia, close cooperation between the pathologist and surgeon is recommended.l? In conclusion, a remnant of normal tissue is no absolute prerequisite for a diagnosis of adenoma and is identified in only 50% to 60% of proven adenoma cases (Fig. 38-7). The precise histopathologic definition of parathyroid adenoma has remained elusive. Studies using molecular approaches have established that parathyroid adenomas are clonal proliferations. Some studies demonstrated clonal rearrangements of the parathyroid hormone gene and further evidence for clonality through the analysis of the hypoxanthine phosphoribosyltransferase gene." Thus, the monoclonality of adenoma cells is usually reflected by their monomorphic appearance, although cases with a mixed

FIGURE 38-5. A close l: 1 relation of epithelial and stromal cells is observed in normal glands from adults.

FIGURE 38-6. Macroscopic aspect of a parathyroid adenoma showing a nodular configuration with cystic degeneration in a brown gland.

Pathology

370 - - Parathyroid Gland

FIGURE 38-7. Parathyroid adenoma. A rim of normocellular parathyroid tissue with adipose cells surrounds a proliferation of chief and oncocytic cells.

FIGURE 38-8. Parathyroid hyperplasia. Nodular proliferation of parenchymal cells admixed with normocellular parathyroid tissue at the periphery of a hyperplastic gland.

cellular population exist. The cells are larger than normal, and the nuclei show hyperchromasia, atypia, and an increased DNA content." Focally, there is syncytia formation, with variable numbers of nuclei surrounded by basophilic cytoplasm, probably as a result of cell degeneration.

In classic chief cell hyperplasia, these cells are mixed with oncocytic and transitional oncocytic cells. Stromal fat cells are decreased, and vascular supply is provided by large, thick-walled vessels. The parenchymal cells frequently show a nodular arrangement, usually at the beginning of the disease. These nodules consist of polygonal cells with abundant cytoplasm and a medium-sized or small, centrally located nucleus. In the internodular tissue, parenchymal cells are mixed with stromal elements (Fig. 38-8). In the occult form of parathyroid hyperplasia, confusion with a parathyroid adenoma or a large normal parathyroid gland can occasionally occur, and its functional significance is uncertain. To distinguish between parathyroid hyperplasia and parathyroid adenoma, it is important to know the gross appearance of all glands at surgery. 17 In primary chief cell hyperplasia, enlargement of more than two parathyroid glands is frequently observed, whereas the great majority of adenomas involve a single gland. Hence, no single morphologic parameter is able to resolve the differential diagnosis (Table 38-1); instead, the distinction between adenoma and hyperplasia is based on the combination of gross features plus histologic parameters. When a normal parathyroid gland is documented histologically, most experts believe that the abnormal gland or glands are adenomas.

Adenoma Variants Oncocytic adenomas are rare neoplasms composed of oncocytic cells. Ultrastructural studies have revealed the presence of abundant mitochondria in the cytoplasm of oncocytic cells. The major criteria for the diagnosis of oncocytic adenomas, according to Wolpert and coworkers.P are as follows: (l) more than 90% of cells showing oncocytic features, (2) histologically normal parathyroid tissue in a biopsy of another gland, and (3) postoperative normocalcemia. Lipoadenomas (hamartomas) are lesions consisting of proliferation of stromal and parenchymal elements. Grossly encapsulated, lipoadenomas appear soft, yellow-tan, and lobulated. Histologically they are composed mainly of abundant adipose tissue with myxoid changes and fibrosis, admixed with chief and oncocytic cells arranged in thin branching cords."

Hyperplasia Primary parathyroid hyperplasia is defined as an absolute increase in chief cells, oncocytic cells, and transitional oncocytic cells mixed with stromal elements in multiple parathyroid glands, in the absence of a known stimulus for parathyroid hormone hypersecretion. 17 Clinically, parathyroid hyperplasia does not differ significantly from adenomas. However, parathyroid hyperplasia is associated with the dominantly inherited multiple endocrine neoplasia (MEN) types land 2. In contrast, parathyroid hyperplasia is generally absent in MEN 28. 23 In more than half of the cases, the hyperplastic glands weigh less than 1 g. According to macroscopic and microscopic morphology, three patterns of hyperplasia have been recognized: classic, pseudoadenomatous, and occult."

Parathyroid Embryology, Anatomy, and Pathology - -

371

(posterior) side of the thyroid and are adjacent to the recurrent laryngeal nerve (upper posterior and lower anterior). About 80% of patients with primary hyperparathyroidism have solitary parathyroid tumors (adenomas), 1% have carcinoma, and 19% have hyperplasia or more than one abnormal parathyroid gland.

REFERENCES

FIGURE 38-9. Parathyroid carcinoma. Nodular arrangement of neoplastic parathyroid cells surrounded by fibrous tissue. A, The centers of the nodules show ischemic necrosis and calcification. B, Intrathyroidal metastasis of parathyroid carcinoma: small nests of neoplastic cells mixed with thyroid follicles.

Carcinoma Parathyroid carcinoma is responsible for 0.5% to 2% of cases of primary hyperparathyroidism. It is a slow-growing neoplasm of the parenchymal cells.'? On gross examination, parathyroid carcinoma is an illdefined mass, usually larger than adenomas, with adherence to surrounding tissues. The cut surface is irregularly nodular, gray-tan, and firm. Microscopically, it consists of neoplastic parenchymal cells that show atypia, mitotic figures, capsular and vascular invasion, and, of paramount importance, thick fibrous bands interspersed among the neoplastic cells. Not all of these features can be observed in every case; fibrous bands are present in 90%, mitotic activity in 80%, capsular invasion in 75%, and vascular invasion in 10% of cases in some series.17,25 The tumor cells making up parathyroid carcinoma are arranged in trabecular, sheetlike, or rosette-like patterns. Occasionally, the neoplastic cells form nodular structures with central calcification and necrosis (Fig. 38-9). Nuclear morphology is variable, from minimal atypia to marked pleomorphism with clumped chromatin and enlarged nucleoli.'? Cytoplasm is clear, eosinophilic, and granular, sometimes mimicking the plasmacytoid cytoplasm of the cells of medullary thyroid carcinoma. Because cytologic features broadly overlap, the distinction between parathyroid carcinoma and parathyroid adenoma is mainly based on the invasive character of the former.17,25

Summary The parathyroid glands ongmate from the third (lower parathyroids) and fourth (upper parathyroids) branchial pouches. These four glands are usually situated on the dorsal

1. Alveryd A. Parathyroid glands in thyroid surgery. Acta Chir Scand 1968;389: 1. 2. Welsh DA. Concerning the parathyroid glands: A critical anatomical and experimental study. J Anat Physiol 1898;32:292. 3. Halsted WS, Evans HM. The parathyroid glandules. Their blood supply, and their preservation in operation upon the thyroid gland. Ann Surg 1907;46:489. 4. Boyd JD. Development of the thyroid and parathyroid glands and the thymus. Ann R Coli Surg Engl 1950;7:455. 5. Norris EH. The parathyroid glands and the lateral thyroid in man: Their morphogenesis, histogenesis, topographic anatomy and prenatal growth. Contrib EmbryoI1937;159:249. 6. Thompson NW, Eckhauser FE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:814. 7. Akerstrom G, MaImaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95:14. 8. Wang CH. The anatomic basis of parathyroid surgery. Ann Surg 1976;183:271. 9. McGarity WC, Bostwick 1. Technique of parathyroidectomy. Am Surg 1976;40:657. 10. Gilmour JR. Embryology of the parathyroid glands, thymus and certain associated rudiments. J Pathol Bacteriol 1937;45:507. 11. Gray SW, Skandalakis JE, Akin JT, et al. Parathyroid glands. Am Surg 1976;40:653. 12. Curtis GM. The blood supply of the human parathyroids. Surg Gynecol Obstet 1930;315:805. 13. Pyrtek LJ, Painter RL. An anatomic study of the relationship of the parathyroid glands to the recurrent laryngeal nerve. Surg Gynecol Obstet 1964;119:509. 14. F1ament JB, Delattre JF, Pluot M. Arterial blood supply to the parathyroid glands: Implications for thyroid surgery. Anat Clin 1982;3:279. 15. Abu-Jawdeh GM, Roth SI. Parathyroid glands. In: Sternberg SS (ed), Histology for Pathologists. New York, Raven Press, 1992,p 311. 16. Ghandur-Mnaymneh L, Cassady J, Hajianpour MA, et al. The parathyroid gland in health and disease. Am J Pathol 1986;125:292. 17. Delellis RA. Tumors of the parathyroid gland. In Atlas of Tumor Pathology, 3rd series, fascicle 6. Washington, DC, Armed Forces Institute of Pathology, 1993, p I. 18. Ghandur-Mnaymneh L, Kimura N. The parathyroid adenoma. A histopathologic definition with a study of 172 cases of primary hyperparathyroidism. Am J PathoI1984;115:70. 19. Bomstein-Quevedo L, Gamboa-DomfnguezA, Angeles-Angeles A, et aI. Histologic diagnosis of primary hyperparathyroidism: A concordance analysis between three pathologists. Endocr PathoI2001;12:49. 20. Arnold A, Staunton CE, Kim HG, et al. Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. N Engl J Med 1988;318:658. 21. Mallette LE. DNA quantitation in the study of parathyroid lesions. A review. Am J Clin Pathol 1988;98:305. 22. Wolpert HR, Vickery AL Jr, Wang CA. Functioning oxyphil cell adenomas of the parathyroid gland. A study of 15 cases. Am J Surg Pathol 1989;13:500. 23. DeLellis RA, Dayal Y, Tischler AS, et al. Multiple endocrine neoplasia (MEN) syndromes: Cellular origins and interrelationships. Int Rev Exp Pathol 1986;28:163. 24. Black WC, Haff RC. The surgical pathology of parathyroid chief cell hyperplasia. Am J Clin PathoI1970;53:565. 25. Schantz A, Castleman B. Parathyroid carcinoma. A study of 70 cases. Cancer 1973;31:600.

Parathyroid Hormone: Regulation of Secretion and Laboratory Determination Jonas Rastad, MD, PhD • Peter Ridefelt, MD, PhD • Wen T. Shen, MD

The parathyroid gland is exceptional among human tissues because its principal secretory product, parathyroid hormone (PTH), is involved in a direct feedback loop, which tightly regulates the serum calcium concentration. This secretion is potently inhibited by calcium through calcium sensors on the parathyroid cell surface, and PTH exerts its effects through a specific receptor in the peripheral target tissues. In the past, disturbances in this system were difficult to recognize clinically because of inadequate assays for PTH and calcitriol. Despite the improvements in these assays, however, management of patients with the broad spectrum of metabolic calcium disturbances is still complicated by limitations in knowledge. This chapter provides a background for subsequent chapters on hyperparathyroidism by outlining the normal physiologic regulation of PTH secretion, describing the derangements in PTH and calcium regulation in primary and secondary hyperparathyroidism (HPT), and defining the current methods for determining serum PTH values.

Physiologic Regulation of Parathyroid Hormone Release Several endogenous substances, including peptides, steroid hormones, and amines, have been found to influence PTH release.I-' It is apparent, however, that calcium is the most potent regulator of PTH secretion. Analyses of normal parathyroid cells have shown that acute changes in extracellular calcium concentration induce rapid changes in PTH release.v' Studies in vitro and in vivo5-9 support the concept that the dose-response relationship between calcium and PTH is inversely sigmoidal, with the steepest part of the curve corresponding to the physiologic concentration range for ionized calcium (Ca2+j) (Fig. 39-IA). Minor alterations within the physiologic calcium concentration range can thus induce considerable secretory responses (Fig, 39-2), and 372

reduction of ionized plasma calcium by 0.04 mmollL may elevate serum PTH by 100% or more. Circadian variation in serum PTH values differs between men and women, and blunting of this variation in HPT seems to occur in vivo,10,I 1 whereas the presence and pathophysiologic significance of rapid pulsations in the release of PTH await clarification. 12,13 Stepwise alterations in extracellular calcium concentration have suggested that more sudden changes may elicit greater PTH responses, whereas rapid decreases in plasma calcium may be counteracted most effectively." The amplitude and direction of the change in calcium concentration also influence the magnitude of the secretory response. 15,16 A nonsuppressible component of PTH secretion persists even when the extracellular calcium concentration is markedly elevated (see Figs. 39-IA and 39-2). The extent of this component is partly related to discrepant sensitivities of PTH assays to different portions of the PTH molecule. Under normal circumstances, the basal serum PTH value is positioned closer to the level of maximal suppression than stimulation, which implies a potential to counteract decreased plasma calcium levels." The steep slope of the dose-response relationship between external calcium and PTH release in euparathyroid patients also supports the notion that shifts in the position and slope of the doseresponse curve significantly influence the steady-state serum PTH value.S'? Chronic changes in serum calcium lead to a shift in the calcium-PTH dose-response curve, whereas acute changes in serum calcium move the PTH secretory responses along the prevailing dose-response curve.7,8.14.18 Moreover, chronic hypocalcemia is characterized by a maintained, albeit numerically reduced, stimulation of PTH secretion in response to a further reduction of the calcium concentration (Fig. 39-3). The rapid effect of extracellular calcium on PTH release suggests that calcium directly interferes with the PTH release process, but the nature of this interference has been

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colleagues."

only partially clarified. It has been demonstrated that external calcium mainly regulates secretion of newly synthesized hormone, which may bypass the relatively few secretory granules in the parathyroid cells.!? Intracellular degradation with release of carboxyterminal PTH fragments occurs especially at high extracellular calcium concentrations. This attenuates the biologic activity of the secretory product because the calcium-regulating properties of PTH reside in its aminoterminal portion. The secretion of PTH is also modulated by transcription of the PTH gene, which consists of three exons and is located in chromosome 11 (1lp15).2o PTH is synthesized as a precursor molecule (pre-pro-PTH) and undergoes sequential cleavage." The pre-pro-signal

peptide is important for cellular transport and extrusion of the intact (1-84) PTH molecule. A single amino acid mutation in this sequence has been found to cause insufficient PTH secretion in familial hypoparathyroidism.P Similar actions have also been ascribed to PTH itself, and this may partially explain the existence of the carboxyterminal portion of PTH. Messenger RNA (mRNA) levels for PTH are increased within hours by low extracellular calcium, consistent with

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374 - - Parathyroid Gland the effects of calcium on PTH secretion.P<' Furthermore, calcitriol lowers PTH mRNA levels and inhibits PTH secretlon.P-" This action is associated with a shift of the calcium dependence of PTH secretion toward lower calcium values rather than interference with the slope of the doseresponse curve." Calcitriol binds to its receptor (vitamin D receptor) and interacts with the 5' -flanking promoter region of the PTH gene." The PTH gene also contains cyclic adenosine monophosphate (cAMP)-responsive elements." whereby its transcription may be regulated by, for example, corticosteroids, vasoactive intestinal polypeptides, and estrogen.

Intracellular Messengers Regulating Parathyroid Hormone Release Regulation of hormone release involves translation of extracellular signals through interacting second messenger systems such as cytoplasmic Ca 2+ j , cAMP, and diacylglycerol production through phosphoinositol hydrolysis. It has been demonstrated that external calcium acts through all of these messenger systems of the parathyroid cell." Calcium interferes with parathyroid adenylate cyclase and cAMP-dependent protein kinases.F This mode of action has been seen in many agents besides calcium and other cations that stimulate or inhibit PTH release.' It is unlikely, however, that the regulation of parathyroid cell secretion by external calcium is controlled principally through cAMP-dependent mechanisms.

The same conclusion has been drawn for the pathologic parathyroid tissue of patients with HPT, despite its altered adenylate cyclase activity." It has also been demonstrated that cAMP appears to regulate the release of PTH that is less newly synthesized than that secreted under the influence of external calcium." Although guanidine nucleotide-binding (G) proteins regulate cAMP production, the role of G proteins in regulating parathyroid Ca 2+ j and PTH release is unclear. 34 A rise in extracellular calcium momentarily elevates Ca 2+ j to an unusually high level in normal human parathyroid cells.t-" As with calcium-regulated PTH secretion, there is a sigmoidal but positive dose-response relationship between Ca 2+ j and external calcium (see Fig. 39-IB). The midpoints of these dose-response curves for calcium-regulated secretion and Ca 2+ j are correlated. Half-maximal inhibition of PTH release is attained at lower external calcium concentrations than the corresponding elevation of Ca 2+ j . Moreover, the secretion is inversely and linearly related to Ca 2+ j within essentially physiologic and supraphysiologic concentrations of calcium." In the very low concentration range of external calcium, however, both Ca 2+ j and PTH release are stimulated by a rise in external calcium. A stepwise increase in external calcium elicits a biphasic Ca 2+ j response in normal parathyroid cells (Fig. 39-4A). This response consists of a rapid Ca 2+ j transient peak followed by a slower steady-state elevation, which seems to persist for as long as the external stimulus is maintained. The rapid Ca 2+ j peak may also be induced in the absence of external calcium by inositol 1,4, 5-triphosphate-mediated release of intracellular calcium from

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FIGURE 39-4. Effects of stepwise increases in extracellular calcium from 0.5 to 3.0 mmol/L on cytoplasmic calcium (A) and parathyroid hormone (PTH) release (B) of normal bovine parathyroid cells loaded with intracellular concentrations of fura-2 of about 0.1 (0) and 0.5 (e) mmol/L. PTH and extracellular calcium concentrations in the perfusate were measured in 5-second samples. PTH release is expressed in percentages of the initial secretion at 0.5 mmol/L extracellular calcium. Values represent mean ± standard deviation. (From Wallfelt C, Lindh E, Larsson R, et al. Kinetic evidence for cytoplasmic calcium as an inhibitory messenger in parathyroid hormone release. Biochim Biophys Acta 1988;969:257. Reprinted with permission of Elsevier Science-NL, Sara Burgerhartstraat 25, 1055 KV Amsterdam, The Netherlands.)

Parathyroid Hormone: Regulationof Secretionand LaboratoryDetermination - - 375 the endoplasmic reticulum.Fr" In contrast, the steady-state Ca2+ j elevation depends on calcium influx through the plasma membrane.t-" This permeability change may be caused by a calcium-mediated increase in inositol tetrakisphosphate. Improvements in the technical handling of parathyroid cells have confirmed that the steady-state Ca 2+ j elevation actually consists of rather impressive oscillations in the calcium concentration (unpublished data). The frequency, but not amplitude, of these oscillations is regulated by external calcium, and the oscillations are sensitive to calcium channel blockers (Fig. 39-5). Such oscillations are expected to enhance the sensitivity of calcium-regulated Ca2+ j and PTH release and to reduce intracellular exposure to potentially damaging steady-state elevations in Ca 2+ j . Moreover, a direct relationship between synchronized Ca 2+ j oscillations and pulsatile hormone release has been established in other cell systems.'? A strong argument for Ca 2+ j as the principal regulator of PTH release has been built by studies of the kinetics of PTH regulation by calcium." Parathyroid cells equipped experimentally with low calcium-buffering capacity demonstrated a momentary rise in Ca2+ j, which rapidly reached a steady-state level upon a stepwise increase in external calcium (see Fig. 39-4). Cells provided with higher buffering capacity, however, displayed slower calcium-induced rises in Ca 2+ j and sluggish alterations in PTH release. High extracellular calcium also increases hydrolysis of the phosphoinositides into not only inositol trisphosphates but also diacylglycerol, whereby activation of classic protein kinase C is expected to occur. Protein kinase C activation at low extracellular calcium concentrations inhibits PTH release but stimulates PTH secretion at high external calcium levels." The role of protein kinase C in PTH secretion remains to be elucidated because there is discordant activation of protein kinase C at low and inositol trisphosphate at high external calcium levels.42,43 Electrophysiologic analyses have demonstrated that inhibition of PTH release by high external calcium levels is associated with depolarization of the parathyroid cell." Studies of transmembrane calcium fluxes, however, revealed that calcium influx occurs through a calcium-activated and voltage-independent permeability and that calcium influx current

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causes the depolarization." A calcium receptor on the parathyroid cell surface was postulated. This receptor was unusual in that a verapamil analog, which blocks voltagesensitive calcium channels, would stimulate calcium influx and raise the Ca 2+ j of the parathyroid cells. 45 Several other divalent cations (e.g., magnesium) can cause transient rises in Ca 2+ j by intracellular mobilization. Even the trivalent cation lanthanum, which is restricted to the cell exterior, may raise parathyroid Ca 2+ j and inhibit hormone release." These findings provide additional arguments for the presence of a surface cation sensor on the parathyroid cell. Activation of this sensor seems to regulate phosphoinositol metabolism and protein kinase C activity, whereas G protein involvement in the messenger cascade is questionable. Moreover, Ga 3+ inhibits PTH release by an apparently different mechanism from the sensor coupled to Ca 2\ 47 Consequently, there may be several cation-sensitive mechanisms involved in the regulation of PTH secretion. Indeed, it has been postulated that proteins with calcium receptor function are expressed not only on parathyroid cells but also on proximal kidney tubule cells, placental cytotrophoblasts, surfactant-producing alveolar pneumocytes, and thyroid C cells. 31,48 Such sensors may thus be widely distributed and function at several sites in systemic and cellular calcium homeostasis.

Parathyroid Calcium Sensor Proteins A calcium sensor protein on the parathyroid cell surface was identified by monoclonal antibodies generated by immunization with human adenoma cells." Such a monoclonal antibody abolished the calcium-regulated Ca 2+ j and PTH release of normal and pathologic parathyroid cells. 50 ,51 The antibody blocked the calcium-induced Ca 2+ j transient intracellular calcium mobilization as well as the steady-state elevation resulting from calcium influx. Because the antibodies also competed with calcium binding to the parathyroid cell surface, the findings supported the idea that the antibodies interfered with the calcium sensor rather than an associated calcium channel. A survey of normal human tissues revealed that this calcium sensor was also expressed by the proximal kidney tubule and placental cytotrophoblast cells."? Cloning of the calcium sensor recognized by the antibodies revealed a 500-kd glycoprotein with a single membranespanning domain; this protein belongs structurally to the low-density lipoprotein (LDL) receptor superfamily.F Particular homology was demonstrated with the rat Heymann's nephritis antigen, which constitutes a large glycoprotein of the proximal kidney tubule and possibly serves as an autoantigen of experimental nephritis. The calcium-binding motifs of the calcium sensor are probably composed of repetitive epidermal growth factor (EGF)-like modules, and calcium sensitivities of the LDL superfamily of proteins are in the range of the extracellular concentration of ionized plasma calcium. Kinetic studies of these proteins indicate the presence of positive cooperativity for the interaction of calcium, whereby multiple binding sites can efficiently alter protein signaling. Under these circumstances, cells equipped with the sensor are allowed to respond efficiently to the narrow alterations in Ca 2+ j , which are required for

376 - - Parathyroid Gland adequate maintenance of systemic calcium homeostasis. A receptor-bound 44-kd protein may help to translocate the large sensor protein to the cell surface. Interestingly, the calcium sensor is partially internalized in parathyroid carcinomas as well as in malignant tumors originating from both the kidney tubules and placental cytotrophoblasts.P Moreover, it seems to be involved in the regulation of cell proliferation, at least in transformed cytotrophoblast cells. Another protein with calcium-sensing function has been identified in the bovine parathyroid by expression cloning in oocytes." This 120-kd protein is G protein-coupled and contains the characteristic seven-transmembrane domains of peptide receptors as well as putative calcium-binding sites. Transfection of this molecule to eukaryotic cells demonstrated linkage to regulation of Ca 2+j, but calcium sensitivity of this protein is within a concentration range that exceeds the ionized plasma calcium level. Receptors for this and related proteins are also present in the cortex and outer medulla of the kidney, the nervous system, and the thyroid. The protein shows significant homology to glutamate receptors mostly expressed in the central nervous system and with known association to voltage-dependent calcium channels. Coupling of this protein to PTH release is at present unclear. By linkage analysis using highly polymorphic DNA probes, the gene for benign familial hypocalciuric hypercalcemia (FHH) was mapped to chromosome 3q21-24 in four families (i.e., the location of the 120-kd protein gene).55FHH has been coupled to mutations in this protein whereby its Ca 2+j regulatory property is lost."

Regulation of Parathyroid Hormone Release in Hyperparathyroidism Derangement of calcium-controlled PTH release is an obligatory characteristic of the pathologic parathyroid tissue from hypercalcemic patients with adenoma and hyperplasia of sporadic primary HPT; familial HPT resulting from multiple endocrine neoplasias (MENs); secondary or tertiary HPT of renal, gastrointestinal, and lithium-induced diseases; and parathyroid carcinoma.s-" The disturbance is characterized by variable calcium insensitivity of PTH secretion. The calcium-PTH response curve is shifted to the right, and the slope is decreased (see Figs. 39-lA and 39-3). The sigmoidal dose-response relationship is essentially maintained, and very few, if any, individuals demonstrate nonsuppressible secretion. This shift in the position and the inclination of the calcium-PTH curve correspond to similar changes in the regulation of Ca 2+j within abnormal parathyroid tissues (see Fig. 39-lB). The inverse linear relationship between Ca 2+j and PTH secretion is thus maintained, but it is less steep than in the normal parathyroid parenchyma. Rare exceptions to this rule involve individuals with minimal calcium suppression of PTH secretion despite considerable increases in Ca 2+j.58-60 The calcium insensitivities of Ca 2+i and PTH release correlate with one another and with the degree of hypercalcemia in the patient.6.58 The correlation with serum calcium values may explain the finding of less pronounced derangements in calcium regulation of PTH

release among primary parathyroid hyperplasias 61,62 because the chief cell hyperplasia of sporadic primary HPT might be overrepresented in mild hypercalcemia.P There is also evidence that the functional cellular abnormality may be more pronounced in larger compared with smaller glands as well as in nodular compared with diffusely enlarged portions of hyperplastic parathyroid tissue. 64,65 The abnormal parathyroid tissue from patients with HPT is also characterized by decreases in the maximal and minimal Ca 2+j values (Fig. 39-1B), which can be obtained at high and low steady-state concentrations of extracellular calcium, respectively.W? Corresponding changes, however, in the rate of PTH secretion have not been consistently observed.s-" Although the clinical significance of the PTH secretory rate remains to be clarified.P patients with HPT secrete more intact PTH during induction of both hypo- and hypercalcemic conditions in vivo,7,8 This increase is partially explained by the mass of parathyroid parenchyma, but this is difficult to evaluate, especially because the cells of abnormal glands are heterogeneous in their functional derangement.sv'" Nevertheless, PTH release per unit cell is reduced in HPT, and this reduction seems more pronounced in larger parathyroid glands.6,68 Ca 2+j is poorly regulated in oxyphilic parathyroid cells in comparison with chief cells from the same glands, and the potential for PTH secretion of these cells is unclear.f Another intriguing finding from studies of human parathyroid tissue is the presence of decreased calcium sensitivity of Ca 2+j in the chief cells from normalsized glands associated with single parathyroid adenomas.P Although the extent of this derangement is less pronounced than in adenomas, it may explain why serum PTH is transiently elevated after adenomectomy'<" The consistent findings of impaired regulation of Ca 2+j, despite maintained Ca 2+i inhibition of secretion in pathologic parathyroid cells, suggest that the principal pathophysiologic disturbance may be confined to the calcium sensing and gating of the cell surface. This assumption is supported by observations of normalization of the calcium-controlled secretion upon experimental increases in calcium permeability of the surface membrane." It is also emphasized by studies with monoclonal antiparathyroid antibodies,67,n which reveal reduced expression of the 500-kd calcium sensor in the pathologic parenchyma of all previously investigated adenomatous and hyperplastic glands. The reduced immunoreactivity is accompanied by diminished mRNA levels for the receptor protein. These derangements are evidently not secondary to the hypercalcemia per se because "rims of normal parathyroid tissue" outside adenoma capsules as well as adenoma-associated glands display an intense and virtually normal receptor expression.w'" The intensity of antibody reactivity, however, differs considerably within the pathologic parathyroid parenchyma and further supports variable secretory disturbances among the cells of individual glands. Elevated protein kinase C activity may contribute to the hypersecretion of PTH in HPT.s' This elevation is presumed to cause a right shift in the dependence of Ca 2+j on extracellular calcium, mainly through partial uncoupling of the calcium sensor from the signaling machinery of the parathyroid cells." Furthermore, the suppressive effects of calcitriol on PTH mRNA synthesis are decreased in parathyroid adenomas,

Parathyroid Hormone: Regulation of Secretion and Laboratory Determination - -

which may exhibit dysfunctional vitamin D receptors." Because calcitriol inhibits the rate of PTH release without altering the suppressive effects of calcium.P:" parathyroid vitamin D resistance may contribute to PTH hypersecretion even at normal calcitriol levels, A similar line of reasoning applies to the evidence for a decreased number of vitamin D receptors in the enlarged glands of patients with uremic HPT,76 Because the prevalence of primary HPT rises with age for both men and women,?? age-related reductions in the serum calcitriol concentration, the concomitant elevation of intact serum PTH values, and the reduced calcium responsiveness of PTH secretion substantiate a central role for calcitriol in the pathogenesis of HPT.78

Parathyroid Cell Proliferation HPT is invariably associated with an increased mass of parathyroid parenchyma. The parenchymal cell weight, however, may only be marginally elevated, and hypercalcemia can be alleviated by excision of pathologic glands weighing less than the normal parathyroid tissue of an individual. These findings suggest that deranged secretory regulation rather than increased cell mass is the principal cause of elevated serum PTH levels and hypercalcemia of HPT. Indeed, it has been suggested that a primary mutation increasing the secretory set-point might initiate and stimulate cell proliferation and that this stimulation declines when plasma calcium settles at the genomically determined level." Increased cell mass nevertheless may determine the portion of PTH secretion not suppressible by calcium.s? whereby hypercalcemia might be related to a complex mixture of increases in cell number and rates of hormone secretion per cell. Parathyroid cell turnover is normally very low, and the cells can be triggered to leave the quiescent Go stage by hypocalcemia and calcitriol deficiency.F:" These findings may be clinically relevant because reduced calcitriol levels are characteristically found even in subclinical disturbances of renal function. This circumstance also includes many elderly patients, who seem to display an unusual propensity for the development of primary HPT, especially in climates associated with limited sun exposure. 77,82 Parathyroid cells in culture display gradually increasing calcium insensitivities of Ca 2+ j and PTH release, which develop in parallel to enhanced proliferation.F Calcitriol inhibits proliferation but not hypertrophy and functional dedifferentiation of cultured cells. Hitherto unidentified factors in the circulation may interact in this coupling of function to proliferation because serum-free culture abolishes hyperplasia and decreased calcium sensitivity of cultured cells.P In this context, it is interesting to note that a mitogenic factor with ability to stimulate parathyroid cell replication has been reported in the plasma of patients with MEN 1.84 The MENl gene has been mapped to chromosome llq 13 and might encompass the cell-signaling phospholipase C~3.85 The constitutional mutation of this dominantly inherited disease is unmasked by loss of the wild-type allele, which suggests that tumorigenesis is related to inactivation of a tumor suppressor gene at the MENl locus." Similar allelic losses have also been found in subsets of sporadic parathyroid adenomas and consequently may represent

377

important promoters of parathyroid growth." Rearrangements of the PTH gene and overexpression of the protooncogene PRADl on chromosome llq13 have been identified primarily in large parathyroid adenomas. 88.89 The PRADl gene encodes cyclin Dl, which is important in the Gl-S phase transition that commits cells to divide."? Consistent with findings of X-chromosome inactivation analysis," unequivocally enlarged MEN 1 lesions and a major proportion of sporadic parathyroid adenomas are monoclonal tumors, which may nevertheless develop polyclonal hyperplasia.F-" In the multiglandular parathyroid involvement of sporadic and MEN I-associated primary HPT, there is considerable variation in expression of the 500-kd calcium sensor protein. This phenotypic variation is particularly striking between chief cell nodules of individual glands 67.94 and indicates that such homogeneously appearing nodules may represent individual cell clones. Hyperplastic parathyroid tissue has not been found to display a monoclonal pattern upon analysis of restriction fragment length polymorphisms.?' This circumstance, however, does not exclude the presence of multiple monoclonal lesions, which indeed has been suggested by analysis of X-chromosome inactivation." Similarly, the characteristically multiglandular and asymmetric parathyroid enlargement in uremic HPT may represent both monoclonal and polyclonal components together with complex admixtures of vitamin D deficiency and parathyroid vitamin D resistance. Indeed, the larger nodules from patients with hypercalcemia of uremic HPT have displayed clonal allelic losses involving the MENl gene on chromosome 11.96 Parathyroid carcinomas, but not adenomas, have also revealed allelic losses of the retinoblastoma gene,"? and increased expression of protooncogenes c-myc and c-fos has been associated with parathyroid cell proliferation.?" It has been demonstrated that sporadic parathyroid carcinomas frequently possess mutations of the HRPT2 gene, which encodes the parfibromin protein, and that these HRPT2 mutations have pathogenetic implications." These and hitherto unrecognized secondary genomic alterations may contribute to the appearance of complex and heterogeneous characteristics upon analysis of pathologic parathyroid tissue and highlight the limitations in our current knowledge about the causes and pathogenetic mechanisms contributing to parathyroid growth and secretory derangements in HPT.

Autocrine Regulation of Parathyroid Cell Secretion and Proliferation Sparse information is available on the expression and actions of growth factors in the parathyroid parenchyma. Insulin-like growth factor I and its receptor seem to be expressed by parathyroid tissue, and EGF may playa role in cellular proliferation.l'" Fibroblastic growth factors (FGFs) are mitogenic peptides synthesized by parathyroid epithelial and endothelial cells. Production of acidic FGF increases under hypocalcemic conditions, when high-affinity receptors for this peptide seem to translocate to the parathyroid cell surface.l'" Because the peptide lacks a classic consensus signal peptide sequence, however, meager secretion from cells is

378 - - Parathyroid Gland characteristic and perhaps involves mechanisms other than the conventional endoplasmic reticulum-Golgi complex. 102 It has long been known that human parathyroid tissue secretes chromogranin A, an equivalent to secretory protein 1.103 This acidic protein is costored in the secretory granules and cosecreted with PTH in response to alterations in the extracellular calcium concentration.Pv''" whereas calcitriol exhibits opposite effects on PTH and chromogranin A gene transcription.I'" Pancreastatin and other cleavage products of the chromogranin A peptide precursor have been found to inhibit PTH release in various species. 104,107,IOS The possibility of intraglandular autocrine or paracrine control of PTH release exists. Theoretically, such a mechanism could participate in sharpening or elongating the responses of the parathyroid gland to secretory agonists or antagonists. The relevance of this phenomenon remains to be elucidated, however, because human pancreastatin I-52 and 34-52 fail to influence human PTH release."? Moreover, the chief and oxyphil cells of human parathyroid glands express PTH-related protein (PTHrP) on the surface membrane, which may have paracrine or autocrine roles in the adult parathyroid. I 10,111 Endothelin is a potent smooth muscle cell constrictor, which exists in different isoforms and binds to specific receptors. Endothelin is synthesized by parathyroid cells and perhaps parathyroid endothelial cells, and endothelin receptors are expressed by the parathyroid parenchyma.l'
Peripheral Parathyroid Hormone Metabolism Intact PTH 1-84 is rapidly cleared from the human circulation and has a half-life of only a few minutes.19.114 This degradation ensures that activation of the PTH receptor can be closely regulated by parathyroid cell secretion of PTH. Moreover, there is no evidence for dynamic regulation of peripheral PTH metabolism. PTH clearance mainly depends on high-capacity uptake of Kupffer cells in the liver and on glomerular filtration. A small amount of PTH, however, appears in the urine because of tubular reabsorption and proteolysis. Circulating PTH is molecularly heterogeneous and contains various carboxyterminal peptide sequences arising by cleavage, mainly at residues 33 to 43. Although only 15% of intact PTH 1-84 is metabolized to such circulating fragments, they make up at least half, and sometimes substantially more, of the immunoreactive PTH in the circulation. 1I5•1I6 This discrepancy is due to the release of such fragments from the parathyroid gland, sequestration from Kupffer cells, and slower clearance from the circulation than for intact hormone. The metabolism of these fragments depends only on intact renal function; consequently, the fragments are accumulated to a considerable degree in renal insufficiency. In contrast, very few aminoterminal PTH fragments exist in the circulation of euparathyroid individuals,

although these fragments may become appreciable in primary and secondary HPT.

Parathyroid Hormone Receptor To characterize normal and pathologic systemic calcium homeostasis, it is pertinent to clarify some aspects of the cloned PTH receptor,'!" Apart from the classic targets of PTH in bone and kidney, the receptor has been demonstrated in fibroblasts, chondrocytes, lymphocytes, smooth muscle cells, and fat cells. This allows PTH to induce hypotension and bowel relaxation and to influence chronotropism and inotropism of the heart in addition to its classic actions on bone turnover and calcium, phosphate, and vitamin D metabolism in the kidney. The receptor also binds PTHrP with similar efficiency. Because PTHrP exerts a variety of hitherto partially clarified functions, studies on the common PTH-PTHrP receptor and its actions are hampered by difficulties in determining the biologically relevant agonist. Activation of the PTH receptor's cAMP-generating capacity requires PTH amino acids 1-24, and PTH 1-34 is essentially as potent as the full-length peptide. I IS However, various PTH fragments may activate other second messenger systems of the receptor with variable efficiency, whereby complex modes of differential interactions may exist. Moreover, specialized binding sites for midregional and carboxyterminal PTH sequences of unknown functional significance may occur,'!" The PTH receptor belongs to the growing family of peptide receptors characterized by seven transmembrane domains and G protein coupling. Expression of this receptor is sensitive to PTH, and prolonged exposure to the ligand can reduce the number of available receptors, whereby target cell functions are less effectively activated. 120 HPT of uremia is a striking example in this phenomenon, with its frequently profound elevation of intact serum PTH levels and comparably modest rise in serum calcium values. Internalization and partial recycling of the receptor protein are the mechanisms for this modulation. 12l Decreased affinity for PTH and desensitization of the cAMP response may modulate the peripheral actions of PTH.122 Other substances such as glucocorticoids as well as vitamin A and D metabolites may interfere with PTH receptor expression, although their in vivo actions in humans remain to be established. Inherited variants of pseudohypoparathyroidism may be caused by dysfunctions in the PTH receptor, its associated G proteins, and different second messenger systems such as adenylate cyclase and phospholipase C. 123

Parathyroid Hormone Assays Assaying for PTH in vivo has been notoriously difficult because of its picomolar concentrations in the circulation as well as its molecular heterogeneity. This heterogeneity is due to parathyroid gland secretion of various carboxyterminal PTH fragments (especially when PTH release is suppressed), hepatic proteolysis, and accumulation of midregional and carboxyterminal fragments caused by slow renal clearance in

Parathyroid Hormone: Regulation of Secretion and Laboratory Determination - - 379

kidney disease. In principle, PTH may be assayed for bioactivity as well as by radioimmunologic and immunometric methods. Although the former two are currently of limited clinical interest, their mechanisms deserve mention. PTH bioassays use either directly analyzed cAMP concentrations in urine or cAMP production of cell systems to assess biologic PTH activity of patients' sera. l24,125 Although such assays may be sensitive in the range of picograms of PTH (per milliliter), they are limited in routine use. These techniques are laborious. They are hampered by the concomitant activation of the PTH-PTHrP receptor by both ligands despite their very limited sequence homology. PTHrP is the most common cause for humoral hypercalcemia of malignancy. PTH bioassays do not distinguish between these two hormones. Moreover, cAMP responses of the PTH-PTHrP receptor might mirror its activation only partially because of the involvement of multiple second messenger systems, whereby bioassays may underestimate activity of circulating PTH. Radioimmunoassays were previously the most widely used means of PTH determination. This technique primarily uses a polyclonal, high-affinity antibody to which binding of radioiodinated PTH is allowed to compete with PTH to be measured in serum. By generating standard curves for binding of the radioactive ligand as a function of its concentration, the amount of iodinated PTH not displaced from the antibody can be used to approximate the concentration of PTH in the serum sample. Naturally, a host of factors require characterization and optimization to secure performance of such analyses. Some of these factors are antibody affinity, radiolabeling of PTH without interference with its immunoreactivity, and stability of the tracer peptide to be displaced.!" Particular problems have been caused by the use of bovine PTH as a tracer. Bovine PTH was selected because of its availability and the presence of tyrosine residues suitable for iodination. To reduce other difficulties, results have been reported in equivalents of pooled human sera. Moreover, analysis with characterized human PTH fragments has demonstrated multiple immunoreactivity of available displacement assays despite their characterization as "aminoterminal," "midregional," or "carboxyterminal." In view of the substantially lower circulating concentration of intact PTH in comparison with fragments encompassing various portions distal to the aminoterminal region, radioimmunoassays have been dependent on satisfactory renal function for reliable use in vivo and are variably limited in the recognition of mild to moderate primary HPT as well as the discrimination of HPT from other causes of hypercalcemia. 127,128 Displacement assays separate patients with primary HPT from overtly euparathyroid control subjects, provided that renal function is normal.P? This separation, however, naturally depends on the biochemical decision levels by which HPT is considered to prevail and current limits for the application of operative treatment verifying existence of the disease. Even with these assays, however, some 20% of individuals with malignancy-associated hypercalcemia demonstrate false-positive PTH elevations. This phenomenon is possibly related to circumstances other than limited specificity toward PTHrP.129,130 Hypothetically, nonspecific interaction of serum in these patients cannot be excluded as

a cause of this phenomenon. It might also be related to disproportionally increased parathyroid gland secretion of midregional and carboxyterminal PTH fragments recognized by these assays. Moreover, the total weight of abnormal parathyroid tissue is generally strongly correlated with serum PTH measured by displacement assay, which indeed also applies to total serum calcium.v' Because the variation among patients is considerable, however, measurements from many patients are required to establish these relationships. Neither biochemical variable, therefore, should be expected to be applicable to predict the degree of glandular enlargement.

Immunometric Assays Routine diagnosis of primary HPT and evaluation of the extent of secondary HPT have been greatly facilitated by the development of immunometric "sandwich" assays. Briefly, these assays use a pair of antibodies that recognize different regions of PTH.131-134 One of these antibodies, preferentially monoclonal, is immobilized, whereas a polyclonal antiserum with greater affinity is labeled with radioiodine (immunoradiometric assay) or chemoluminescence. Because of cooperation of the antibodies, such a sandwich assay is more sensitive than either antibody alone in displacement radioimmunoassays. With careful selection of antibodies, the immunometric assays are specific and sensitive for intact PTH, which allows identification of insufficient PTH secretion of hypoparathyroidism as well as a wide range of PTH levels without sample dilution. Moreover, it is technically favorable to tag antibodies rather than peptides. A vast excess of PTH fragments might hinder a small fraction of intact PTH from binding to the immobilized antibody and from reacting in the assay, a circumstance that has been suggested to occur in analyses for PTH of rare parathyroid gland aspirates.P" The immunometric analyzing process is faster than with radioimmunoassays. By reducing incubation times, the analysis can be done in 15 to 30 minutes and, consequently, can be used intraoperatively.136-138 Such speed of processing, however, is accompanied by a reduction in assay sensitivity. Clinical analysis with immunometric PTH assays usually separates hypercalcemic patients with HPT from patients with other causes of hypercalcemia. This is particularly evident with respect to malignancies of nonparathyroid origin, although some 5% to 10% of these patients demonstrate intact serum PTH in the lower portion of the normal range. Nonparathyroid tumors that produce intact PTH are exceptionally rare. Examples of such tumors include ovarian and small cell carcinomas as well as thymomas.P''<" The immunometric assays demonstrate that clinically overt derangements in renal function are accompanied by very early elevation in intact serum PTH values. This circumstance reflects the onset of parathyroid gland hyperactivity rather than accumulation from impaired clearance, although indirect evidence suggests that a prolonged half-life of intact serum PTH may exist, at least occasionally, in uremia.F' The distribution of intact serum PTH values and recognition of primary HPT among otherwise healthy individuals largely depend on how patients are recruited. In a health screening study of 5200 menopausal women, biochemical

380 - - Parathyroid Gland levels for the recognition of primary HPT were deliberately set low to include those with mild disease (unpublished data). Briefly, individuals demonstrating hypercalcemia (albumin-corrected total serum calcium> 2.60 mmol/L) and intact serum PTH greater than or equal to 25 ngIL (reference range, 12 to 55 ng/L), serum calcium 2.50 to 2.60 mmol/L and serum PTH greater than or equal to 35 ng/L, or serum PTH greater than or equal to 55 ngIL in combination with a previousserum calcium concentrationexceeding 2.55 mmol/L were presumed to have primary HPT. Among the identified individuals, about two thirds showed normal total and ionized serum calcium values, and a similar proportion (69%) showed intact serum PTH within the reference range. Under a stratified case-control treatment program, more than half the patients have been subjected to parathyroid surgery. These individuals were representative of the entire group with respect to total serum calcium values, and operation verified the presence of parathyroid abnormalities in all of them. These findings are described not to provoke arguments about the indications for parathyroid exploration but to demonstrate that even these limits appear to underestimate the prevalence of HPT, and that intact serum PTH measured by immunometric assay may be normal in many patients with mild HPT. The proportion of such patients is assumed to be 5% to 20%.

Summary Findings of parathyroid surface proteins acting as calcium receptors have improved our understanding of the secretory dysfunctions leading to the hypercalcemia of HPT, and it is hoped that research on the regulation of function of these proteins will provide new treatments for HPT. The diagnosis of HPT has improved substantially since the introduction of sensitive and specific assays for the intact 84-amino acid peptide. Such immunoradiometric or immunochemoluminescent sandwich assays should accurately differentiate HPT from other causes of hypercalcemia. Moreover, these assays enable recognition of most patients with HPT, but their efficiency in this respect depends on applied criteria for biochemical recognition and operative confirmation of parathyroid disease.

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101. Sakaguchi K. Acidic fibroblast growth factor autocrine system as a mediator of calcium-regulated parathyroid cell growth. J BioI Chern 1992;267:24554. 102. Mignatti P, Morimoto T, Rifkin DB. Basic fibroblast growth factor, a protein devoid of secretory signal sequence, is released by cells via a pathway independent of the endoplasmic reticulum-Golgi complex. J Cell PhysioI1992;151:81. 103. Cohn DV, Zangerle R, Fischer-Colbie R, et aI. Similarity of secretory protein-I from parathyroid gland to chromogranin A from adrenal medulla. Proc Natl Acad Sci USA 1982;79:6056. 104. Fasciotto BH, Gorr SoU, DeFranco DJ, et al. Pancreastatin, a presumed product of chromogranin-A (secretory protein I) processing, inhibits secretion from porcine parathyroid cells in culture. Endocrinology 1989; 125: 1617. 105. Mouland AJ, Hendy GN. Regulation of synthesis and secretion of chromogranin-A by calcium and 1,25-dihydroxycholecalciferol in cultured bovine parathyroid cells. Endocrinology 1991;128:441. 106. Ridgeway RD, MacGregor RR. Opposite effects of 1,25-(OHhD3 on synthesis and release of PTH with secretory protein I. Am J Physiol 1988;254:E279. 107. Fasciotto BH, Trauss CA, Greeley GH, et al. Parastatin (porcine chromogranin A347-419), a novel chromogranin A-derived peptide, inhibits parathyroid cell secretion. Endocrinology 1993; 133:461. 108. Drees BM, Hamilton JW. Pancreastatin and bovine parathyroid cell secretion. Bone Miner 1992;17:335. 109. Ridefelt P, Hellman P, Stridsberg M, et al. Different secretory actions of pancreastatin in bovine and human parathyroid cells. Biosci Rep 1994;16:221. 110. Kitazawa R, Kitazawa S, Maeda S, Kobayashi A. Expression of parathyroid hormone-related protein (PTHrP) in parathyroid tissue under normal and pathological conditions. Histol Histopathol 2002;17:179. 111. Sakaguchi K, Ikeda K, Curcio F, et aI. Subclones of a rat parathyroid cell line (PT-r): Regulation of growth and production of parathyroid hormone-related peptide (PTHRP). J Bone Miner Res 1990;5:863. 112. Fuji Y, Moreira JE, Orlando C, et al. Endothelin as an autocrine factor in the regulation of parathyroid cells. Proc Natl Acad Sci USA 1991;88:4235. 113. Eguchi S, Hirata Y, Imai T, et al. Endothelin receptors in human parathyroid gland. Biochem Biophys Res Commun 1992;184:1448. 114. Juppner H, Potts JT Jr. Immunoassays for the detection of parathyroid hormone. J Bone Miner Res 2oo2;17:N81. 115. Martin KJ, Hruska KA, Freitag 11, et aI. The peripheral metabolism of parathyroid hormone. N Engl J Med 1979;302:1092. 116. D'Amour P, Lazure C, LaBelle F. Metabolism of radioiodinated carboxy-terminal fragments of bovine parathyroid hormone in normal and anephric rats. Endocrinology 1985;117:127. 117. Abou-Sarnra AB, Jiippner H, Force T, et aI. Expression cloning of a common receptor for parathyroid hormone and parathyroid hormonerelated peptide from rat osteoblast-like cells; a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci USA 1992;89:2732. 118. Tregear GW, van Rietschoten J, Greene E, et aI. Bovine parathyroid hormone: Minimum chain length of synthetic peptide required for biological activity. Endocrinology 1973;93:1349. 119. Rao LG, Murray TM. Binding of intact parathyroid hormone to rat osteosarcoma cells; major contribution of binding sites for the carboxyterminal region of the hormone. Endocrinology 1985; 117:1632. 120. Urena P, Kubrusly M, Mannstadt M, et al. The renal PTHlPTHrP receptor is down-regulated in rats with chronic renal failure. Kidney Int 1994;45:605. 121. Teitelbaum AP, Silve CM, Nyiredy KO, et aI. Down-regulation of parathyroid hormone (PTH) receptors in cultured bone cells is associated with agonist-specific intracellular processing of PTH-receptor complexes. Endocrinology 1986; 118:595. 122. Pun KK, Ho PWM, Nissenson RA, et al. Desensitization of parathyroid hormone receptors on cultured bone cells. J Bone Miner Res 1990;5:1193. 123. Levine MA. Clinical spectrum and pathogenesis of pseudohypoparathyroidism. Rev Endocr Metab Disord 2000;1:265. 124. Broadus AB. Nephrogenous cyclic AMP. Recent Prog Horm Res 1981;37:667.

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Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy Geeta Lal, MD • Orlo H. Clark, MD

Primary hyperparathyroidism is a relatively common problem, and reportedly 100,000 new cases are detected each year in the United States."One of every 500 women and 1 of every 2000 men older than 40 years have primary hyperparathyroidism. A population-based study in Sweden suggested that about 2% of postmenopausal women have hyperparathyroidism.' The disease entities to be considered in the differential diagnosis of hypercalcemia are shown in Table 40-1. Primary hyperparathyroidism and malignancy account for 90% of all patients with hypercalcemia. Primary hyperparathyroidism is the most common cause of hypercalcemia in outpatients, whereas malignancy is the most common cause of hypercalcemia in hospitalized patients.' Malignancy-associated hypercalcemia has traditionally been considered to include three distinct syndromes: (1) humoral hypercalcemia of malignancy, (2) hypercalcemia associated with bone metastases, and (3) hypercalcemia associated with hematologic malignancy (multiple myeloma). Humoral hypercalcemia of malignancy occurs in patients with solid tumors of the lung, breast, kidney, head and neck, and ovary without bone metastases and is known to be mediated primarily by parathyroid hormone-related peptide (PTHrp).4 A comparison of the biochemical characteristics of primary hyperparathyroidism and humoral hypercalcemia of malignancy is shown in Table 40-2. PTHrP also plays a role in the hypercalcemia associated with bone metastases' and multiple myeloma." Interestingly, primary bone tumors such as osteogenic sarcoma seldom cause hypercalcemia," Primary hyperparathyroidism may be distinguished from the other causes of hypercalcemia by careful history, physical examination, and laboratory investigations.

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Clinical Manifestations Most patients diagnosed with primary hyperparathyroidism today do not have the classic or historical clinical manifestations of this disorder such as osteitis fibrosa cystica, nephrolithiasis, nephrocalcinosis, peptic ulcer disease, gout, or pseudogout. The pentad of symptoms-painful bones, kidney stones, abdominal groans, psychic moans, and fatigue overtones-is more common, although most patients have few dramatic symptoms. The symptoms and other associated complications of primary hyperparathyroidism are listed in Table 40-3. Several investigators have documented that manifestations such as fatigue, weakness, exhaustion, polydipsia, polyuria, nocturia, joint pain, bone pain, constipation, depression, anorexia, nausea, heartburn, and several associated conditions such as nephrolithiasis and hematuria occur more often in patients with primary hyperparathyroidism than in those with thyroid nodules.v''' Furthermore, only symptoms of fatigue, bone pain, and weight loss seemed to correlate with the severity of hypercalcernia.f Younger patients are more likely to present with nonspecific complaints such as fatigue and lethargy. II The pathophysiologic mechanisms explaining why many of these manifestations occur more often in patients with even mild primary hyperparathyroidism are unknown. However, studies have documented changes in neurotransmitters in the cerebrospinal fluid of patients with primary hyperparathyroidism. 12 Several groups have used a standardized health status assessment tool such as the SF-36 (the Medical Outcomes Study Short-Form Health Survey) to assess symptoms and

Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy - - 385

health state in patients with primary hyperparathyroidism. This multidimensional health assessment tool has several domains that evaluate physical function, role limitation (physical and emotional), social function, bodily pain, mental health, energy, and general health perception. 13 Burney and colleagues first demonstrated that patients with primary hyperparathyroidism scored lower than healthy control subjects in all domains of the SF-36. 14 Other studies confirm that these patients are indeed impaired in several domains'<'" and have also shown that the impairments in functional status are independent of the degree of elevation of serum calcium levels." Even patients with minimal hypercalcemia and parathyroid hormone elevation benefit from parathyroidectorny.!? More recently, Pasieka and Parsons designed and validated a disease-specific surgical outcome tool for patients with primary hyperparathyroidism. The items in their Visual Analog Scale (VAS) questionnaire include symptoms of bone and joint pain, fatigue, mood swings, depression, abdominal pain, weakness, irritability, memory loss, headaches, pruritus, increased thirst, and proximal muscle weakness. The study group of patients with primary hyperparathyroidism had significantly more symptoms than a comparison group of patients with nontoxic thyroid disease." Studies have also documented that patients with primary hyperparathyroidism have an increased incidence of fractures, 19 muscle weakness," and cardiovascular disease.v-?

Rarely, patients may be completely asymptomatic. We documented truly asymptomatic hyperparathyroidism in only 2% to 4.6% of consecutive patients referred for

parathyroidectomy.s-'?

On physical examination, patients may demonstrate signs such as band keratopathy, a deposition of calcium in Bowman's membrane just inside the iris of the eye. This condition is caused by chronic eye diseases such as uveitis and glaucoma and by trauma but also occurs in systemic conditions associated with high calcium or phosphate levels. It is therefore not specific for primary hyperparathyroidism.P Evidence of fibro-osseus jaw tumors should be sought. Patients with this manifestation are more likely to develop parathyroid carcinoma" The neck should be examined for masses, thyroid nodules, and concurrent lymphadenopathy. Parathyroid tumors are seldom palpable, except in patients with profound hypercalcemia (~14 mg/dL). A palpable neck mass in a patient with primary hyperparathyroidism is more likely to be a thyroid lesion. However, approximately 50% of parathyroid cancers are palpable.P

Laboratory Investigations In patients with hypercalcemia, it is usually relatively easy to make the diagnosis of primary hyperparathyroidism by documenting an increased blood intact or two-site parathyroid hormone (PTH) level and normal or increased urinary calcium concentration. The two-site or intact PTH (iPTH) assays do not cross-react with PTHrP, the most common peptide secreted by nonparathyroid cancers." PTHrP crossreacts with some mid- or C-terminal PTH assays and causes a falsely elevated PTH value. Some patients may have more than one reason for an increased calcium level, such as metastatic breast cancer and primary hyperparathyroidism. In these patients, an iPTH assay is most valuable for

386 - - Parathyroid Gland documenting that primary hyperparathyroidism is also present. In addition, the presence of a mild hypokale~c, hypochloremic alkalosis points to mali~nancy as th.e cau~atl~e factor, whereas a mild hyperchloremic metabohc aCIdoSIS suggests hyperparathyroidism. A few patients have also been documented as having nonparathyroid tumors that make pure PTH.27 In these situations, sele~tiv~ ven~us catheterization for iPTH of the neck and mediastinal veins as well as veins draining the tumor is useful in documenting whether the hypercalcemia is caused by the tumor or by coexistent primary hyperparathyroidism. Open or fine-need~e biopsy of the tumor and assay for iPTH are also of help in these rare situations." The only other metabolic condition that can mimic primary hyperparathyroidism from a laboratory point of view-that is, increased blood calcium and increased iPTH-is benign familial hypocalciuric hypercalcemia (BFHH).28,29 These patients, however, have low urinary calcium. It is important, therefore, to obtain a 24-hour urine sample for calcium and creatinine to determine the urinary calcium level, especially in patients who have never had documented normocalcemia. Patients with BFHH have urinary calcium levels less than 100 mg per 24 hours and have family members younger than 10 years with hypercalcemia, a situation that almost never occurs in patients with sporadic hyperparathyroidism or even in patients with familial hyperparathyroidism or hyperparathyroidism associated with multiple endocrine neoplasia (MEN) type 1 and MEN 2. Furthermore, the serum calcium-to-creatinine clearance ratio is usually less than 0.01 in patients with BFHH, whereas it is typically greater than 0.02 in patients with primary hyperpar~thyroidism." BFHH is inherited in an autosomal dommant fashion with nearly 100% penetrance but variable expression. The genetic locus for BFHH maps to the long arm of chromosome 3 and has been identified as the calcium-sensing receptor gene (CASR).31,32 Patients with BFHH are heterozygous for CASR mutations. When this is a homozygous mutation, the patient has neonatal hyperparathyroidism." The latter is often life threatening and warrants total parathyroidectomy . parathyroid , autotransp lantati WIth antanon and cryopreserva ti o~. 3133 '. Identifying patients with BFHH is crucial because these individuals do not benefit from parathyroidectomy. Patients with primary hyperparathyroidism also often have a low (50%) or low-normal (40%) blood phosphorus level and an increased (>33) chloride-to-phosphorus ratio." As mentioned earlier, a mild hyperchloremic metabolic acidosis is often present. About 30% of patients with primary hyperparathyroidism have an increased uric acid level, and 15% have an elevated alkaline phosphatase level. 34,35 Most patients with primary hyperparathyroidism also have an increased or high-normal 1,25-dihydroxyvitamin D 3 level." It is also important to document the serum blood urea nitrogen and creatinine levels, and perform serum protein electrophoresis. The latter helps to eliminate the diagnosis of multiple myeloma. Patients with primary hyperparathyroidism who have increased bone alkaline phosphatase (with other normal liver enzymes) have high-turnover bone disease and are susceptible to postparathyroidectomy hypocalcemia. In patients with osteitis fibrosa cystica, the blood magn~sium and potassium levels can be low, and hypomagnesemia can contribute to postoperative tetany.

Normocalcemic Hyperparathyroidism Patients with primary hyperparathyroidism can also be normocalcemic. Most of these individuals are detected because of recurrent nephrolithiasis or osteoporosis.'? The reasons for normocalcemic hyperparathyroidism include (1) vitamin D deficiency, (2) low serum albumin, (3) pancreatitis, (4) increased phosphate intake, (5) excessive hydration, and (6) a low-normal blood calcium set point with an increase above the patient's normal calcium level but still within the normal range.'? The diagnosis of normocalcemic hyperparathyroidism is usually made by documenting an increased total PTH level with or without an increased blood ionized calcium level. However, patients with renal leak hypercalciuria must be excluded. The increased PTH level in patients with renal leak is secondary to the excessive calcium loss in the urine; one can diagnose renal leak hypercalciuric patients by treating them with thiazide diuretics, With treatment, the urinary calcium level falls and the secondary increase in the blood PTH also decreases to normal. In patients with normocalcemic hyperparathyroidism, the urine calcium and blood PTH remain elevated." Normocalcemic hyperparathyroidism is discussed in more detail Chapter 45.

Radiologic Investigations Patients with classic osteitis fibrosa cystica have subperiosteal bone resorption best observed on the radial aspect of the middle and distal phalanges on hand radiographs. Other skeletal manifestations of severe primary hyperparathyroidism include bone cysts, osteoclastomas or "brown tumors," pathologic fractures, and general demineralization. The skull may exhibit a finely mottled, ground-glass appearance, with loss of definition of the inner and outer cortices." Abdominal flat plates or ultrasonography may reveal renal stones. Bone densitometry studies are currently being performed more frequently and may be utilized in assessing the effects of primary hyperparathyroidism on bone. Primary hyperparathyroidism mainly leads to loss of bone at cortical sites such as the distal radius. Bone density is relatively preserved at sites such as the lumbar spine, which is rich in cancellous bone.'? This is in contrast to the bone density changes seen in menopause. In the latter, the lumbar spine is the major target of bone mineral loss. Despite these findings, lumbar spine density improves after parathyroidectomy.f-" Localizing tests such as ultrasonography, sestarnibi scanning, magnetic resonance imaging, or computed tomography scanning are used by some clinicians to make or confirm the diagnosis of primary hyperparathyroidism. One should emphasize, however, that the diagnosis of primary hyperparathyroidism is made by metabolic testing; localiza~ion te~ts often identify the tumor site but do not make the dIagnOSIS, because both false-positive and false-negative localization tests occur.'?

Indications for Operative Treatment As discussed earlier, the clinical profile of primary hyperparathyroidism has undergone a distinct change over the

Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy - - 387

past few decades, particularly with the introduction of automated blood chemistry panels. The 1990 National Institutes of Health Consensus Development Conference on the Management of Asymptomatic Primary Hyperparathyroidism was convened to set forth evidence-based diagnosis and management guidelines for this group of patients. The panel recognized surgery as the only definitive treatment for primary hyperparathyroidism and recommended parathyroidectomy for any individual with overt complications and symptoms such as nephrolithiasis, fractures, and neuromuscular syndrome. In addition, surgery was recommended for asymptomatic patients with' (1) serum calcium more than 1 to 1.6 mg/dL (0.25 to 0.4 mM) above the accepted normal reference range; (2) 24-hour urine calcium greater than 400 mg (10 mM); (3) a 30% reduction in creatinine clearance compared with age-matched normal individuals; (4) bone mineral density more than 2 standard deviations (SD) below that of age-, gender-, and race-matched controls; (5) age younger than 50 years; and (6) in whom medical surveillance is not possible or desirable. The vague neurobehavioral axis symptoms (weakness, increased fatigue without overt muscle weakness) were deemed nonspecific and not sufficient in and of themselves to recommend surgery, unless these symptoms were thought to be related to hyperparathyroidism. The panel also recommended that patients not undergoing surgery understand the importance of regular, longterm follow-up and undergo (1) biannual measurements of blood pressure, serum calcium serum creatinine and creatinine clearance and (2) annual abdominal radiography (and/or ultrasonography), 24-hour urine calcium test, and bone mass measurement. Patients were also to be advised on the importance of adequate mobility and seeking prompt medical attention for any intercurrent illness causing dehydration, both of which can worsen existing hypercalcemia. Since the last consensus meeting in 1990, there has been an accumulation of data on the natural history of asymptomatic hyperparathyroidism and the long-term effects of untreated hyperparathyroidism. Moreover, localizing studies are more accurate, readily available, and utilized. Several minimally invasive surgical approaches have also been developed, as have novel medical therapies. Therefore, a follow-up Workshop on Asymptomatic Primary Hyperparathyroidism: A Perspective for the 21st Century was held at the National

Institutes of Health in April 2002 to re-evaluate the recommendations of the previous consensus meeting. The revised recommended indications for surgery along with the reasons for the change are as follows": 1. Serum calcium greater than 1 mg/dL (0.25 mM) above the upper reported normal reference range The range was lowered because the panel believed that even patients with this degree of elevation of serum calcium were at risk for developing symptoms and complications of hyperparathyroidism. 2. 24-hour urine calcium excretion 400 mg/day (unchanged) 3. A 30% decrease in creatinine clearance compared with age-matched control subjects (unchanged) 4. Bone density at the lumbar spine, hip, or distal radius greater than 2.5 SD below peak bone mass (T-score less than -2.5) Hyperparathyroidism classically leads to loss of cortical bone mass. However, a subset of patients with primary hyperparathyroidism have marked bone density loss at sites of cancellous bone such as the spine, and parathyroidectomy has been demonstrated to increase bone mass at these sites. 44•45 T-scores, which represent deviations from an individual's optimal bone mass, seem to be a more reasonable indicator of fracture risk than Z-scores, which compare bone mineral density with that of age- and sex-matched cohorts. Hence, the panel recommended bone mineral density measurement at three sites and a change to T- rather than Z-score measurements. 5. Age younger than 50 years (unchanged) 6. Patients for whom medical surveillance is not possible or desirable (unchanged) The panel also cautioned against the use of neuropsychological abnormalities, cardiovascular disease, gastrointestinal symptoms, menopause, and elevated serum or urine indices of increased bone turnover as sole indications for parathyroidectomy. Rather, these factors should be weighed in the context of the individual patient. Although bisphosphonates and calcimimetics show promise, data are insufficient to recommend medical management in patients with asymptomatic primary hyperparathyroidism and only parathyroidectomy offers curative treatment. The new recommendations for follow-up of patients not undergoing surgery are compared with the previous recommendations in Table 40-4.

388 - - Parathyroid Gland

Rationale for Parathyroidectomy There is good evidence that in about 80% of patients the clinical manifestations improve after successful parathyroidectomy.8,9,10,46,47 Thus, fatigue, exhaustion and weakness, polydipsia, polyuria and nocturia, bone and joint pain, constipation, nausea, and depression improve in some patients.8.10,46,47 This is also true for associated conditions. In these patients, new kidney stones usually stop forming, osteoporosis stabilizes or improves, peptic ulcer disease often resolves, and pancreatitis becomes less likely.46,47 Thus, both neuropsychiatric and somatic problems improve in most, but not all, patients (Figs. 40-1 to 40_4).10,48 Increased fracture risk and weakness also improve after successful parathyroidectomy in most, but certainly not all, patients.Jv" Objective increase in muscular strength has also been documented after successful parathyroidectomy." Patients can also resume a regular diet with or without calcium supplementation and hypercalcemia is not a concern when patients are hospitalized for other medical problems. Several quality of life studies have been performed using standardized tools such as the SF-36 health survey in patients with primary hyperparathyroidism, and demonstrated that patients experience an improvement in health status and quality of life after surgical correction. 14-17,50 Furthermore, this benefit was independent of preoperative calcium levels." Psychological distress, as measured by the General Health Questionnaire, has also been shown to

be ameliorated by parathyroidectomy.-' In contrast to the aforementioned generic quality of life tools, Pasieka and Parsons have developed a patient-based outcome tool specifically for primary hyperparathyroidism.F A multicenter study using this questionnaire indicated that the Parathyroidectomy Assessment of Symptoms is a reliable measure of the symptoms seen in patients with hyperparathyroidism, as shown in Figures 40-5 and 40-6, and that these symptoms improve after parathyroidectomy.P It therefore seems that there are both classic and more subtle clinical manifestations of primary hyperparathyroidism that warrant medical evaluation and, in most patients, parathyroidectomy. This is especially true because parathyroidectomy, when performed by an experienced surgeon, is successful in more than 95% of patients. Furthermore, the operation usually takes less than 2 hours, blood is virtually never required, complications occur in less than 2% of patients, and hospitalization is usually for 24 hours, unless the patient has other serious medical problems or severe osteitis fibrosa cystica with a markedly elevated blood alkaline phosphatase level preoperatively," The latter patient requires treatment with oral and intravenous calcium and 1,25-dihydroxyvitamin D (Rocaltrol, 0.25 to 1 ug orally daily) postoperatively because of hypocalcemia and occasionally hypomagnesemia as a result of "bone hunger." Another and perhaps more important reason for recommending parathyroidectomy is that patients with primary hyperparathyroidism appear to be at risk for premature death primarily because of cardiovascular disease and cancer, as

FIGURE 40-1. Changes in the frequency of symptoms after surgery in parathyroid and thyroid patients. (From Chan AK, Duh QY, Katz MH, et al. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: A case-control study. Ann Surg 1995;222:402.)

Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy - -

FIGURE 40-2. Changes in the frequency

of associated conditions after surgery in parathyroid and thyroid patients. (From Chan AK, Duh QY, Katz MH, et al. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: A case-control study. Ann Surg 1995;222:402.)

FIGURE 40-3. Neuromuscular recovery after parathy-

roidectomy in primary hyperparathyroidism with patients having thyroid operations as controls. (From Chou FF, Sheen-Chen SM, Leong CPo Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism. Surgery 1995;117:18.)

so = standard deviation, Preop = preoperative

Postop = postoperative 1 week, Late = postoperative 4 weeks P with paired t test

389

390 - - Parathyroid Gland

FIGURE 40-4. Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism with patients having thyroid operations as controls. (From Chou FF, Sheen-Chen SM, Leong CPo Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism. Surgery 1995;117:18.)

SD = standard deviation, Preop = preoperative Postop = postoperative 1 week, Late = postoperative 4 weeks P with paired t test

documented in the classic study by Palmer and coworkers>' and confirmed by the studies of Sivula.t' Hedback21,56,57 and their colleagues. Of equal importance, as documented by Hedback and colleagues, is that the increased death rate, even in patients with mild primary hyperparathyroidism, can be

reversed by successful parathyroidectomy. Of interest is the finding that in young patients and in those with the least severe hypercalcemia, the survival curve returns to normal most quickly." Patients between the ages of 55 and 70 years seem to receive the greatest survival benefit,21,56.57

FIGURE 40-5. Comparison of Parathyroidectomy Assessment of Symptoms (PAS) scores between patients with primary hyperparathyroidism (HPT) and those with thyroid cancer at one center. "P < .001; Pre op = preoperative; Post op = postoperative. (From Pasieka J, Parsons L, Demeure M, et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942.)

FIGURE 40-6. The Parathyroid Assessment of Symptoms (PAS) scores from three centers over time, "P < .001; Pre op = preoperative; Post op = postoperative. (From Pasieka J, Parsons L, Demeure M, et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942,)

Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy - - 391

Conclusion In conclusion, the diagnosis of primary hyperparathyroidism can be made with nearly 100% confidence by documenting an increased serum PTH level in a patient with increased ionized or total calcium without hypocalciuria. Making the diagnosis is important, because preoperative vague or classic symptoms or metabolic conditions associated with primary hyperparathyroidism often improve after parathyroidectomy, as does long-term survival.

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21. Hedback G, Tisell LE, Bengtsson BA, et al. Premature death in patients operated on for primary hyperparathyroidism. World J Surg 1990;14:829. 22. Hedback G, Oden A. Increased risk of death from primary hyperparathyroidism-An update. Eur J Clin Invest 1998;28:271. 23. Sugar A. Conjunctival and corneal degenerations. In: Yanoff M, Duker JS (eds), Ophthalmology, 2nd ed. Philadelphia, Mosby, 2004, p 449. 24. Szabo J, Heath B, Hill VM, et al. Hereditary hyperparathyroidism-jaw tumor syndrome: The endocrine tumor gene HRPT2 maps to chromosome Iq21-q31. Am J Hum Genet 1995;56:944. 25. Kebebew E. Parathyroid carcinoma. Curr Treat Options Oncol 2001;2:347. 26. Budayr AA, Nissenson RA, Klein RF, et al. Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med 1989;111:807. 27. Strewler GJ, Budayr AA, Clark OH, Nissenson RA. Production of parathyroid hormone by a malignant nonparathyroid tumor in a hypercalcemic patient. J Clin Endocrinol Metab 1993;76:1373. 28. Heath H 3rd. Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am 1989;18:723. 29. Gunn IR, Wallace JR. Urine calcium and serum ionized calcium, total calcium and parathyroid hormone concentrations in the diagnosis of primary hyperparathyroidism and familial benign hypercalcaemia. Ann Clin Biochem 1992;29:52. 30. Marx SJ, Attie MF, Stock JL, et al. Maximal urine-concentrating ability: Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. J Clin Endocrinol Metab 1981;52:736. 31. Pollak MR, Brown EM, Chou YH, et al. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993;75:1297. 32. Chou YR, Brown EM, Levi T, et al. The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families. Nat Genet 1992;1:295. 33. Fujimoto Y, Hazama H, Oku K. Severe primary hyperparathyroidism in a neonate having a parent with hypercalcemia: Treatment by total parathyroidectomy and simultaneous heterotopic autotransplantation. Surgery 1990;108:933. 34. Clark OH. Hyperparathyroidism. In: Oh C (ed), Endocrine Surgery of the Thyroid and Parathyroid Glands. St. Louis, CV Mosby, 1985, P 172. 35. Duh QY, Morris RC, Arnaud CD, Clark OH. Decrease in serum uric acid level following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 1986;10:729. 36. Bilezikian JP, Silverberg SJ, Gartenberg F, et al. Clinical presentation of primary hyperparathyroidism. In: Bilezekian JP, Marcus R, Levine MA (eds), The Parathyroids. New York, Raven Press, 1994, p 457. 37. Siperstein AE, Shen W, Chan AK, et al. Normocalcemic hyperparathyroidism. Biochemical and symptom profiles before and after surgery. Arch Surg 1992;127:1157. 38. Bringhurst FR, Demay MB, Kronenberg HM. Hormones and disorders of mineral metabolism. In: Williams RH, Wilson JD (eds), Williams Textbook of Endocrinology. Philadelphia, WB Saunders, 1998, p 1155. 39. Silverberg SJ, Shane E, de la Cruz L, et al. Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 1989;4:283. 40. Silverberg SJ, Gartenberg F, Jacobs TP, et al. Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism. J Clin Endocrinol Metab 1995;80:729. 41. Silverberg SJ, Shane E, Jacobs TP, et al. A IO-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249. 42. Arici C, Cheah WK, ltuarte PH, et al. Can localization studies be used to direct focused parathyroid operations? Surgery 2001;129:720. 43. Bilezikian JP, Potts IT Jr, El-Hajj Fuleihan G, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: A perspective for the 21st century. J Clin Endocrinol Metab 2002;87:5353. 44. Abe Y, Ejima E, Fujiyama K, et al. Parathyroidectomy for primary hyperparathyroidism induces positive uncoupling and increases bone mineral density in cancellous bones. Clin Endocrinol (Oxf) 2000;52:203. 45. Silverberg SJ, Locker FG, Bilezikian JP. Vertebral osteopenia: A new indication for surgery in primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81:4007.

392 - - Parathyroid Gland 46. Uden P, Chan A, Duh QY, et al. Primary hyperparathyroidism in younger and older patients: Symptoms and outcome of surgery. World J Surg 1992;16:79l. 47. Clark OH. "Asymptomatic" primary hyperparathyroidism: Is parathyroidectomy indicated? Surgery 1994;116:947. 48. Chou FF, Sheen-Chen SM, Leong CPo Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism. Surgery 1995;117:18. 49. Deutch SR, Jensen MB, Christiansen PM, Hessov I. Muscular performance and fatigue in primary hyperparathyroidism. World J Surg 2000;24:102. 50. Sheldon DG, Lee FT, Neil NJ, Ryan JA Jr. Surgical treatment of hyperparathyroidism improves health-related quality of life. Arch Surg 2002;137:1022. 51. Okamoto T, Kamo T, Obara T. Outcome study of psychological distress and nonspecific symptoms in patients with mild primary hyperparathyroidism. Arch Surg 2002;137:779. 52. Pasieka JL, Parsons LL. A prospective surgical outcome study assessing the impact of parathyroidectomy on symptoms in patients

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54. 55. 56. 57.

with secondary and tertiary hyperparathyroidism. Surgery 2000; 128:531. Pasieka JL, Parsons LL, Demeure MJ, et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942. Palmer M, Adami HO, Bergstrom R, et al. Survival and renal function in untreated hypercalcaemia. Population-based cohort study with 14 years of follow-up. Lancet 1987;I :59. Sivula A, Ronni-Sivula H. Observations on 334 patients operated on for primary hyperparathyroidism. Ann Chir GynaecoI1985;74:66. Hedback G, Oden A, Tisell LE. The influence of surgery on the risk of death in patients with primary hyperparathyroidism. World J Surg 1991;15:399. Hedback G, Oden A, Tisell LE. Parathyroid adenoma weight and the risk of death after treatment for primary hyperparathyroidism. Surgery 1995;117:134.

Natural History of Untreated Primary Hyperparathyroidism Goran Akerstrom, MD • Ewa Lundgren, MD

In the early descriptions of patients with primary hyperparathyroidism (HPT), the disease was recognized as a rare disorder and was associated with severe incapacitating bone symptoms, prevalent renal stones, devastating muscular weakness, and often early death from renal failure. Since the introduction in the mid-1970s of automated equipment allowing routine measurements of serum calcium by multiphasic laboratory screening on liberal indications, primary HPT has been diagnosed with increased frequency. I The disease has been revealed to be particularly prevalent in postmenopausal women, and many such patients have had a milder ailment than was common some decades ago. These patients have typically lacked the bone or renal stone complications of HPT and have instead exhibited vague symptoms of fatigue or psychiatric disability or have appeared asymptomatic.P Because general policies of management in primary HPT have been based on studies of symptomatic patients, it has not been obvious that primary HPT detected at a mild and uncomplicated stage requires the same treatment. Accordingly, it has been suggested that subsets of patients with primary HPT may be subjected to surveillance rather than surgery.v' Concomitantly, the diagnosis of HPT has become easier and more precise with the introduction of new methods for measurement of intact serum parathyroid hormone (PTH). HPT can now be diagnosed with assurance, even in cases with no more than borderline elevations of serum calcium.v'

Epidemiology Epidemiologic data on the prevalence of primary HPT are sparse for most countries. An autopsy study of a Swedish population revealed parathyroid adenoma in 2.4% and "subclinical" disease represented by micronodular chief cell hyperplasia in another 7%, with an apparent continuum of abnormality ranging from hyperplastic micronodular lesions to the adenomas." Borderline hypercalcemia could be clinically detected in occasional patients with hyperplastic glands containing larger, predominant nodules or in those

with tiny adenomas, whereas more marked elevation of serum calcium was associated with adenomas of more conspicuous size.? The histologic abnormalities were particularly common in older individuals of both genders and related to histologic signs of nephrosclerosis, even in the absence of clinically detectable renal dysfunction," These findings substantiate the presence of prevalent subclinical and clinical parathyroid disease within the elderly Swedish population. They also mirror problems in clinical management of patients with primary HPT because an increased incidence of micronodular hyperplasia and tiny adenomas has been encountered when patients with borderline hypercalcemia have been liberally submitted to parathyroid exploration."!" Population screening has confirmed the prevalence of parathyroid disease in Sweden, but it has also demonstrated that prevalence data depend on the age of the population studied as well as the level of hypercalcemia that is used to distinguish patients with HPT from normal individuals. I 1·13 Accurate screening for detection of hypercalcemia also requires that repeated serum calcium determinations be used in such surveys. I 1.13 A health screening survey of employees aged 20 to 63 years within Stockholm County in Sweden included repeated measurements of serum calcium and revealed hypercalcemia supposedly resulting from HPT, with an overall prevalence of 0.4% to 0.6%.11 Elevated serum calcium levels were detected in approximately 0.3% of men and 1% of women older than 50 years. This screening used serum calcium levels greater than 2.65 mmol/L (10.6 mg/dL) to define hypercalcemia, and older age groups, in which HPT is in fact most common, were not included. In another health screening survey in Gavle County of Sweden, 16,401 individuals had repeated serum calcium determinations over a 2-year period (1969 and 1971).13 Altogether, 172 individuals were found to have hypercalcemia, with serum calcium levels higher than the normal reference of 2.60 mmol/L on both occasions, without other obvious reasons such as vitamin D or oral calcium medication or malignancy." This corresponded to approximately 1% of the population, 0.3% of men and 1.6% of women.

393

394 - - Parathyroid Gland In women older than 60 years, the prevalence of hypercalcemia was close to 3% (Fig. 41-1),13,14 Female predominance in screening surveys may be partly related to significantly higher normal means of serum calcium in postmenopausal women than in men of the same age, implying that even minimal increases in serum calcium could be more easily detected. 13 This probably does not explain a female overrepresentation in clinically detected HPT, which is also likely to be related to regulatory disturbances within the diseased parathyroid tissue. Although most of the hypercalcemic individuals in this study did not have a parathyroid operation and the diagnosis is not undisputable, it is reasonable to assume that the majority of them had HPT.13,14 In a population screening in which serum calcium levels were determined in conjunction with a mammographic health survey, a comparable prevalence of HPT of 2.2% was found for postmenopausal women with a mean age of 59 years." The majority of hypercalcemia cases were borderline, and most of the individuals were elderly. Similar high prevalence estimates of hypercalcemia and presumable HPT were documented in a more recent health screening survey from Norway.16 Although figures depend on definition criteria, the disease can be expected in at least 2% of postmenopausal women.P:" Reports from the United States and Europe have suggested that the incidence of HPT may be declining, perhaps because of more restricted use of multichannel screening tests for hypercalcemia.lv't-" Comparison of health survey figures and hospital statistics in Sweden and the United States indicates that even if surgery were done for relatively liberal indications, currently only about one tenth of all patients with HPT in the population are subjected to parathyroidectomy.13,19,20 Considering the high prevalence figures of the health surveys, it is reasonable that studies aim to clarify whether surgery for primary HPT is also of benefit for patients with a mild, asymptomatic, and uncomplicated disease or whether such patients may be safely monitored without surgery.

Women (n=149) Number 31

70- Men (n=27) Number 60-69

5

50-59

6

40-49

3

30-39

8

48 OJ

If

41 26 2

2

25-29

3

r,

20

10

10 Per million

20

30

FIGURE 41-1. Prevalence of hypercalcemia in men and women of different age groups in the Gavle County Health Survey. (Adapted from Palmer M, Jakobsson S, Akerstrom G, et al. Prevalence of hypercalcemia in a health survey: A 14-year follow-up of serum calcium levels. Eur J Clin Invest 1988;18:39. Copyright 1988 by Blackwell Science Ltd.)

Follow-up of Health Survey-Detected Hypercalcemia In the Stockholm health survey, 27 randomly selected hypercalcemic patients underwent neck exploration, and all were found to have parathyroid adenoma." Another group of 23 hypercalcemic patients (mean age, 55 years) was monitored with regular checkups and compared with ageand sex-matched normocalcemic control subjects during a to-year period." Their initial mean serum calcium of 2.75 mmollL remained unchanged during the study period, and there was no notable deterioration of kidney function in routine serum analyses. A significant elevation of systolic and diastolic blood pressures in the hypercalcemic individuals compared with control subjects at initiation of the follow-up persisted throughout the 10-year study period. 2l,22 In the Gavle health survey, the mean age of hypercalcemic individuals was 59 years, and their mean serum calcium was 2.72 mmol/L." Eleven patients initially had surgery because of marked hypercalcemia (2.83 to 3.63 mmollL), and another 21 underwent surgery between 1971 and 1983 to 1984 when a follow-up study was performed." The majority of the patients with hypercalcemia were neither informed about their hypercalcemia nor treated. At the follow-up study in 1983 to 1984,57 patients had died and 7 were lost to follow-up. Scrutiny of patients' records did not indicate that any of these individuals had had severe hypercalcemia or renal insufficiency.P'P Of the remaining 95 patients, 47 still had a serum calcium level greater than 2.60 mmollL in 1983 to 1984, and 48 subjects with serum calcium levels slightly below this normal limit had displayed intermittent hypercalcemia in the intervening years. 13 For the majority of hypercalcemic individuals, the serum calcium remained more or less constant throughout the study period, and no patient (including those who subsequently had parathyroid surgery) showed markedly progressive hypercalcemia or an abrupt rise in serum calcium levels.P Serum creatinine levels were above normal in 15 patients at the 1983 to 1984 follow-up, but only 3 patients had a more marked elevation of serum creatinine, and these individuals had either urea nitrogen above normal at the initial screening or obvious nonparathyroid causes of renal impairment.P Using national registration numbers and the causes of death registry, survival was compared between individuals who were hypercalcemic at the 1969 to 1971 survey and matched normocalcemic control subjects." Survival during the l4-year follow-up was significantly lower among the hypercalcemic individuals.P The difference in survival steadily increased and became more marked after 5 years from the initial health survey.F' The hypercalcemic individuals also had significantly higher diastolic and systolic blood pressures as well as serum uric acid and a tendency toward higher glucose and cholesterol levels. Using multivariate analyses, higher levels of serum calcium were associated with increased mortality in patients older than 60 years, but this effect diminished in the oldest age groups. Life table analyses revealed a significant difference in survival between hypercalcemic persons and control subjects at age 70 or younger but not for those older than 70 years (Fig. 41_2),23 The increased mortality in the hypercalcemic

Natural History of Untreated PrimaryHyperparathyroidism - - 395

... ~~ FIGURE 41-2. Survival curves for hypercalcemic subjects and matched control subjects from the Gavle County Health Survey. (From Palmer M, Adami H-O, Bergstrom R. et al. Survival and renal function in persons with untreated hypercalcaemia: A population-based cohort study with 14 years of follow-up. Lancet 1987;1:59. © by the Lancet Ltd., 1987.)

Subjects> 70 years

Subjects s 70 years

All subjects

-

__...._"'"._ / Controls

.....

'"--

····t..·-i

"1

/

/'

/

Hypercalcemics

50

I

5

,

p=0.9

p=0.0025

p=0.0135 ,

,

10

13

5

10

13

5

10

13

Time offollow up (years)

group was not due to any single disease group, but the number of deaths caused by cardiovascular diseases was predominant and distinctly higher than expected. No deaths were caused by hypercalcemic crisis, renal failure, or other conditions that were obviously related to the hypercalcemic state." When examined for symptoms, the hypercalcemic individuals exhibited similar but less significant psychiatric symptoms when compared with patients with clinically detected primary HPT14.24.25 but more symptoms than the normocalcemic control patients. The hypercalcemic individuals were subsequently subjected to a 25-year follow-up, showing a tendency to lowering (or even normalization) of the hypercalcemia but continuing to have increased mortality in comparison with control subjects." The excess mortality was significant among individuals 70 years of age or younger and was valid for cardiovascular disease only." The studies indicate that the risk for progression of hypercalcemia or marked deterioration of renal function is low in borderline hypercalcemic primary HPT. The risk for subclinical renal impairment in HPT and thereby reduced levels of active vitamin D, which could contribute to the increased cardiovascular death rate (and also to lowering or normalization of the hypercalcemia), has been emphasized.'? The raised mortality has, however, not been found in all series28.29 and may depend on the severity and duration of HPT.27 The psychiatric disturbance may be a notable complication in individuals with intellectual occupations and cause states of confusion in elderly people but may not always be impressive in patients with borderline hypercalcemia.P

Conservative Follow-up in Clinically Detected Primary Hyperparathyroidism In 1981, Scholz and Purnell reported a prospective lO-year follow-up study from the Mayo Clinic aiming to evaluate the disease course in patients with asymptomatic primary HPT who were not subjected to surgery.30.31 This study remains

the most important long-term follow-up of conservatively managed primary HPT; it was initiated in 1968 and terminated in 1980.30.31 The intent was to clarify the natural history of the disease and to determine possible risks for progression into a symptomatic or complicated stage that ultimately would require surgery. A further aim was to determine whether such progression could be detected before significant complications developed." Patients included in this study had serum calcium levels of less than 11 mg/dL (2.75 mmollL), normal renal function (evaluated by serum creatinine), absence of roentgenographically demonstrated bone disease (evaluated by roentgenography of the thorax, hands, and skull), and absence of metabolically active or infected renal lithiasis or nephrocalcinosis (investigated by excretory urography). When radioimmunoassays for PTH determination became available during the study, it was also required that the patients have inappropriately elevated PTH to establish the diagnosis definitively. The patients were subjected to a comparatively extensive follow-up. Altogether, 142 patients (Table 41-1) ultimately fulfilled the criteria for participation in the study. During the first 30 months of the study, 21 patients (15%) underwent parathyroid surgery; in the next 30 months, 3 additional patients (2%) underwent surgery; and during the last 7 years before completion of the follow-up, still another 9 patients (6%) were subjected to surgery, that finally 33 (23%) of all patients underwent operation. One of these patients had probable hypercalcemic crisis. Sixteen patients had previous negative parathyroid explorations and were excluded from the final evaluation. Of the unoperated patients, 32 died during the follow-up period, 10 declined follow-up, and 9 could not be traced when the study was terminated. Of the 42 patients remaining in the unoperated group, 12 became spontaneously normocalcemic, and there was some doubt regarding the original diagnosis in these cases; 30 patients with persistently elevated serum calcium were available for follow-up in 1980, and in all of them the diagnosis was supported by elevated PTH levels. Cumulative follow-up data were obtained for 24 of these 30 patients and revealed no progression in 21 patients;

396 - - Parathyroid Gland

1 patient had advancing osteoporosis, 1 showed a modest increase in serum calcium, and another experienced a rise in serum creatinine. When deceased and noncompliant patients were excluded, the final compilation of data (including patients undergoing parathyroid surgery) revealed increased serum calcium in 10% of the patients (including one patient with probable hypercalcemic crisis, but a subtle rise in others), decreased renal function in 8%, active renal stone disease in 6%, bone disease in 5%, and psychological problems to the extent that parathyroid surgery was indicated in 5% (Table 41-2). The authors concluded that, for the comparatively few patients in whom adequate data could be collected for the whole study period, marked disease progression was noted only in a minority. Although the authors recommended surgical exploration by an experienced surgeon for the patients with asymptomatic HPf, they also concluded that patients who declined surgery or who had contraindications to operation could be monitored with minimal risk provided that the

patients and their physicians were willing to commit themselves to a rigid follow-up program. However, the authors noted that the conservative follow-up had been time consuming and expensive, and it had been difficult to make the patients comply with this type of follow-up. Several authors have subsequently reported conservative management of patients with primary HPT. Most of these studies have comprised fewer patients, some of whom had persistent hypercalcemia after failed parathyroid operations and others had surgery deferred because of associated illness. Many such patients have had higher serum calcium levels, and some already had symptoms or complications of parathyroid disease before the conservative follow-up. Rohl and colleagues'" thus monitored 30 patients with more severe hypercalcemia for an average of 3 years. Renal lithiasis developed in seven patients and bone disease in one patient; the total incidence of symptoms or complications was 27%. Adams'! described 31 patients with serum calcium levels less than 3.0 mmollL who were managed conservatively for 1 to 12 (mean, 4) years. Before the study, 12 patients had typical clinical features of primary HPT, mainly renal stones. Eighteen patients were considered asymptomatic; many of these were elderly women, often with hypertension. The patients had repeated measurements of serum calcium, creatinine, and alkaline phosphatase levels during follow-up. One of the patients with renal stones experienced deteriorating renal function, poorly controlled hypertension, and a marked rise in serum calcium, for which parathyroid surgery was ultimately required. A large parathyroid tumor was resected, but renal function and hypertension did not improve. In two other patients, a rise in serum calcium was partially attributed to thiazide treatment and thyrotoxicosis, respectively. No patient experienced life-threatening hypercalcemia, and mean serum calcium and creatinine levels did not change significantly during the follow-up. The authors concluded that they had failed to identify any criterion whereby patients who were destined to experience progressive disease could be identified. In this study, minor fluctuations in serum calcium were common and were thought to be mainly methodologic. Some patients, however, displayed more distinct variations, and the serum calcium levels were then typically lower during the winter, apparently related to a fall in vitamin D levels (Fig. 41-3). The author concluded that patients with HPT who avoid sun exposure can experience osteomalacia and lower serum calcium levels. Van't Hoff and coworkers" described 32 patients with primary HPT monitored for a mean of 4 years. Many of these patients had failed operations or were considered unfit to undergo parathyroid operation because of associated diseases, and some patients had refused surgery. Several patients had renal stones, and some had a serum calcium level greater than 3.0 mmollL prior to follow-up. Although the mean serum calcium and mean serum creatinine did not change significantly for the whole group of patients during the conservative management, one patient with a serum calcium level of 3.3 mmollL experienced pancreatitis and impaired renal function, and three patients underwent parathyroid surgery. The frequency of symptomatic renal stones and complications may have indicated a more liberal attitude toward operation.

Natural History of Untreated Primary Hyperparathyroidism - -

2.9

~

E 2.7 E

2.5

1'0]

Phosphate

0.5

1,5]

~ 0.5 S

i i i

WSW

S

I

WSW

FIGURE 41-3. Seasonal variations in the serum concentrations of calcium and parathyroid hormone (iPTH) in a patient with asymptomatic hyperparathyroidism. S = summer; W = winter (arrows). (From Adams PH. Conservative management of primary hyperparathyroidism. J R Coli Physicians Lond 1982;16:184.)

Paterson and colleagues" reported on 14 patients who for various reasons were not operated on and were managed conservatively for 5 to 23 years. One patient had osteitis fibrosa and died with fibrosarcoma, four patients originally presenting with renal calculi experienced further episodes of renal stones, and serum creatinine levels were finally raised in two patients. Three patients experienced progressive hypercalcemia. Corlew and associates" reported a more carefully explored series of 47 patients with primary HPT who either refused surgery or were not offered this option, some of whom were considered poor surgical risks. The diagnosis was accurately established in these patients by measurement of albumin-corrected serum calcium and intact PTH. The patients were classified into three groups on the basis of their levels of serum calcium; one fourth had serum calcium levels higher than 2.78 mmol/L. Sixteen of the 47 patients (34%) either died or suffered from complications that the authors considered to be possibly related to primary HPT, such as peptic ulcer disease (8 patients), with bleeding in some cases; renal failure (5 patients); renal calculus (1 patient); hypercalcemic crisis (1 patient); and ventricular conduction defect (1 patient). With the exception of the patient with hypercalcemic crisis, who initially belonged to the group with the lowest serum calcium levels, the serum calcium levels did not change significantly during the follow-up period. It was, however, impossible for the authors to predict the likelihood of progression or the severity of complications. The authors concluded that they had found nonoperative management inappropriate in good-risk primary HPT patients with reasonable life expectancy, and they suggested that most patients with significant elevation of serum calcium should undergo surgery.

397

Heath and Heath" reviewed 122 personal patients with primary HPT who were managed conservatively. Parathyroidectomy was recommended for patients with complications and definite symptoms of the disease, whereas for asymptomatic patients and those with mild, nonspecific symptoms, surgery was offered only if they were young; the threshold for being young declined during a 10-year period from 60 to 40 years. Diagnosis was based on hypercalcemia associated with elevated or high-normal serum PTH levels. The most common symptom in men was renal stones and in women tiredness and lethargy, and these symptoms were present in 10% of the conservatively monitored group. Ninety-five patients were available for follow-up after a mean of 6 years; in four patients, renal stones developed but serum calcium and creatinine levels did not deteriorate. Fifteen patients died. Although no deaths were attributable to HPT, the group of patients who subsequently died had a rise in serum creatinine levels, but because these patients had several other medical problems, this was not necessarily related to the parathyroid disorder. Thirteen patients were lost to follow-up. Rubinoff and coauthors'" reported a retrospective cursory screening of symptoms and complications in 160 patients who were found to be hypercalcemic on routine multiphasic laboratory examination, and they compared each hypercalcemic person with a matched normocalcemic control subject for a mean follow-up of 8.5 years. Fifteen patients had a parathyroid adenoma removed during the study. Apart from a higher incidence of hypertension and gallstones among the hypercalcemic individuals, the study recorded no differences regarding symptoms or routine estimates of renal function when comparison was made with control subjects. Posen and colleagues'? reported a retrospective survey of 142 patients who underwent successful parathyroid surgery, another 33 patients who had persistent hypercalcemia after a neck exploration, and 90 patients in whom surgery was deferred for various reasons. Although selection bias and variable follow-up (mean, 3 years) might have influenced the outcome in this study, the authors found a similar rate of vertebral crush fractures in all three groups. Forearm osteodensitometry showed higher bone mineral content in the group subjected to successful parathyroid surgery. One patient with persistent HPT experienced progressive, severe osteoporosis during conservative management and died with multiple spontaneous fractures. These studies seem to substantiate the results of the Scholz and Purnell" study in that rapidly progressive disease is relatively rare in patients with primary HPT. A minority of patients experience a marked increase in serum calcium or serum creatinine, but because such progression cannot be predicted in the individual patient, careful and close follow-up is mandatory if parathyroidectomy is not done. The studies indicate that renal damage may be irreversible, and conservative management, therefore, appears inappropriate in patients with more marked elevation of serum calcium or notable signs of renal function deterioration. Evidently, such patients should be offered a chance of amelioration of the parathyroid disease even if this should require a reoperative parathyroid procedure. Rapid progression of hypercalcemia may occur unexpectedly, as emphasized by Corsello and colleagues,"

398 - - Parathyroid Gland who within a 2-year period had five patients who experienced rapidly increasing serum calcium levels and "parathyroid crisis" while being monitored for mild primary HPT. One patient had parathyroid carcinoma, initially presenting with mild hypercalcemia; the others had benign parathyroid lesions. Rao and coworkers" examined the course of untreated mild asymptomatic primary HPT fortuitously discovered by multiphasic biochemical screening. Patients in this study had hypercalcemia persisting at repeated measurements, with serum calcium levels between 2.65 and 3.0 mmollL, and inappropriately high PTH levels or elevated nephrogenous cyclic adenosine monophosphate. The patients lacked symptoms attributable to HPT, showed no evidence of active renal stone disease, had serum creatinine levels less than 133 umol/L, had no radiographic osteitis fibrosa, and had a forearm bone density measurement that was not less than 2.5 standard deviations below the expected level. Of the original 198 patients subjected to conservative follow-up, 80 patients remained with adequate data from repeated measurements of bone density, serum calcium, and creatinine. These patients had a mean age of 61 years and initial mean serum calcium of 2.77 mmollL. They were monitored for 1 to 11 (median, 3.2) years at regular intervals of 6 to 12 months. The mean initial and final levels of serum calcium, serum creatinine, creatinine clearance, PTH (midand C-terminal assay), and forearm bone mineral density at proximal and distal sites of the radius normalized for age, gender, and race were virtually identical. A modest increase in alkaline phosphatase levels was noted in persons with longer follow-up and was apparently related to increased age. No episodes of worsening of hypercalcemia were noted, and there were no changes in renal function or appearance of symptoms of renal lithiasis. The initial mean levels for proximal and distal forearm bone density were significantly reduced, but there was no accelerated bone loss during follow-up apart from that expected with increasing age. The authors suggested that the lack of progression of biochemical parameters or bone loss in primary HPT was compatible with a biphasic disease course. They suggested that an initial short period of disease progression was likely to be followed by a long period of disease stability because they would otherwise have noted derangement of biochemical parameters or accelerated bone loss. The observations were considered to support nonsurgical surveillance in patients with mild asymptomatic and uncomplicated primary HPT, but the authors were unable to obtain adequate follow-up information in more than half of the original group of patients who had been managed conservatively. A subsequent report from the same authors'? included an additional 26 patients who initially had shorter follow-up. This increased the length of the study period to slightly more than 4 years without changing the biochemical parameters or the conclusions of the study. Rudnicki and Transbel'" reported time-limited follow-up in 24 patients with mild primary HPT for an average of nearly 3 years and found that mean ionized serum calcium levels remained stable, whereas levels of intact serum PTH increased significantly. A subgroup of patients whose PTH levels increased by 78% also had a small but significant increase in serum ionized calcium, whereas in the remaining

patients serum PTH levels increased modestly (22%) and ionized calcium levels were unchanged. The serum creatinine concentrations were stable throughout the study. The authors concluded that other studies of mild to moderate primary HPT did not include information on the course of parathyroid function and that primary HPT may progress even when serum calcium levels remain unchanged. They further emphasized that conditions commonly associated with old age, such as poor vitamin D intake and impaired vitamin D synthesis, could be responsible for impairment of intestinal calcium absorption, with a resulting compensatory hypersecretion of PTH. Silverberg and coworkers" reported a lO-year prospective follow-up of 121 HPT patients, 61 of whom were subjected to parathyroidectomy (according to indications established at the National Institutes of Health Consensus Conference Statement, 1991, concerning diagnosis and management of asymptomatic HPT4), whereas 60 patients did not undergo surgery. The majority of nonoperated patients were asymptomatic, but in some patients surgery was not undertaken despite the presence of kidney stone disease. All nonoperated symptomatic patients with kidney stones experienced progressive disease with recurrent stone attacks during follow-up, whereas none of the operated patients had such recurrences. Among nonoperated, asymptomatic patients, 27% had progressive disease with worsened hypercalcemia, increased hypercalciuria, and decrease in bone mineral; the remaining patients had apparently stable disease. The authors concluded that women with HPT seemed to be at risk for disease progression with significant loss of bone mineral, especially at menopause, and should therefore be liberally considered for parathyroidectomy. They also inferred that some asymptomatic patients experience disease progression over time, and all patients not undergoing surgery should therefore have biannual measurements of serum calcium, urinary calcium excretion, and bone mineral density.

Progression of Symptoms The clinical manifestations of HPT tend to be related to the level of hypercalcemia, even if this is not always evident because of slow disease progression, individual susceptibility, and to some extent also gender and age dependence of symptoms." Younger men are particularly likely to experience renal stones, sometimes even with only mild hypercalcemia. For renal stones, the individual susceptibility is more important than the level of hypercalcemia, and the risk for this particular symptom is probably most efficiently revealed by the patient's history. Urinary calcium excretion has been an uncertain predictor of the risk for kidney stones among patients who have previously not had this symptom.f Males excrete 25% to 30% more calcium in the urine than females, and whites also have higher excretion than blacks." In postmenopausal women, renal stones occur infrequently (generally less than 5%) and are often clinically silent. Osteitis fibrosa cystica is now an uncommon finding in patients with primary HPT and is most often seen in patients with severe hypercalcemia. Bone density measurements have, however, demonstrated an average reduction in

Natural History of Untreated Primary Hyperparathyroidism - - 399

cortical bone of nearly 20% among current patients with primary HPT, and the bone loss tends to be most pronounced in postmenopausal women.44-49 Total and trabecular bone mass is often significantly but less markedly reduced.r'r" Bone density measurements are recommended at the distal radius, hip, and lumbar spine because a subset of patients have more apparent reduction in the spine than other sites." The risk for fracture appears to be increased for the vertebra, distal leg, and forearm and returns to normal after parathyroid surgery.SO,SI The bone loss may be most evident at the time of menopause and may constitute an important indication for surgery in female patients." No bone loss has been detected in postmenopausal women with borderline hypercalcemia, but losses were significant when the serum calcium level was higher than 2.74 mmol/L." In postmenopausal women with primary HPT, a neuropsychiatric disability with symptoms of tiredness, lethargy, weakness, and easy fatigue is the most common feature. Although these are not traditional symptoms of HPT, they are typical for the disease, and many patients report improvement after successful parathyrotdectomy." The oldest patients may present with mental confusion, even without profound hypercalcemia, and their mental capacity may recover dramatically after operation.f It is important that these symptoms be recognized as features of the disease and constitute indications for surgery. The psychiatric disability is generally more evident when serum calcium levels are more markedly elevated, but the effects of surgery on the symptoms may sometimes be difficult to predict in individual patients." Clinically evident renal failure is currently an unusual complication of primary HPT. Reductions of creatinine clearance and urinary concentrating capacity, however, occur in more than one third of patients with mild hypercalcemia, indicating that impairment of glomerular as well as tubular function may occur silently.'? Serum creatinine measurements are crude estimates and rise only after creatinine clearance is substantially reduced, and creatinine levels also decrease with declining muscle mass of aging."? Reduction of creatinine clearance is a complication of the disease and an evident indication for surgery." Hypertension is twice as common in patients with primary HPT as in the general population and may be more severe in association with impaired renal function. However, it does not parallel the degree of hypercalcemia and is generally unaffected by parathyroid surgery.47A8,S2 Hypertension and other risk factors for cardiovascular disease may also be of concern with respect to decreased survival in primary HPT,26,27 which is evident also in mild hypercalcemia. 23,26,27,34,53.s4 Hypercalcemia and primary HPT have been associated with increased risk of death in cardiovascular disease in Scandinavian studies but not in two North American series. 26-29 The increased mortality has appeared related to the severity of HPT and renal function impairment." HPT of significant degree or long duration may cause renal impairment that is not always disclosed by creatinine values, and resulting reduced levels of active vitamin D may contribute to development of cardiovascular disease. The increased death risk has appeared reversed if patients with primary HPT have been operated on at an earlier disease stage.

Summary Indications for parathyroidectomy are indisputable in patients with primary HPT who exhibit clear and classic symptoms or marked hypercalcemia. The value of parathyroidectomy in asymptomatic patients with mild to moderate hypercalcemia has, however, been debated. Studies of the natural history of untreated primary HPT document that rapid increases in the serum calcium level, progression of symptoms or complications, or both is uncommon in patients with borderline hypercalcemia. Less clear is our knowledge about the long-term consequences of somewhat more marked hypercalcemia because no study has yet presented adequate follow-up of such patients for a prolonged period of time. It appears as if many patients with moderately elevated serum calcium levels «3.0 mmollL) have symptoms and silent complications of HPT if they are carefully studied. Although rapid progression of hypercalcemia is unusual, serum calcium levels, nevertheless, tend to increase progressively over years of observation in some patients. This advancing hypercalcemia may be obscured by declining levels of active vitamin D, resulting from dietary deficiency, lack of sun exposure, and impairments of renal function. Because these factors lower serum calcium levels, progression of HPT may not be detected. 7,ss.s6 The impact of such relative vitamin D deficiency may be difficult to determine and may simultaneously be part of the pathogenesis of primary HPT in elderly people. The natural course of primary HPT is causally related to the genetic and functional abnormalities within the diseased parathyroid tissue. Variable tumor biology and clinical progression may, therefore, depend on heterogeneity of tumor genetics.V Occasionally, patients' metabolic problems progress rapidly and are then reflected in excessively raised serum calcium values. These patients may have parathyroid tissues that harbor exceptional and critical mutations with oncogene activation or recruitment of growth factors. A PRADl oncogene rearrangement has been described in this context and has been associated with the largest parathyroid adenomas, whereas a menin gene abnormality has also been evident in sporadic, mild HPT.S8 Rare patients with initially mild hypercalcemia but rapidly advancing disease may have parathyroid carcinoma.v' In addition, stepwise "clinical" progression may occur during observation in patients with primary HPT, possibly representing development of secondary mutations that cause accelerated growth of the tumor. Thus, a history of mild primary HPT has been reported in up to one third of patients with hypercalcemic crisis. Because it is not yet possible to predict whether progressive disease will occur in any patient, extended follow-up is crucial if surgery is deferred in primary HPT.S9.6O Younger patients seem to be at greater risk for progressive disease. The absence of marked progression of complications in most patients with mild primary HPT allows medical surveillance in older persons with borderline hypercalcemia (i.e., with increments of serum calcium to less than 2.75 to 2.85 mmol/L, or 11.0 to 11.4 mg/dL) and in those with associated illnesses. Medical surveillance is probably inappropriate in younger patients and in those with more

400 - - Parathyroid Gland

marked hypercalcemia. Nonoperative management in any circumstance requires that the presence of symptoms or complications be carefully excluded and that precise monitoring of symptoms and metabolic function be done." A new consensus statement" has substantiated a risk for disease progression if patients with HPT are monitored without surgery and therefore issued a general recommendation for parathyroidectomy in patients with serum calcium values raised 0.25 mmol/L above the normal reference.

REFERENCES I. Heath H III, Hodgson SF, Kennedy MA. Primary hyperparathyroidism: Incidence, morbidity, and economic impact in a community. N Engl J Med 1980;302: 189. 2. Palmer M, Ljunghall S, Akerstrom G, et al. Patients with primary hyperparathyroidism operated on over a 24-year period: Temporal trends of clinical and laboratory findings. J Chronic Dis 1987;40: 121. 3. Potts JT. Management of asymptomatic hyperparathyroidism. J Clin Endocrinol Metab 1990;70:1489. 4. NIH Consensus Development Conference Panel. Diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus development conference statement. Ann Intern Med 1991;114:593. 5. Nussbaum SR, Potts JT. Immunoassays for parathyroid hormone 1-84 in the diagnosis of hyperparathyroidism. J Bone Miner Res 199I; 6(Suppl 2):43. 6. Ljunghall S, Hellman P, Rastad J, et al. Primary hyperparathyroidism: Epidemiology, diagnosis and clinical picture. World J Surg 1991;15:681. 7. Akerstrom G, Rudberg C, Grimelius L, et al. Histologic parathyroid abnormalities in an autopsy series. Hum Pathol 1986; 17:520. 8. Akerstrom G, Bergstrom R, Grimelius L, et al. Relation between changes in clinical and histopathological features of primary hyperparathyroidism. World J Surg 1986;10:696. 9. Wallfelt C, Ljunghall S, Bergstrom R, et al. Clinical characteristics and surgical treatment of sporadic primary hyperparathyroidism. Surgery 1990;107:13. 10. Tominaga Y, Grimelius L, Johansson H, et al. Histological and clinical features of non-familial primary parathyroid hyperplasia. Pathol Res Pract 1992;188:115. II. Christens son T, Hellstrom K, Wengle B, et al. Prevalence of hypercalcaemia in a health screening in Stockholm. Acta Med Scand 1976;200:131. 12. Groth TL, Ljunghall S, DeVerdier CH. Optimal screening for patients with hyperparathyroidism with use of serum calcium observations: A decision-theoretical analysis. Scand J Clin Lab 1983;43:699. 13. Palmer M, Jakobsson S, Akerstrom G, et al. Prevalence of hypercalcemia in a health survey: A 14-year follow-up of serum calcium levels. Eur J Clin Invest 1988;18:39. 14. Ljunghall S, Jakobsson S, Joborn C, et al. Longitudinal studies of mild primary hyperparathyroidism. J Bone Miner Res 1991;6:SIII. 15. Lundgren E, Rastad J, Thurfjell E, et al. Population-based screening for primary hyperparathyroidism with serum calcium and parathyroid hormone values in menopausal women. Surgery 1997;294:287. 16. Jorde R, Benaa KH, Sundsfjord J. Primary hyperparathyroidism detected in a health screening. The Tromse Study. J Clin Epidemiol 2000;53: 1164. 17. Bilezikian JP, Potts JT Jr. Asymptomatic primary hyperparathyroidism: New issues and new questions-Bridging the past with the future. J Bone Miner Res 2002;17(SuppI2):N57. 18. Wermers RA, Khosla S, Atkinson EJ, et al. The rise and fall of primary hyperparathyroidism: A population-based study in Rochester, Minnesota, 1965-1992. Ann Intern Med 1997;126:433. 19. Melton LJ. Epidemiology of primary hyperparathyroidism. J Bone Miner Res 1991;6:S25. 20. Ljunghall S, Rastad J, Akerstrom G. Primary hyperparathyroidism: Prevalence, pathophysiology, pertinent findings and prognosis. In: Heersche JNM, Kanis JA (eds), Bone and Mineral Research 8. New York, Elsevier Science, 1994, p I. 21. Christensson TAT. Primary hyperparathyroidism-pathogenesis, incidence and natural history. In: Rothmund M, Wells SA Jr (eds), Parathyroid Surgery: Progress in Surgery. Basel, Switzerland, Karger, 1986, p 1.

22. Christensson TAT, Hellstrom K, Wengle B. Blood pressure in subjects with hypercalcaemia and primary hyperparathyroidism detected in a health screening programme. Eur J Clin Invest 1977;7:109. 23. Palmer M, Adami H-O, Bergstrom R, et al. Survival and renal function in persons with untreated hypercalcaemia: A population-based cohort study with 14 years of follow-up. Lancet 1987; 1:59. 24. Joborn C, Hetta J, Lind L, et al. Self-rated psychiatric symptoms in patients with primary hyperparathyroidism. Surgery 1989;105:72. 25. Joborn C, Hetta J, Johansson H, et al. Psychiatric morbidity in primary hyperparathyroidism. World J Surg 1988;12:476. 26. Lundgren E, Lind L, Palmer M, et al. Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years. Surgery 2001;130:978. 27. Hedback G, Oden A. Death risk factor analysis in primary hyperparathyroidism. Eur J Clin Invest 1998;28: 10II. 28. Soreide JA, van Heerden JA, Grant CS, et al. Survival after surgical treatment for primary hyperparathyroidism. Surgery 1997;122:1117. 29. Wermers RA, Khosla S, Atkinson EJ, et al. Survival after the diagnosis of hyperparathyroidism: A population-based study. Am J Med 1998;104:115. 30. Purnell DC, Smith LH, Scholz DA, et al. Primary hyperparathyroidism: A prospective clinical study. Am J Med 1971;50:670. 31. Scholz DA, Purnell DC. Asymptomatic primary hyperparathyroidism. Mayo Clin Proc 1981;56:473. 32. Rohl PE, Wilkinsson M, Clifton-Blight P, et al. Hyperparathyroidism: Experiences with treated and untreated patients. Med J Aust 1981; I:519. 33. Adams PH. Conservative management of primary hyperparathyroidism. J R Coli Phys Lond 1982; 16:184. 34. Van't Hoff W, Ballardie FW, Bicknell EJ. Primary hyperparathyroidism: The case for medical management. Br Med J (Clin Res Ed) 1983;287:1605. 35. Paterson CR, Bums J, Mowat E. Long-term follow-up of untreated primary hyperparathyroidism. Br Med J (Clin Res Ed) 1984;289: 1261. 36. Corlew DS, Bryda SL. Bradley EL, et al. Observations on the course of untreated primary hyperparathyroidism. Surgery 1985;98: 1064. 37. Heath DA, Heath EM. Conservative management of primary hyperparathyroidism. J Bone Miner Res 1991;6:S117. 38. Rubinoff H, McCarthy N, Hiatt RA. Hypercalcemia: Long-term follow-up with matched controls. J Chronic Dis 1983;36:859. 39. Posen S, Clifton-Bligh P, Reeve TS, et al. Is parathyroidectomy of benefit in primary hyperparathyroidism? Q J Med 1985;215:241. 40. Corsello SM, Folli G, Crucitti F, et al. Acute complications in the course of "mild" hyperparathyroidism. J Endocrinol Invest 1991;14:971. 41. Rao DS, Wilson RJ, Kleerekoper M, et al. Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: Evidence for biphasic disease course. J Clin Endocrinol Metab 1988;67:1294. 42. Parfitt AM, Rao DS, Kleerekoper M. Asymptomatic primary hyperparathyroidism discovered by multichannel biochemical screening: Clinical course and considerations bearing on the need for surgical intervention. J Bone Miner Res 1991;6:S97. 43. Rudnicki M, Transbel 1. Increasing parathyroid hormone concentrations in untreated primary hyperparathyroidism. J Intern Med 1992;232:421. 44. Silverberg SJ, Shane E, Jacobs T, et al. A IO-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249. 45. Lafferty FW, Hubay CA. Primary hyperparathyroidism. A review of the long-term surgical and nonsurgical morbidities as a basis for a rational approach to treatment. Arch Intern Med 1989; 149:789. 46. Bilezikian JP, Potts JT Jr, EI-Hajj Fuleihan G, et al. Summary statement from a Workshop on Asymptomatic Primary Hyperparathyroidism: A perspective for the 21st century. J Clin Endocrinol Metab 2002;87:5353. 47. Mitlak BH, Daly M, Potts JT Jr, et al. Asymptomatic primary hyperparathyroidism. J Bone Miner Res 1991;6:SI03. 48. Davies M. Current therapy. Primary hyperparathyroidism: Aggressive or conservative treatment? Clin Endocrinol (Oxf) 1992;36:325. 49. Nagant de Deuxchaisnes C, Devogelaer JP, Huaux JP. Long-term followup of untreated primary hyperparathyroidism. Br Med J (Clin Res Ed) 1985;290:64. 50. Vestergaard P, Mollerup CL, Gedse Frekjer V, et al. Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 2000;321:598.

Natural History of Untreated Primary Hyperparathyroidism - - 401 51. Vestergaard P, Mosekilde L. Fractures in patients with primary hyperparathyroidism: Nationwide follow-up study of 1201 patients. World J Surg 2003;27:343. 52. Heath H III. Clinical spectrum of primary hyperparathyroidism: Evolution with changes in medical practice and technology. J Bone Miner Res 1991;6:S63. 53. Hedback G, Tisell L-E, Bengtsson B-A, et al. Premature death in patients operated on for primary hyperparathyroidism. World J Surg 1990;14:829. 54. Hedback G, Oden A, Tisell L-E. The influence of surgery on the risk of death in patients with primary hyperparathyroidism. World J Surg 1991;15:399. 55. Turner G, Brown RC, Silver A, et al. Renal insufficiency and secondary hyperparathyroidism in elderly patients. Ann Clin Biochem 1991;28:321.

56. Siperstein AE, Shen W, Chan AK, et al. Normocalcemic hyperparathyroidism: Biochemical and symptom profiles before and after surgery. Arch Surg 1992;127:1157. 57. Arnold A. Genetic basis of endocrine disease 5. Molecular genetics of parathyroid gland neoplasia. J Clin Endocrinol Metab 1993;77:1108. 58. Carling T, Correa P, Hessman 0, et aI. Parathyroid MEN] gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism. J Clin Endocrinol Metab 1998;83:2960. 59. Sarfati E, Desportes L, Gossot D, et al. Acute primary hyperparathyroidism. Br J Surg 1989;76:979. 60. Bondeson A-G, Bondeson L, Thompson NW. Clinicopathological peculiarities in parathyroid disease with hypercalcaemic crisis. Eur J Surg 1993;159:613.

Metabolic Complications of Primary Hyperparathyroidism Gerhard Prager, MD • Claudette Abela, MD • Bruno Niederle, MD

In 1925, the Viennese surgeon Felix Mandl removed for the first time a parathyroid tumor in a patient with symptomatic primary hyperparathyroidism (PHPT).1 The patient was confined to bed and suffered from classic renal and osseous symptoms: recurrent renal calculi, osteitis cystica fibrosa, disabling bone pain, and fatigue. Postoperatively, the patient improved dramatically but unfortunately died 10 years later from the consequences of progressive renal disease.F Since then there has been a dramatic improvement in the outcome of patients with PHPT after parathyroidectomy.' Careful analysis of patients with PHPT reveals that postoperative metabolic complications occur in patients with a long history of PHPT.3,4 For example, the death rate related directly or indirectly to PHPT ranges from 1% to 12%. Death in patients with PHPT is mainly caused by cardiovascular disease (~68%S) and acute or chronic renal failure (~8%3). Over the last 50 years, the clinical picture of PHPT has changed from a "rare" illness characterized by bone disease and renal calculi to a "common" disease characterized by more subtle or no clinical manifestations.f Articles from Scandinavia and North America':" have documented an increasing number of patients with PHPT who are diagnosed because hypercalcemia is detected on undirected routine serum calcium determinations and the diagnosis confirmed by parathyroid immunoassays.f-"!' PHPT is a relatively common, worldwide disorder with a reported incidence ranging from 0.1 % in Central Europe,'? Australia, 12 and South Africa" to as high as 0.52% in Sweden.v?" Heath 14 in England reported that among his patients with PHPT, fewer than 10% have renal calculi and fewer than 10% have bone disease, whereas more than 80% have either vague ill health or are asymptomatic, PHPT patients may be classified as symptomatic, minimally symptomatic, or asymptomatic. Symptomatic patients have renal, skeletal, or gastrointestinal disease or a combination. Osseous disease is defined as osteitis fibrosa, subperiosteal resorption, pathologic bone fractures, and aeroosteolysis. Minimally symptomatic patients have bone pain, diffuse osteopenia, or hypertension and the so-called hypercalcemia syndrome, which includes depression, lethargy, apathy,

402

weakness, loss of memory, confusion, insomnia, headaches, and myopathy with muscular weakness as well as other general manifestations like polyuria and polydypsia, weight loss, vomiting, nausea, or epigastric discomfort without any apparent organic origin.' Asymptomatic patients have neither symptoms nor signs attributable to PHPT (Table 42-1), In this chapter, we describe metabolic manifestations and complications other than the typical well-known, classic manifestations in both treated and untreated patients with PHPT that are described elsewhere in this textbook. Several metabolic complications are not usually attributed to PHPT. Patients with PHPT, for example, may have impaired glucose tolerance and diabetes mellitus. IS,16 Both hyperuricemia-!? and hyperlipidemia's may be increased in patients with PHPT, These conditions may have an adverse effect on hypertension and concomitant cardiovascular disease, and these conditions may contribute to the increased morbidity and mortality in patients with PHPT, even after successful parathyroidectomy. 11,19,20 The severity of the metabolic manifestations that occur in patients with PHPT cannot be predicted by the presence or absence of symptoms. Age, serum calcium level, and renal function are similar in patients with or without symptoms,":" although asymptomatic patients appear to have slightly lower serum calcium levels (Table 42-2). Some symptoms and metabolic changes improve, at least in part, after parathyroidectomye-P On the other hand. about one quarter of asymptomatic patients develop symptoms of PHPT within

1 decade."

Arterial Hypertension In 1958, Hellstrom and associates'? suggested a relationship between hypertension and PHPT; these authors reported that 53% oftheir 95 patients had blood pressures of 1501100 mm Hg or greater. Several series have quoted a prevalence ranging from 21 % to 57% (Table 42_3).28-33 This wide range may be a result of different patient ages as well as different definitions of hypertension. Lafferty!' showed that hypertension

Metabolic Complications of Primary Hyperparathyroidism - - 403

was twice as common among hyperparathyroid patients compared with the general population.W PHPT and hypertension are associated with an increased risk of cardiovascular disease and possibly stroke.r' Bostrom and Alverydr' as well as Palmer and colleagues'" reported a higher mortality rate (61%) mainly because of cardiovascular disease in

patients with hypercalcemia and PHPT. Unfortunately,hypertension failed to improve in 92% after parathyroidectomy." The pathogenesis of hypertension in patients with PHPT has not been completely defined. Studies involving the renin-angiotensin system suggest no direct relationship with the hypertension.v-" Salahudeen and coworkers"

404 - - Parathyroid Gland

found no correlation between blood pressure and total serum calcium in PHPT patients." This is in contrast to the situation with essential hypertension in which a significant positive correlation between blood pressure and total serum calcium has been described.tv" as well as an inverse correlation or no correlation between serum ionized calcium

and hypertension.v-t' Parathyroid hormone (PTH) is said to play a permissive role in the hypertensive action of hypercalcemia.tv" Bernini and associates" compared plasma renin activity in patients with PHPT and essential hypertension and a normotensive control group. They only found a weak relation between PTH and plasma renin activity,

Metabolic Complications of Primary Hyperparathyroidism - - 405

suggesting that hypertension in PHPT is probably of heterogeneous origin. As mentioned, the response of hypertension after successful parathyroidectomy has been variable. Successful cure of hyperparathyroidism only occasionally leads to a lowering of blood pressure to normal. Renal impairment also usually does not improve after successful parathyroidectomy.27.37.39.47.48 Salahudeen and colleagues'? suggested that impaired renal function in PHPT may be the primary event to hypertension.f because the glomerular filtration rate measured by chromium l-edetic acid clearance did not change after parathyroidectomy in their careful study. Declining renal function, in the absence of obstructive renal calculi and nephrocalcinosis, can be related to progressive hypertension.w" The reaction of normotensive PHPT patients to pressor agents has been studied by Rodriguez-Portales and Fardella." Normotensive parathyroid patients had an abnormal response to pressor agents (i.e., norepinephrine and angiotensin II) similar to that found in patients with idiopathic hypertension. This abnormality persisted 6 months after surgical cure even if the blood pressure remained within the normal limits. Lewanczuk and Pang" reported the presence of a parathyroid hypertensive factor (PHF), which is assumed to be secreted by the parathyroid glands. PHF is a circulating hypertensive factor found in a proportion of patients with essential hypertension as well as in spontaneously hypertensive rats. Preoperative values of this factor were raised in hypertensive patients with PHPT. Patients with PHPT and PHF preoperatively had lower blood pressures after successful parathyroidectomy and PHF levels became undetectable. These results suggest that the parathyroid gland can express PHF in humans and that such expression may be responsible for a proportion of the.high incidence of hypertension in PHPT.52 Middeke and Schrader'" showed that hypertensive PHPT patients had a normal circadian blood pressure profile with a normal nocturnal blood pressure fall. The circadian nocturnal blood pressure profile tends to fall by about 15 mm Hg in systolic and diastolic readings and was no different from that seen in normotensive subjects, as opposed to other secondary forms of hypertension (e.g., renal and endocrine forms of hyperthyroidism, primary hyperaldosteronism, and Cushing's syndrome). After successful parathyroidectomy, blood pressure in hypertensive PHPT patients usually remains mainly unchanged4.36.37.39.48,49.54-56 and may increase with time. 27,3o,57 Follow-up studies as long as 22 years after successful parathyroidectomy showed increased hypertension in 9.2% of symptomatic patients and 13.3% of minimal symptomatic patients, whereas asymptomatic patients showed no elevation of blood pressure.t'" The onset of hypertension after parathyroidectomy in PHPT patients who were normotensive occurs in 17% to 33% of patients. 21 On the contrary, reversibility in the form of improvement or normalization of hypertension after parathyroidectomy has also been observed. Improvement in 20% to 50% of patients has been reported.27,58-62 Because hypertension only decreases in a few patients after parathyroidectomy, hypertension is not an indication for surgery in patients with otherwise uncomplicated mild PHPT,37.48.49 However, hypertension is more common after parathyroidectomy in patients who were symptomatic.

Cardiovascular Disease Another interesting finding is the concurrent incidence of cardiovascular disease.l'" Cardiovascular complications are the most common cause of death in patients with successfully treated and untreated PHPT.3,19,20,35 In a follow-up study of 12.3 years, Hedback and colleagues'? showed that, of 896 PHPT patients, 294 had died during follow-up. One hundred-fifty-six patients (53%) died from cardiovascular disease-50 (32%) patients from myocardial infarction, 44 (28%) from stroke, 53 (34%) from heart failure, and 9 (6%) from generalized atherosclerosis. Ronni-Sivula" reported that 23 (68%) of the 34 patients with PHPT who died did so from cardiovascular disease-l 8 (53%) from cardiac disease, 4 (12%) from stroke, and 1 (3%) from vascular disease (thrombosis of the mesenteric artery)]. In this study, there was no difference in the mortality between minimal symptomatic and asymptomatic patients. Bondeson and coworkers's reported that 132 (44%) of 300 patients with PHPT had coronary artery disease preoperatively. Langle and associates-' reported that 11 (23%) of 48 patients with minimal symptomatic and 5 (7%) of 77 of the symptomatic patients suffered from coronary heart disease, whereas 64 (48%) of 132 showed hypertrophy of the left ventricular wall. A study performed on 54 patients with PHPT and 54 age- and sex-matched controls showed a significant incidence of aortic (63%) and mitral valve (49%) calcifications in PHPT patients compared with the 13% found in the normocalcemic controls. Metastatic myocardium calcification was noted in 69% of the patients." The full pattern of cardiac abnormalities, although mild, was exhibited in asymptomatic patients.P These findings suggest that metabolic disorders occur even in patients with asymptomatic PHPT and raise the question whether so-called asymptomatic PHPT actually exists. According to these findings, Smith and colleagues's found an increased arterial stiffness in patients with mild to moderate PHPT. This provides a mechanism for the development of left ventricular hypertrophy in normotensive PHPT patients and is likely to contribute significantly to both cardiovascular morbidity and mortality. In contrast to these studies, Barletta and coworkers's found neither pathologic echocardiographic parameters nor an alteration of the mechanical properties of the brachial and carotid arteries before or after successful parathyroidectomy in 14 patients with mild asymptomatic PHPT. The improved survival after parathyroidectomy raises the question about whether early operation could influence the course of these cardiac manifestations. Regression of left ventricular hypertrophy and a slower progression of cardiac calcifications has been documented postoperatively.W" Some investigators believe that elevation of cytoplasmic calcium increases aortic pressure, elevated wall tension, and adrenergic stimulation'" and results in cardiac hypertrophy. Because all the hypertensive patients in the study by Stefenelli and associates's had antihypertensive therapy and, therefore, had a mean resting blood pressure similar to that of the nonhypertensive patients, the higher incidence of hypertrophy is likely to be a consequence of elevated PTH or calcium concentrations rather than a consequence of raised blood pressure. This finding may explain the reversibility of cardiac hypertrophy after parathyroidectomy.

406 - - Parathyroid Gland Endothelium-independent vasodilation was found to be impaired in PHPT patients without clinical evidence of coronary heart disease compared to normocalcemic control subjects. 68,69 In a follow-up study," the restoration of normocalcemia by parathyroidectomy could not improve the vascular reactivity, but on the other hand, no further progression of vascular disease could be seen. Despite evidence from long-term follow-up, it is still controversial as to whether parathyroidectomy significantly decreases the morbidity and mortality associated with hyperparathyroidism.V" A 15-year follow-up of operated and unoperated PHPT patients showed that mild PHPT is associated with an increase in blood pressure with age. However, this particular study showed aggravation of hypertension after parathyroid surgery.'? Hedback and associates'S" reported an increased risk of premature death in patients after parathyroidectomy in all age groups, with the highest relative risk of death occurring in patients between 55 and 70 years of age. The risk in younger patients and in those with less severe disease returned to a normal survival curve most quickly after successful parathyroidectomy. There was also a shift from an increased risk of death toward a normal risk of death as time passed after surgery, indicating a positive effect of parathyroidectomy on survival. Over the years, there has been a change in trend toward a more rapid normalization of the risk of death (i.e., approximately after 5 years if the patient was operated on in 1980, but not until after 9 years if operated on in 1975). This effect appears to be due to the increased number of mild cases in the more recent series that benefited from early detection and treatment. This study indicated that patients with PHPT of shorter duration have less risk of death. In a further study," the same authors showed an increased risk of death for patients undergoing surgery for mild or moderate PHPT in Sweden between 1987 and 1994. The recent publication of their longterm findings showed "a 50% increased death risk of hypertensive hyperparathyroid patients compared with that of the normotensive patients, but the yearly death risk decrease after surgery for the hypertensive patients was almost doubled as compared with the decrease of the normotensive patients. Cardiovascular disease was directly related to serum calcium level, adenoma weight, osteitis fibrosa, and serum creatinine and inversely related to glomerular filtration rate and urine osmolality'T In another follow-up study of 14 years, the overall survival in 172 untreated hypercalcemic subjects with mild hyperparathyroidism was lower than that of the matched normocalcemic subjects. This trend became obvious within 5 years of presentation." These results support the recommendation for parathyroidectomy for virtually all patients with PHPT.

Psychiatric Symptoms Several authors have documented the common occurrence of nonspecific symptoms such as weakness, fatigue, and mental depression in PHPT.7,24,25 A wide spectrum of psychological symptoms ranging from mild personality changes to severe depression and psychosis has been described. These psychiatric symptoms develop in PHPT patients irrespective of the serum calcium level. Joborn and colleagues" reported that

hypercalcemic patients with asymptomatic PHPT (i.e., no kidney stones or osteitis fibrosa cystica) presented with similar although less pronounced psychiatric disturbances as did patients with symptomatic PHPT, Confusion and delirious states sometimes dominate the clinical picture and occur in about 5% of cases. 75-79 Peterson" correlated the level of hypercalcemia to the severity of the psychiatric symptoms. He also reported the return to the premorbid mental status postoperatively. Personality changes and affective disturbances were associated with plasma calcium levels of 12 to 16 mg/elL (3 to 4 mmol/L). Acute organic brain syndromes with altered levels of consciousness, paranoid ideation, and hallucinations were noted at plasma calcium levels of 16 to 19 mg/elL (4 to 4.5 mmol/L)." However, even slight increases in the serum calcium and PTH levels may produce serious psychiatric symptorns.Y'" Joborn and colleagues" reported that 10 of 13 patients with organic brain syndrome had senile dementia. Twelve of these patients were admitted to a mental hospital. Eight of these patients improved after parathyroidectomy, and 7 of them were able to return to their homes. The postoperative improvement was related to the duration of the mental symptoms. All 8 patients who improved had a clinical history of dementia of fewer than 2 years. Patients with a longer history of mental illness were likely to recover. These studies document that impressive psychological improvement can occur after successful parathyroidectomy in patients with PHPT.81,82 Psychosis involves the disturbance of thought content, thinking processes with perceptual aberrations, paranoid or persecutory ideation, and delusions." Hallucinations and delusions have been reported to occur in about 10% of patients who have psychiatric symptoms,?6,83 Recovery from paranoid states after parathyroidectomy becomes evident after 48 hours." Solomon and coworkers'" showed that all 18 patients suffering from PHPT had clinical multidimensional psychological distress in the individual areas of obsession-compulsion, interpersonal sensitivity, depression, anxiety, hostility, psychosis, sleep disturbance, and lack of concentration." Depression and lethargy are the most common characteristics experienced by this group of patients.80 An improvement approaching normal was achieved 1 month after surgery. Solomon and coworkers'" found no group differences for somatization and phobic anxiety before and after parathyroidectomy in their 18 patients. Clark and associates.s' however, did document more symptoms in patients with PHPT and resolution of somatic symptoms as well as neuropsychiatric symptoms after parathyroidectomy. No correlation was found between the clinical symptoms and the biochemical constellation.rv" Serious depression is noted in about 10% of patients with PHPT and may be associated with headache (Table 42-4).76 Fatigue normally develops first. Anxiety, depression, and irritability have been noted in up to one third of cases.P The severity of psychiatric symptoms is not linearly related to the degree of hypercalcemia or to PTH values/" The psychological symptoms generally begin to improve within 1 month after successful parathyroidectomy.5,ll,21,24.25,75,80,85,86 Disturbances in monoamine turnover have been documented in patients with PHPT and psychiatric syrnptoms.f-" The cerebrospinal fluid (CSF) concentrations of total and

Metabolic Complications of Primary Hyperparathyroidism - - 407

ionized calcium were higher in 22 unselected PHPT patients. CSF concentrations of PI'H were also higher than in the reference group; monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid were lower. 5-HIAA correlated inversely with CFS ionized calcium. Endogenous depression has been reported to coincide with lowered monoamine metabolites. The central neurotransmitter activity might be influenced by the higher calcium concentrations present in the CSF. Sedation and depression have also been associated with higher CSF calcium concentrations." The precise neurophysiologic reasons for the psychological changes have yet to be clarified, although it has been suggested that excess PI'H enhances the permeability of the blood-brain barrier, raising the CSF concentration of calcium, albumin, and urate. After successful parathyroidectomy, both total and ionized CSF calcium decrease." Postoperative follow-up shows major improvements in anxiety, cognition, depression, fearfulness, and confidence. Preoperative electroencephalograms obtained from seven patients with asymptomatic PHPI' and mild from hypercalcemia were generally abnormal, showing a shift of frequencies toward abnormal slower frequencies «7 Hz; normal range is >9 Hz).89 All seven patients had normal electroencephalograms 3 to 5 months postoperatively. However, this small group of patients showed no consistent postoperative improvement in any of the psychological parameters, although patients with secondary hyperparathyroidism did.89 A biochemical relationship was not found.t" In a recent study, Prager and colleagues?" demonstrated a significant improvement of the patients' cognitive performance (concentration, retentiveness) by parathyroidectomy, applying standardized psychological tests. No correlation between the improvement of concentration/retentiveness and the serum calcium and PI'H levels, age, and gender was found in this study. Pasieka and coworkers?' developed a patient-based surgical outcome tool. They found a significant improvement in the quality of life and self-rated health after parathyroidectomy in patients suffering from PHPI'; these findings were confirmed by Sheldon and coworkers'? using the Short Form Health Survey (SF-36).

Neuromuscular Disease Neuromuscular disease mainly manifests itself as fatigue and weakness, especially in the proximal muscles of the lower extremities.v" Aching muscles, paresthesias, and

unsteadiness of gait have also been reported.V? The incidence of these symptoms varies from 30% to 80%,83,93 probably due to the criteria used, diligence of the respective observers, and patient selection. Muscle weakness and fatigability are subjective symptoms. Both symptoms can be explained by decreased muscle strength on the one hand or lack of mental energy from depression and lethargy on the other hand. Hedman and associates?" studied an unselected series of PHPI' patients to assess the association between these symptoms and muscle strength before and after surgery, A significant increase in the isokinetic strength of knee extension and knee flexion at higher angular velocities was found 3 months after surgery, suggesting that type II (fast twitch) muscle fibers were predominantly affected. The results of this study support the clinical impression that PHPI' surgery is beneficial to patients with muscular symptoms.rv" Joborn and colleagues." however, were unable to find any significant abnormalities of nerve conduction velocity or neuromuscular transmission in unselected PHPI' patients." Joborn and coworkers documented that even patients with mild to moderate HPI' without apparent muscular symptoms had impaired muscle function. Reinvestigation 6 months postoperatively showed improvement in only one patient who had severe preoperative muscular symptomatology.P-" A 1988 study" showed no significant difference in muscle strength between those patients with subjective impairments and the control patients. Seven months postoperatively, the PHPT patients had increased their muscle strength by 8%. These studies demonstrate that patients with PHPI', especially those with neuromuscular symptoms and muscle weakness, improve their muscle strength slightly after parathyroidectomy. Patten and associates'" concluded, on the basis of the clinical, electromyographic, and biopsy evidence, that the neuromuscular abnormality in PHPI' is probably neuropathic in origin." Electromyograms of 12 patients showed short-duration, low-amplitude motor unit potentials in some patients and abnormally high-amplitude, long-duration polyphasic potentials in others. Motor nerve conduction velocities and distal sensory latencies were normal. The major finding on muscle biopsy was atrophy of both type I (slow twitch) and type II muscle fibers, with type II fibers being more extensively involved. With the restoration of normocalcemia, neuromuscular symptoms improved within days to weeks after surgery.88 In contrast, Turken and colleagues" demonstrated that 22 (52%) of 42 patients had neuromuscular symptoms consisting

408 - - Parathyroid Gland either of muscle cramps (45%), paresthesias (45%), or both (18%). No patient showed classic hyperparathyroid neuromuscular disease (muscle weakness, atrophy, hyperreflexia, abnormal gait, or tongue fasciculations). Electromyographic and nerve conduction studies were performed in 9 patients with neurologic abnormalities." None showed myopathy or signs of motor unit denervation. These results differed significantly from those reported earlier," There is clearly a trend toward subtle, earlier neuropathy that also manifests itself among socalled asymptomatic patients. Unfortunately, Turken and colleagues did not report the postoperative results."

Carbohydrate Metabolism It has been frequently reported that PHPT patients have a higher risk of developing impaired glucose tolerance or diabetes mellitus. 3•15,16,18,99 Hyperinsulinemia in patients with PHPT suggested that these patients have a reduced insulin sensitivity and therefore impaired glucose tolerance. lOO- 105 Several studies have shown that up to 8% of patients with PHPT suffer from diabetes mellitus as compared with 2% of normocalcemic patients (Table 42_5).16,18,99,106,107 Whether diabetes mellitus itself is associated with the metabolic abnormalities in PHPT alone or with other known risk factors such as age, obesity, and hypertension is uncertain. Kumar and colleagues 108 showed that PHPT patients have a higher tendency to develop diabetes mellitus in the absence of the earlier mentioned risk factors. Those PHPT patients with impaired glucose tolerance are also likely to have reduced beta cell function. Reduced beta cell function may be a result of the direct effects of PTH and calcium on beta cells, reducing insulin-secretory capacity.'?' Patients lacking adequate beta cell function may therefore acquire overt diabetes because of the reduced capacity of insulin secretion. On the other hand, other studies in nondiabetic hyperparathyroid patients have shown no major change in glucose tolerance in the presence of hyperinsulinemia, suggesting a state of insulin resistance. 101.105.110 A complete understanding of the pathophysiologic mechanisms responsible for the disturbed carbohydrate metabolism in patients with PHPT is not yet known. Downregulation of the insulin receptor has been shown to be present in patients with PHPT. Hyperinsulinemia with mild suppression of endogenous glucose turnover after a glucose load test seems to explain this phenomenon.l'<'!'

In ViV0 1l2 and in vitro!" studies have indicated that PTH also has a stimulatory effect on hepatic glucose production, necessitating a compensatory augmentation of beta cell insulin production. Although Bevilacqua and coworkers 114 failed to detect any effect of acute PTH administration in dogs on hepatic or peripheral glucose metabolism, acute exposure of the pancreatic islets cells to PTH has a direct effect on glucoseinduced insulin secretion. 109 This effect was modulated by an increase in cytosolic calcium.l'" whereas chronic administration of PTH was associated with inhibition of insulin release.l" Hellman I 16 was able to demonstrate the positive influence of hypercalcemia on glucose-induced insulin secretion and on insulin secretion independent of glucose and, therefore, the induction of hyperinsulinemia. Hypophosphatemia might also contribute to the insulin resistance and downregulation of insulin receptors in patients with PHPT. In vivo glucose studies have shown a decrease in insulin-induced peripheral glucose uptake under hypophosphatemic conditions. I 17 Kautzky-Willer and colleagues'P? showed that after parathyroidectomy in patients with PHPT, severely impaired insulin resistance definitely improved. Basal as well as stimulated insulin secretion levels are reduced after parathyroidectomy, although both values fail to return to normal. An improvement in insulin sensitivity also occurred in nondiabetic PHPT patients after parathyroidectomy, whereas normalization of insulin secretion was observed only in patients with normal glucose tolerance. l OO ,103 The normalization of biochemical abnormalities, especially that of calcium, has a much greater impact on insulin sensitivity than on insulin secretion. 100 Postoperative correction of the hypercalcemic state leads to an increased insulin sensitivity and, therefore, to the possibility of severe hypoglycemia in insulin-dependant diabetes. 15,118 Improved metabolic control was achieved in 27% of patients with PHPT after parathyroidectomy.P Prager and associates 102 also showed partial improvement in glucose utilization after parathyroidectomy. These patients were clinically symptomatic, and this might explain the more pronounced disturbance of carbohydrate metabolism. Despite the factors just mentioned, Ljunghall," Bannon, I 19 and their coworkers found no significant changes in the requirement for insulin in insulin-requiring diabetics after parathyroidectomy. Valdemarsson and associates'j" found 26.4% of their study population to have some form of impairment of glucose

Metabolic Complications of Primary Hyperparathyroidism - - 409

metabolism compared to a 4% to 6% prevalence of noninsulin-dependent diabetes in a well-defined region in their country, suggesting a more frequent disturbance of glucose metabolism in patients suffering from PHPT. In this study, a significant decrease of glucose in patients with unknown diabetes or impaired glucose tolerance could be shown. In summary, PHPT worsens coexisting diabetes mellitus. PHPT is associated with an abnormal glucose metabolism as a result of alterations in insulin sensitivity, as well as changes in endogenous glucose turnover and beta cell secretion. Parathyroidectomy corrects some of these biochemical parameters, mainly insulin hypersecretion and insulin resistance, but it only partially ameliorates the metabolic state.

Lipoprotein Metabolism Discrepant findings on lipoprotein metabolism in PHPT include increased and decreased levels of serum triglycerides, decreased serum cholesterol, increased serum very-lowdensity-lipoproteins (VLDL), and no changes at all.121-124 Hagstrom and colleagues-" found decreased high-densitylipoprotein (HDL) cholesterol, increased total triglycerides, and VLDL cholesterol, and an elevated atherogenic index in patients with mild PHPT. Parathyroidectomy normalized the dyslipidemia within 1 year. Five-year surveillance of PHPT patients without treatment was found to be associated with a maintained increase in total triglycerides and the atherogenic index and a decrease in HDL cholesterol levels. These findings favor operative intervention rather than conservative surveillance, even in patients with asymptomatic, mild PHPT. It has also been reported that increased PTH levels both in vivo and in vitro increase lipolysis, perhaps causing the elevated VLDL levels. 126. 127 In a further study, Valdemarsson and coworkers'P found 9.2% of their patients with PHPT to have preoperative hypertriglyceridemia. They did not observe any significant changes of the mean cholesterol or triglyceride levels in their patients 1 year after operation, but they did find a significant decrease of triglycerides in the male subgroup. The authors speculated that this difference could be related to the activity of lipoprotein lipase, a key enzyme in triglyceride degradation known to be affected by insulin.

Hyperuricemia Hyperuricemia occurs frequently in PHPT. Auerbach and associates' showed that 22 (32%) of 56 patients had uric acid concentrations greater than 7 mg/dL. Postoperatively, there was no significant change in 6 patients (27%). In 14 patients (64%), the serum level fell by more than 1 mg/dl..?? Duh and colleagues'? reported similar findings in a larger group of patients. An increased concentration of urate in PHPT has been described by several authors. 1?128.129 Valdemarsson and coworkers-" found a significant decrease of serum urate among men and women 1 year after successful surgery for PHPT. Furthermore, they showed a significant correlation between ionized calcium and intact PTH and urate, indicating an influence of PTH on urate metabolism. In a further study, Westerdahl and associates'P

found urate to be an independent risk factor for the presence of clinically relevant atherosclerotic disease in patients with PHPT.

Chondrocalcinosis and Pseudogout Chondrocalcinosis is defined as the deposition of calcium salts in articular hyaline cartilage and fibrocartilage.P' This study showed that most patients were asymptomatic (21 of 71 [30%]) and that only 4 (5.6%) of 71 had intermittent attacks of pseudogout. Chondrocalcinosis and pseudogout are said to be sufficiently frequent (3.8%) in hyperparathyroidism such that screening of such patients is warranted.P? Occasionally, pseudogout is the initial manifestation. It is characterized by arthritis and pain in one or more joints associated with the presence of calcium pyrophosphate dihydrate crystals in the synovial joint fluid. Acute attacks of pseudogout arthritis may be precipitated by transient or rapid changes in the serum calcium concentration. A rapid change in calcium concentration is often seen after successful surgery, causing attacks of pseudogout, which may complicate the postoperative clinical picture. Unlike the predominance of gouty arthritis, pseudogout rarely involves the foot. The most common joint involved is the knee; less commonly involved are the elbows, wrists, and ankles. Radiographic features of chondrocalcinosis include calcification of articular cartilage and joint effusion that may be characteristic enough to suggest PHPT. Identification of the crystals through aspiration is diagnostic for pseudogout. A series of eight patients in whom pseudogout arthritis developed as the initial clue to PHPT had no further arthritic complaints 6 weeks postoperatively.-" In the same study, 12 patients developed pseudogout acutely after parathyroidectomy. Nonsteroidal anti-inflammatory analgesics brought relief from these symptoms.P? It seems that parathyroidectomy prevents the progression of chondrocalcinosis and in general relieves symptoms, although acute episodes of pseudogout and gout may occur after parathyroidectomy, usually at the nadir of postoperative hypocalcemia.

Summary Neither the degree of hypercalcemia nor the degree of PTH serum level determines the metabolic complications in patients with PHPT. Insidious abnormalities occur in renal function, bone, carbohydrate and lipid metabolism, uric acid metabolism, and cardiovascular metabolism. Beneficial results of parathyroidectomy are unfortunately limited by the degree of irreversible organ damage that occurs prior to parathyroidectomy. Therefore, some of the associated manifestations such as renal disease and hypertension become irreversible and may be progressive, despite successful parathyroid surgery.3.4.20.21,133 Untreated PHPT also carries an increased risk of death, particularly from cardiovascular diseases.!" This risk gradually decreases with time after parathyroidectomy, and surgery is the only therapy proven to be curative for PHPT.14,35,134

410 - - Parathyroid Gland Surgical treatment for patients with asymptomatic, minimally symptomatic, and symptomatic hyperparathyroidism may prevent the consequent development of complications such as renal impairment or hypertension and relieve neuropsychiatric disorders, glucose intolerance, and other clinical manifestations.P'r" Asymptomatic patients appear to receive the same metabolic benefits on bone and renal dysfunction as well as other clinical manifestations as do symptomatic patients, and they return more quickly to a normal life expectancy after successful parathyroidectomy.19,24,25,71,l35,136

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77. Petersen P. Psychiatric disorders in primary hyperparathyroidism. J Clin Endocrinol Metab 1968;28:1491. 78. Leigh H, Kramer SI. The psychiatric manifestations of endocrine disease. Adv Intern Med 1984;29:413. 79. Watson L. The psychiatric aspects of disturbed calcium metabolism: Clinical aspects of hyperparathyroidism. Proc R Soc Med 1968;61:1123. 80. Joborn C, Hetta J, Johansson H, et al. Psychiatric morbidity in primary hyperparathyroidism. World J Surg 1988;12:476. 81. Joborn C, Hetta J, Frisk P, et al. Primary hyperparathyroidism in patients with organic brain syndrome. Acta Med Scand 1986;219:91. 82. Heath DA, Wright AD, Barnes AD, et al. Surgical treatment of primary hyperparathyroidism in the elderly. BMJ 1980;280:1406. 83. Karpati G, Frame B. Neuropsychiatric disorders in primary hyperparathyroidism. Arch Neurol 1964;10:387. 84. Solomon BL, Schaaf M, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med 1994;96: 101. 85. McAllion SJ, Paterson CR. Psychiatric morbidity in primary hyperparathyroidism. Postgrad Med J 1989;65:628. 86. Longo DL, Witherspoon JM. Focal neurologic symptoms in hypercalcemia. Neurology 1980;30:200. 87. Joborn C, Hetta J, Rastad J, et al. Psychiatric symptoms and cerebrospinal fluid monoamine metabolites in primary hyperparathyroidism. Bioi Psychiatry 1988;23:149. 88. Joborn C, Hetta J, Niklasson F, et al. Cerebrospinal fluid calcium, parathyroid hormone, and monoamine and purine metabolites and the blood-brain barrier function in primary hyperparathyroidism. Psychoneuroendocrinology 1991; 16:311. 89. Cogan MG, Covey CM, Arieff AI, et al. Central nervous system manifestations of hyperparathyroidism. Am J Med 1978;65:963. 90. Prager G, Kalaschek A, Kaczirek K, et al. Parathyroidectomy improves concentration and retentiveness in patients with primary hyperparathyroidism. Surgery 2002;132:930. 91. Pasieka JL, Parsons LL, Demeure MJ, et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942. 92. Sheldon DG, Lee FT, Neil NJ, et al. Surgical Treatment of hyperparathyroidism improves health-related quality of life. Arch Surg 2002; 137: 1022. 93. Pallen 8M, Bilezikian JP, Mallette LE, et al. Neuromuscular disease in primary hyperparathyroidism. Ann Intern Med 1974;80:182. 94. Hedman I, Grimby G, Tisell LE. Improvement of muscle strength after treatment for hyperparathyroidism. Acta Chir Scand 1984;150:521. 95. Joborn C, Joborn H, Rastad J, et al. Maximal isokinetic muscle strength in patients with primary hyperparathyroidism before and after parathyroid surgery. Br J Surg 1988;75:77. 96. Joborn C, Rastad J, Stalberg E, et al. Muscle function in patients with primary hyperparathyroidism. Muscle Nerve 1989;12:87. 97. Ljunghall S, Akerstrom G, Johansson G, et al. Neuromuscular involvement in primary hyperparathyroidism. J Neuro11984;231 :263. 98. Turken SA, Cafferty M, Silverberg SJ, et al. Neuromuscular involvement in mild, asymptomatic primary hyperparathyroidism. Am J Med 1989;87:553. 99. Werner S, Hjern B, Sjoberg HE. Primary hyperparathyroidism: Analysis of findings in a series of 129 patients. Acta Chir Scand 1974;140:618. 100. Kautzky-Willer A, Pacini G, Niederle B, et al. Insulin secretion, insulin sensitivity, and hepatic insulin extraction in primary hyperparathyroidism before and after surgery. Clin Endocrinol (Oxf) 1992;37: 147. 101. Prager R, Kovarik J, Schernthaner G, et al. Peripheral insulin resistance in primary hyperparathyroidism. Metabolism 1983;32:800. 102. Prager R, Schernthaner G, Kovarik J, et al. Primary hyperparathyroidism is associated with decreased insulin receptor binding and glucose intolerance. Calcif Tissue Int 1984;36:253. 103. Prager R, Schernthaner G, Niederle B, et al. Evaluation of glucose tolerance, insulin secretion, and insulin action in patients with primary hyperparathyroidism before and after surgery. Calcif Tissue Int 1990;46: I. 104. Kim H, Kalkhoff RK, Costrini NV, et al. Plasma insulin disturbances in primary hyperparathyroidism. J Clin Invest 1971;50:2596. 105. Yasuda K, Hurukawa Y, Okuyama M, et al. Glucose tolerance and insulin secretion in patients with parathyroid disorders: Effect of serum calcium on insulin release. N Engl J Med 1975;292:501.

412 - - Parathyroid Gland 106. Taylor WHo The prevalence of diabetes mellitus in patients with primary hyperparathyroidism and among their relatives. Diabet Med 1991;8:683. 107. Birge RA. Clinicopathologic Conference: Multiple endocrine adenomatosis. Am J Med 1969;47:608. 108. Kumar S, Olukoga AO, Gordon C, et al. Impaired glucose tolerance and insulin insensitivity in primary hyperparathyroidism. Clin Endocrinol (Oxf) 1994;40:47. 109. Fadda GZ, Akmal M, Lipson LG, et al. Direct effect of parathyroid hormone on insulin secretion from pancreatic islets. Am J Physiol 1990;258:E975. 110. Ginsberg H, Olefsky JM, Reaven GM. Evaluation of insulin resistance in patients with primary hyperparathyroidism. Proc Soc Exp BioI Med 1975;148:942. III. Shaw JH, Croxon M, Holdaway I, et al. Glucose, fat, and protein kinetics in patients with primary and secondary hyperparathyroidism. Surgery 1988;103:526. 112. Moxley MA, Bell NH, Wagle SR, et al. Parathyroid hormone stimulation of glucose and urea production in isolated liver cells. Am J PhysioI1974;227:1058. 113. Hruska KA, Blondin J, Bass R, et al. Effect of intact parathyroid hormone on hepatic glucose release in the dog. J Clin Invest 1979;64:1016. 114. Bevilacqua S, Barrett E, Ferrannini E, et aI. Lack of effect of parathyroid hormone on hepatic glucose metabolism in the dog. Metabolism 1981;30:469. 115. Fadda GZ, Akmal M, Premdas FH, et al. Insulin release from pancreatic islets: Effects of CRF and excess PTH. Kidney Int 1988;33: 1066. 116. Hellman B. Stimulation of insulin release after raising extracellular calcium. FEBS Lett 1976;63:125. 117. De Fronzo RA, Lang R. Hypophosphatemia and glucose intolerance: Evidence for tissue insensitivity to insulin. N Engl J Med 1980;303:1259. 118. Akgun S, Ertel NH. Hyperparathyroidism and coexisting diabetes mellitus: Altered carbohydrate metabolism. Arch Intern Med 1978; 138:1500. 119. Bannon MP, van Heerden JA, Palumbo PJ, et al. The relationship between primary hyperparathyroidism and diabetes mellitus. Ann Surg 1988;207:430. 120. Valdemarsson S, Lindblom P, Bergenfelz A. Metabolic abnormalities related to cardiovascular risk in primary hyperparathyroidism: Effects of surgical treatment. J Intern Med 1998;244:241. 121. Christensson T, Einarsson K. Serum lipids before and after parathyroidectomy in patients with primary hyperparathyroidism. Clin Chim Acta 1977;78:411. 122. Ljunghall S, Lithell H, Vessby B, et al. Glucose and lipoprotein metabolism in primary hyperparathyroidism: Effects of parathyroidectomy. Acta Endocrinol (Copenh) 1978;89:580. 123. Vaziri ND, Wellikson L, Gwinup G, et al. Lipid fractions in primary hyperparathyroidism before and after surgical cure. Acta Endocrinol (Copenh) 1983;102:539. 124. Lacour B, Roullet JB, Liagre AM, et aI. Serum lipoprotein disturbances in primary and secondary hyperparathyroidism and effects of parathyroidectomy. Am J Kidney Dis 1986;8:422. 125. Hagstrom E, Lundgren E, Lithell H, et al. Normalized dyslipidaemia after parathyroidectomy in mild primary hyperparathyroidism: Population-based study over five years. Clin Endocrinol (Oxf) 2002;56:253.

126. Sinha TK, Thajchayapong P, Queener SF, et aI. On the lipolytic action of parathyroid hormone in man. Metabolism 1976;25:251. 127. Forster K, Gozariu L, Faulhaber JD. Parathyroid hormone and calcitonin: Influences upon lipolysis of human adipose tissue. Acta Endocrinol (Copenh) 1974;184(Suppl):168. 128. Christensson T. Serum urate in subjects with hypercalcaemic hyperparathyroidism. Clin Chim Acta 1977;80:529. 129. Ljunghall S, A.kerstrom G. Urate metabolism in primary hyperparathyroidism. Urol Int 1982;37:73. 130. Westerdahl J, Valdemarsson S, Lindblom P, et al. Urate and arteriosclerosis in primary hyperparathyroidism. Clin Endocrinol (Oxf) 2001 ;54:805. 131. Van Geertruyden J, Kinnaert P, Frederic N, et al. Effect of parathyroid surgery on cartilage calcification. World J Surg 1986; 10: III. 132. Geelhoed GW, Kelly TR. Pseudogout as a clue and complication in primary hyperparathyroidism. Surgery 1989; 106:1036. 133. ReinhoffWF. The surgical treatment of primary hyperparathyroidism. Ann Surg 1950;131:917. 134. Clark OH, Duh QY. Primary hyperparathyroidism: A surgical perspective. Endocrinol Metab Clin North Am 1989; 18:701. 135. Uden P, Chan A, Duh QY, et al. Primary hyperparathyroidism in younger and older patients: Symptoms and outcome of surgery. World J Surg 1992;16:791. 136. Kaplan RA, Snyder WH, Stewart A, et al. Metabolic effects of parathyroidectomy in asymptomatic primary hyperparathyroidism. J Clin Endocrinol Metab 1976;42:415. 137. Hellstrom J, Ivemark BI. Primary hyperparathyroidism: Clinical and structural findings in 138 cases. Acta Coo Scand Suppl 1962;294: 1. 138. Frank M, Nathan P, Lazebnik J, et al. Clinical experience with hyperparathyroidism in sixty patients, fifty-one of them having urolithiasis. UrolInt 1968;23(4):315. 139. Ohlsson L. Renal function in hyperparathyroidism: A follow-up study three to nine years after surgery comprising 35 cases. Acta Endocrinol (Copenh) 1970;63:161. 140. Chowdhury SD, Gray JG. Renal function and hypertension in primary hyperparathyroidism. Br J Surg 1973;60:53. 141. Rothmund M, Prieto JL, Kummerle F. [Primary hyperparathyroidism (author's transl).] Dtsch Med Wochenschr 1979;104:653. 142. Nainby-Luxmoore JC, Langford HG, Nelson NC, et al. A casecomparison study of hypertension and hyperparathyroidism. J Clin Endocrinol Metab 1982;55:303. 143. Daniels J, Goodman AD. Hypertension and hyperparathyroidism: Inverse relation of serum phosphate level and blood pressure. Am J Med 1983;75:17. 144. Ronni-Sivula H. The state of health of patients previously operated on for primary hyperparathyroidism compared with randomized controls. Ann Chir GynaecoI1985;74:60. 145. Shaha AR, Jaffe BM. Cervical exploration for primary hyperparathyroidism. J Surg OncoI1993;52:14. 146. Joborn C, Hetta J, Palmer M, et al. Psychiatric symptomatology in patients with primary hyperparathyroidism. Ups J Med Sci 1986;91:77. 147. Dotzenrath C, Goretzki PE, Roher HD. West Germany: Still an underdeveloped country in the diagnosis and early treatment of primary hyperparathyroidism? World J Surg 1990; 14:660. 148. Garcia de la Torre N, Wass JAH, Turner HE. Parathyroid adenomas and cardiovascular risk [Review]. Endocr Relat Cancer 2003;10:309.

Natural History of Treated Primary Hyperparathyroidism Lars-Erik Tisell, MD, PhD

In 1925, Mandl of Austria performed the first operation for primary hyperparathyroidism (PHPT).I His patient had sustained a spontaneous thigh bone fracture and was immobilized. Three months after a parathyroid adenoma had been excised, the patient could walk with crutches. The effect of the operation was conspicuous. During the next 4 decades, most patients with PHPT continued to have obvious symptoms relieved by surgery. In the mid-1960s, the number of operations for PHPT started to increase in most centers. This also happened at our hospital, but the number of patients with substantial disease remained remarkably constant.' In patients with mild hypercalcemia, with few or no symptoms, it is difficult to register any immediate positive effects of surgery. Therefore, controversy exists as to whether surgical therapy should be used in such patients. In one study, one third of the population of asymptomatic patients had silent complications such as premature osteopenia and abnormal renal function.' Martin and colleagues" found that the bone loss of mineral content as a result of PHPT is only partially reversible. However, at that time, they and others' believed that surgery for PHPT should not be undertaken solely to prevent osteoporosis. The results of some studies suggest an improvement of muscle strength and psychiatric symptoms after surgery for mild PHPT.6.7 Other observations indicate increased morbidity and mortality among patients with mild hypercalcemia who are observed without surgical treatment. 8 Some studies suggest that PHPT may cause lasting damage, resulting in increased morbidity and mortality for a long time after the parathyroid surgery.':" If PHPT is indeed a risk factor for increased morbidity and premature death, a positive attitude toward early surgery is indicated for patients with asymptomatic PHPT.

Mortality after Surgery for Primary Hyperparathyroidism Three Scandinavian studies examined long-term mortality after surgery for PHPT. Basic data from the three Scandinavian series are given in Table 43-1. The first two series included patients who had been treated during the

same 24-year period.v'? The third series included more patients than the other two together and covered a 30-year period. This series also had the longest follow-up. I 1-13 In the Helsinki study, for the first time, the long-term mortality after surgery for PHPT was compared with that in contemporary control subjects matched for gender and age.?

Surgical Complications and Cure of Primary Hyperparathyroidism None of the series provided information regarding recurrent nerve palsy. Postoperative hypoparathyroidism occurred in 3.4% of the patients in the Uppsala series." In the Goteborg series, hypoparathyroidism occurred in 2.45%. After exclusion of patients who underwent reoperation, patients with multiple parathyroid gland disease, and patients with concomitant thyroidectomy for thyroid tumor, only three patients who experienced hypoparathyroidism remained in the Goteborg series. This shows that hypoparathyroidism is a rare complication in patients with a single parathyroid adenoma. I I The cure rate of PHPT among the survivors at the time of followup was 94% in the Helsinki series" and 91% in the Uppsala series.'? In the Goteborg series, the cure rate was 97%, defined as a stable serum calcium concentration of less than 2.55 mmollL during the first postoperative year. I I

Postoperative Mortality Two of the series supplied information about the mortality within 1 month after surgery (Table 43-2). In the Goteborg study, the mortality for the first half of the series was 1.56%. During the last half of the series, only 1 of 448 patients (0.22%) died postoperatively. II

Long-Term Mortality In the Helsinki series, patients undergoing surgery for appendicitis, varicose veins, or hemorrhoids and matched for age and gender were used as control subjects." In the Uppsala and Goteborg studies, patients were assigned to control groups on the basis of Swedish population statistics and were

413

414 - - Parathyroid Gland

matched for gender, age, and calendar year of surgery.IO·12 During 5 years of observation, the increased mortality in the Helsinki study was 3.9% of the PHPT population (see Table 43-2). The relative risk (RR) of death compared with control subjects was 1.62, with a 95% confidence interval (CI) of 0.91 to 2.94 (Table 43-3). The increased mortality among the PHPT patients was significant (P < .05) (Table 43-4).9 In the Goteborg study, the observed mortality was increased by 13.2% in the PHPT population compared with the expected mortality after a follow-up period of 12.9 ± 6.1 years. The RR was 1.67 and the CI was 1.49 to 1.87. The increase in mortality was highly significant (P < .001).11 In the Uppsala study, the relative cumulative survival ratio between observed survival for the PHPT patients and the expected survival was below I throughout the follow-up period. The decrease in survival after surgery for PHPT was statistically significant only for females between 4 and 12 years after surgery. The survival rate was reduced by 4% after 14 years. The approximate RR in the Uppsala study was 1.45 (see Table 43-3) as calculated on the basis of available data from Palmer and coworkers. 10 The RR represents the ratio between the death hazard functions of the PHPT group and those of the controls. The quotient is a function of time after surgical treatment. In the Goteborg series, it was shown that the RR decreased with time after surgery," In this presentation, the RR is presented as one figure for each series (see Table 43-3). This figure is the mean of the quotients in an interval of postoperative years. The Helsinki, Uppsala, and Goteborg studies involved patients undergoing surgery for PHPT at the three hospitals during the study periods. The three studies showed increased

long-term mortality after surgery for PHPT.9.ll In the largest study with the longest follow-up, the increased mortality was 13.2% of the PHPT population (118 patients).'!

Risk Factors In the Goteborg study.P it was found that age, calendar year of surgery, and time elapsed since surgery were significantly (P < .00 I) and independently correlated with the risk of death (Table 43-5). The importance of calendar year of surgery and time elapsed since surgery is exemplified in Figure 43-1 by patients who were 65 years old at surgery. The RR was twice as high in 1965 as in 1980. For patients operated on in 1965, it took 12 to 14 years before the RR returned to a normal survival curve, whereas in patients operated on in 1980 it took approximately 5 years. The serum calcium concentrations were positively related to the risk of death (P < .01). Both the preoperative serum calcium and serum creatinine concentrations decreased continuously (P < .001) during the period from 1953 to 1982. Consequently, patients operated on during the early years of the study had a more severe disease. This explains in part why an early calendar year could be a risk factor for premature death. The RR of death was raised in all age groups, but patients 55 to 70 years of age at surgery had the highest RR. It was thought that young people had a better restorative capacity and that the aged had many other risk factors, making the risk of PHPT relatively less important. The increase in RR was less pronounced as time passed after surgery but was a consistent finding in all age groups.

Natural History of Treated Primary Hyperparathyroidism - -

In the Uppsala study," serum calcium concentrations and year of surgery did not influence survival. In the Helsinki study," serum calcium concentrations were significantly higher (P < .01) in patients who died than in other patients. In this study, it was noted that the mean parathyroid adenoma weight was higher in the patients who died during follow-up. In the Goteborg series, 13 the weight of the parathyroid adenoma was found to be a predictive factor for the risk of death (P < .001). In the series of713 patients with a single adenoma, the adenoma weights ranged from 75 to 18,100 mg. The median adenoma weight was 610 mg. The adenoma weight at the 20th percentile was 267 mg and at the 80th percentile was 1625 mg. An increase in parathyroid weight from 267 to 1625 mg implied an increase in mortality of 57%. Adenoma weight was significantly correlated with the risk of death (P < .01) even when the influence of the serum calcium concentration had been eliminated. In all other studies and analyses concerning long-term survival, the PHPT populations had been compared with control subjects. In this analysis, for the first time, an increased mortality in the PHPT population

415

could be shown by using a factor bound to PHPT itself. This provides strong independent support for the results of the previous studies.

Causes of Death In all three studies,":'! increased mortality from cardiovascular disease was found among the PHPT patients (Table 43-6). The increased mortality was statistically confirmed in the

Op 1965

Op 1970

Op 1975

Op 1980

Relative Risk

3.5

F..;",,;,...-----------------:l

3.0 2.5

2.0

................

1.5

" " " ----------------------==--', ----

"

1.0

Op

5

10

15

Time after surgery, years

FIGURE 43-1. Chart showing the association between a later year of operation, a lower relative risk for death, and a more rapid postoperative return to the normal survival curve. This figure represents patients who were 65 years old at the time of surgery for primary hyperparathyroidism. (From Hedback G, Oden A, Tisell LE. The influence of surgery on the risk of death in patients with primary hyperparathyroidism. World J Surg 1991;15:400.)

416 - - Parathyroid Gland

Helsinki (P < .05) and Goteborg (P < .00l) studies. In the Goteborg series, 157 patients, or 63 more than expected, died from cardiovascular disease during the follow-up period. In the Helsinki study, 15 more patients than control subjects died from cardiovascular disease. The follow-up studies did not add any information on the mechanisms causing the increased mortality in cardiovascular disease. However, it is interesting that echocardiographic studies have shown a high incidence of left ventricular hypertrophy in patients with PHPT.16,17 In one of these studies, a significant partial regression of the left ventricular hypertrophy was noted 12 months after cure of PHPT.17 Other data have suggested that the echocardiographically measured left ventricular mass is a strong predictor of cardiovascular morbidity and mortality.lv'? A significant increase (P < .(01) in death from malignant disease was found only in the Goteborg study. In that study, 72 patients died of malignant diseases (i.e., 27 more than expected). These malignancies were of 24 different types. Adenocarcinoma of the pancreas, including the papilla of Vater region, was the only tumor that occurred in a significantly increased number (P < .05).11 Table 43-6 shows the percentages of the three main causes of death. It was found that the percentage of patients who died from malignant disease increased with the length of follow-up (see Table 43-1). In the Goteborg study, the long observation time with many deaths helped to detect the association between PHPT and death from malignant disease. The results of the other studies with shorter follow-up periods do not conflict with the observation in the Goteborg study. A link between PHPT and malignant disease had previously been found in a series of 4163 persons who had been reported to the Swedish Cancer Registry because they had surgery for parathyroid adenomas." It is also interesting in this connection that hypercalcemia can induce mitotic activity.2 1,22 Renal disease was the third most common cause of death. In the Goteborg series, 21 of the 25 deaths from renal disease occurred during the first half of the series. The decrease in mortality from renal disease is not only an effect of early surgery for PHPT but also a result of better treatment of patients with renal stones, impaired glomerular filtration rate, or renal infections.

General Discussion In view of the high prevalence figures for PHPT found in population studies, it is apparent that only a proportion of all subjects with PHPT are surgically treated. 23,24 This is also

true in the city of Goteborg, where the medical community has a liberal attitude toward PHPT surgery. Subjects who are under medical care for other diseases are more likely to have PHPT diagnosed and treated. This means that a possible bias has been introduced in all three Scandinavian studies. In the Goteborg study, this possibility was considered.'! A selected series was formed by excluding 171 patients who had their PHPT diagnosed during treatment or follow-up for a disease that could cause increased mortality. These diseases were myocardial infarction, heart failure, arrhythmia, hypertension of more than 2 years' duration before detection of raised serum calcium concentrations, stroke, diabetes, and malignant tumors. In the selected series, the mortality was still significantly higher than expected (P < .(01), as was the mortality from cardiovascular (P < .00 l) and malignant diseases (P < .01). The RR in the selected series was 1.43, with a CI of 1.23 to 1.64 (see Table 43-3). The increased mortality in the selected series during the observation period was 7.8% of the PHPT population, which was 5.4% less than in the total series (see Table 43-2). From the analyses of the selected series, it is obvious that PHPT by itself is associated with an increased risk of premature death from cardiovascular and malignant diseases. Ninety-two percent of the exclusions had been made because of the very two diagnoses that in the selected series had been significantly linked to the increased mortality among PHPT patients. This suggests that when forming the selected series, some patients could have been incorrectly excluded and that the correct value for mortality from PHPT in the total series should be between 7.8% and 13.2%. The total series shows the risk of premature death in all patients who undergo surgery for PHPT. The selected series shows the minimum value for the increased risk of death caused by PHPT itself. The selected series proves that PHPT causes irreversible damage to the body. In a separate study, it was found that the parathyroid adenoma weight was a highly significant predictive factor for the risk of death. This finding was made in the PHPT series itself without using any control subjects. This independent observation strongly supports the association between PHPT and premature death. 13 Premature aging could be a possible explanation for the premature deaths from cardiovascular and malignant diseases. The observation that women with PHPT on average experience menopause 4.5 years earlier than control subjects supports this hypothesis.P The severity of PHPT is usually classified by the serum calcium concentrations. In a 1991 study, asymptomatic and symptomatic PHPT patients had similar preoperative serum calcium concentrations." These findings suggest that serum calcium alone is not responsible for the severity of PHPT. An increase in serum calcium concentrations over that found at diagnosis is seldom found in untreated PHPT patients, even if they are monitored for a long time. 24,27 This means that the duration of the disease can differ considerably among patients with the same serum calcium concentrations, The possible role of duration of disease is seldom mentioned when discussing the morbidity of PHPT. A long-term, prospective, randomized study with two arms, surgery and nonsurgery, is needed to obtain more exact information about the impact of PHPT duration on morbidity and mortality. For ethical reasons, only asymptomatic patients can be included in such

Natural History of Treated Primary Hyperparathyroidism - - 417

a study. In a previous study of patients with asymptomatic PHPT, there was a waning interest on the part of many patients, making it difficult to continue the study." The experience from that study suggests that a prospective, randomized study aimed at defining the influence of PHPT duration on longterm survival is not easily undertaken. The Goteborg study covered 30 years." During the early part of this period, serum calcium determinations were not routinely done for ambulatory and hospitalized patients, and PHPT was considered a rare disease. Therefore, at that time, the duration of the disease before surgery was probably much longer than during the end of the period, when serum calcium determinations were routinely done. The longer duration of PHPT could have contributed to the higher mortality found during the early period of the study. However, the patients then usually had higher serum calcium concentrations than later, and we know that a high serum calcium concentration is a risk factor for mortality (see Table 43-5). Using a survival test, it was found that the relationship between calendar year and risk of death was significant even when the influence of the serum calcium concentrations had been eliminated. 12 This suggests that calendar year of surgery was associated with another risk factor besides the high serum calcium concentration. From this reasoning, it seems logical to assume that the extra risk factor associated with early calendar year is long duration of PHPT. It is impossible to estimate the exact duration of PHPT before diagnosis, but the size of a parathyroid adenoma must be related to the time of its growth and hence to the duration of PHPT. This should be true even if there are observations suggesting that both cell division and parathyroid tumor growth decline during the life span of the tumor," As mentioned, in the Goteborg studies, it was found that the parathyroid adenoma weight was a highly significant predictive factor for the risk of death after cure of PHPT.13 The adenoma weight and the serum calcium concentration were significantly correlated (P < .001). When the influence of the adenoma weight had been eliminated, the serum calcium concentration did not show any correlation with the risk of death. On the other hand, adenoma weight was significantly correlated with risk of death even when the influence of the serum calcium concentrations had been eliminated (P < .01). These calculations show that the parathyroid adenoma weight is a more powerful predictive factor for increased mortality than the serum calcium concentration. 13 A plausible hypothesis to account for this observation is that patients with heavier adenomas had a longer duration of PHPT before they were operated on and were, therefore, subjected to more severe and more lasting damage. In the Goteborg study, a shift from an increased risk of death to a normal risk occurred as time passed after surgery.P This positive effect of surgery was most apparent in recent years, when there was a more positive attitude to the diagnosis and treatment of PHPT. For 65-year-old patients operated on in 1980, it took about 5 years for the survival curve to return to normal. Thus, in untreated patients with PHPT, the risk of death increases with time, whereas after surgical cure of PHPT the risk decreases with time. These observations are strong arguments for early surgery in patients with PHPT. The risk of increased cardiovascular morbidity and premature death in PHPT has also been discussed in several

other studies. Grey and colleagues found that postmenopausal women with mild asymptomatic PHPT had increased body weight and total body fat mass and also a more android fat distribution than age-matched control subjects. They thought that these findings could be relevant to the increased incidence of cardiovascular disease in PHPT.29 A large Danish study showed that patients operated on for PHPT had an increased incidence of myocardial infarcts up to 10 years before surgery. This risk fell to a normal level after surgery. In this study, mortality after surgery was higher than in the general population between 1979 and 1990 but not between 1991 and 1997.30 In a German series, 383 patients with PHPT were observed prospectively after surgery during a period of 10 years. It was found that the mortality in the study population was significantly higher than in the control subjects. The prevalence of patients with symptomatic PHPT in this series was 94%.31 In an interesting study, it was found that increased cardiovascular mortality was found in patients with mild hypercalcemia followed up for 25 years." In another study, it was found that higher serum calcium by itself was associated with increased risk for premature death. The mortality rate in relation to a single serum calcium value was examined in a large population during a mean follow-up of 10.8 years. It was found that men who were younger than 50 years and had serum calcium values greater than 2.45 mmollL had an increased mortality of 20% compared with those with lower serum calcium levels; those with serum calcium greater than 2.60 mmollL had a doubled risk rate. The excess mortality was largely attributable to cardiovascular diseases but also to a significant excess mortality because of malignant disease.P In Europe, several studies have shown an increased risk of premature death in patients operated on for PHPT. Such results were not obtained in studies conducted in the United States at the Mayo Clinic. The patients in the Mayo Clinic series were operated on from 1980 to 1984, and 43% of the 1052 patients in the series had symptomatic PHPT.34 In 1974, a screening program was started at the Mayo clinic, for the early detection of patients with PHPT using routine measurements of serum calcium levels. This program was still ongoing when the 1052 patients referred to above were diagnosed with PHPT. In any 3-year period, more than 90% of Olmsted County residents had at least one measurement of serum calcium level. 35 The patients in the Goteborg series had surgery from 1953 to 1982. Clinical data for the first 274 patients in this series were published in 1973. 36 Eightyseven percent of these patients had PHPT with classic symptoms, and 20 of the 200 patients with renal stones recalled that they had their first renal colic more than 20 years before the diagnosis of PHPT. This means that, in these patients, the actual onset of PHPT predated the clinical recognition by more than 2 decades. In this early series, 29 patients were diagnosed with "hypercalcemic crises." These patients from the 1950s and 1960s did not represent our current patients, but their inclusion in the analyses made it possible to define a number of risk factors for premature death and to study the impact of surgery on survival. Mild hypercalcemia in patients followed for more than 2 decades is accompanied by premature cardiovascular death.P The exemplary screening program at the Mayo Clinic, with early diagnosis and operations, seems to eliminate the risk for premature death in patients with PHPT.

418 - - Parathyroid Gland

REFERENCES 1. Mandl F. Klinisches und Experimentelles zur Frage der lokalisierten und generalisierten Ostitis fibrosa. Arch Klin Chir 1926;143:245. 2. TisellLE, Hedback G, lansson S, et al. Management of hyperparathyroid patients with grave hypercalcemia. World 1 Surg 1991;15:730. 3. Mitlak HE, Daly M, Potts IT lr. Asymptomatic primary hyperparathyroidism. 1 Bone Miner Res 1991;6(SuppI2):103. 4. Martin P, Bergman P, Gillet C, et al. Partially reversible osteopenia after surgery for primary hyperparathyroidism. Arch Intern Med 1986; 146:689. 5. Silverberg Sl, Shane E, de la Cruz L, et al. Skeletal disease in primary hyperparathyroidism. 1 Bone Miner Res 1989;4:283. 6. Hedman I, Grimby G, Tisell L-E. Improvement of muscle strength after treatment for hyperparathyroidism. Acta Chir Scand 1984; 150:521. 7. Joborn C, Hetta 1, Rastad 1, et al. Psychiatric symptoms and cerebrospinal fluid monoamine metabolites in patients with primary hyperparathyroidism. BioI Psychiatry 1988;23:149. 8. Corlew DS, Bryda SL, Bradley EL, et al. Observations on the course of untreated primary hyperparathyroidism. Surgery 1985;98:1064. 9. Ronni-Sivula H. Causes of death in patients previously operated on for primary hyperparathyroidism. Ann Chir GynaecoI1985;74:13. 10. Palmer M, Adami HO, Bergstrom R, et al. Mortality after surgery for primary hyperparathyroidism: A follow-up of 441 patients operated on from 1956 to 1979. Surgery 1987;102:1. 11. Hedback G, Tisell LE, Bengtsson BA, et al. Premature death in patients operated on for primary hyperparathyroidism. World 1 Surg 1990;14:829. 12. Hedback G, Oden A, Tisell LE. The influence of surgery on the risk of death in patients with primary hyperparathyroidism. World 1 Surg 1991;15:399. 13. Hedback G, Oden A, Tisell LE. Parathyroid adenoma weight and the risk of death after treatment of primary hyperparathyroidism. Surgery 1995;117:134. 14. Rudberg C, Akerstrom G, Palmer M, et al. Late results of operation for primary hyperparathyroidism in 441 patients. Surgery 1986;99:643. 15. Ronni-Sivula H, Sivula A. Long-term effect of surgical treatment on the symptoms of primary hyperparathyroidism. Ann Clin Res 1985;17:141. 16. Symons C, Fortune F, Greenbaum RA, et al. Cardiac hypertrophic cardiomyopathy and hyperparathyroidism-An association. Br Heart 1 1985;54:539. 17. Stefenelli T, Mayr H, Bergler-Klein 1, et al. Primary hyperparathyroidism: Incidence of cardiac abnormalities and partial reversibility after successful parathyroidectomy. Am 1 Med 1993;95:197. 18. Levy D, Garrison Rl, Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N Engl 1 Med 1990;322:1561.

19. Koren Ml, Devereux RB, Casale PN, et al. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345. 20. Palmer M, Adami HO, Krusemo VB, et al. Increased risk of malignant diseases after surgery for primary hyperparathyroidism: A nationwide cohort study. Am 1 EpidemioI1988;1127: 1031. 21. Perris AD, MacManus IP, Whitfield IF, et al. Parathyroid glands and mitotic stimulation in rat bone marrow after hemorrhage. Am 1 Physiol 1971;220:773. 22. Elias AN, Sharma BS, Stokes ID, et al. Immunological aberration in primary hyperparathyroidism. Acta Endocrinol (Copenh) 1982;101:47. 23. Christensson T, Hellstrom K, Wengle B, et al. Prevalence of hypercalcemia in a health screening in Stockholm. Acta Med Scand 1976;200:131. 24. Palmer M, Bergstrom R, Akerstrom G, et al. Survival and renal function in untreated hypercalcaemia, population-based cohort study with 14 years of follow-up. Lancet 1987;1:59. 25. Christensson T. Menopausal age of females with hypercalcaemia: A study including cases with primary hyperparathyroidism, detected in a health screening. Acta Med Scand 1976;200:361. 26. Harrison Bl, Wheeler MH. Asymptomatic primary hyperparathyroidism. World 1 Surg 1991;15:724. 27. Scholz DA, Purnell DC. Asymptomatic primary hyperparathyroidism: lO-year prospective study. Mayo Clin Proc 1981;56:473. 28. Parfitt AM, Willgoss D, lakobi 1, et al. Cell kinetics in parathyroid adenomas: Evidence for decline in rates of cell birth and tumour growth, assuming clonal origin. Clin Endocrinol (Oxf) 1991;35:151. 29. Grey AB, Evans MC, Stapleton IP, et al. Body weight and bone mineral density in postmenopausal women with primary hyperparathyroidism. Ann Intern Med 1994;121:745. 30. Vestergaard P, Mollerup CL, Frekjaer VG, et al. Cardiovascular events before and after surgery for primary hyperparathyroidism. World 1 Surg 2003;27:216. 31. Walgenbach S, Hommel G, Bernhard G, et al. Operative Therapie des primaren Hyperparathyreoidismus. Zentralbl Chir 2000; 125:666. 32. Lundgren E, Lind L, Palmer M, et al. Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years. Surgery 2001;130:978. 33. Leifsson BG, Ahren B. Serum calcium and survival in a large health screening program. 1 Clin Endocrinol MetabI996;81:2149. 34. Soreide lA, van Heerden lA, Grant CS, et al. Survival after surgical treatment for primary hyperparathyroidism. Surgery 1997;122:1117. 35. Wermers RA, Khosla S, Atkinson sr, Hodgson SF, O'Fallon WM, et al. The rise and fall of primary hyperparathyroidism: A populationbased study in Rochester, Minnesota, 1965-1992. Ann Intern Med 1997;126:433. 36. Romanus R, Heimann P, Nilsson 0, et al. Surgical treatment of hyperparathyroidism. Prog Surg 1973;12:22.

Asymptomatic Primary Hyperparathyroidism Janice L. Pasieka, MD

Historical Perspective Osteitis fibrosa cystica was first described in the 18th century, although not so named until 1891, when von Recklinghausen reported three patients with giant cell pseudotumor of the bone. 1 Interestingly, one of these patients had a "reddish brown lymph node" below the thyroid. In 1925, Felix Mandl successfully removed a parathyroid adenoma from the neck of a patient suffering from von Recklinghausen's disease." Between 1925 and 1932, all patients operated on for primary hyperparathyroidism (1 0 HPT) had the bone manifestations of osteitis fibrosa cystica. In 1932, however, Albright noted that 80% of all patients with 10 HPT treated at that time had nephrolithiasis. He wondered whether some patients might have renal stones without bone disease. In 1932, he found a patient who presented with renal calculi without significant bone disease, in whom a parathyroid adenoma was found at operation.' Over the next 30 years, as clinicians recognized nephrolithiasis as a manifestation of 10 HPT, the incidence of von Recklinghausen's bone disease declined and most patients with 1 HPT were found to have renal calculi alone or in combination with other early signs of bone disease such as the presence of subperiosteal erosions. Until the mid-1960s, clinically apparent 10 HPT was considered to be relatively uncommon. Occasionally, however, 10 HPT was sometimes discovered by serendipity in patients with an elevated serum calcium level." With the advent in the 1960s of autoanalyzers and routine screening of serum calcium levels, the prevalence of HPT increased to 0.1% to 0.4% as more patients with fewer clinical manifestations of the disease were diagnosed.' 0

Asymptomatic HyperparathyroidismDoes It Exist? With the earlier detection of the disease, the presenting clinical manifestations of 1 HPT have changed drastically since the first successful parathyroidectomy in 1925. The classic symptoms of severe bone pain from osteitis fibrosa cystic a, 0

nephrolithiasis, significant myopathy, and significant neuropsychiatric impairment are seen in less than 20% of the patients who currently present with 10 HPT.6Unlike the presentation in the days of von Recklinghausen and Albright, today only 15% to 20% of patients with 1 HPT present with nephrolithiasis and less than 3% of patients display evidence of osteitis fibrosa cystica."? This change in the presentation of 10 HPT led to a 1990 National Institutes of Health (NIH)-sponsored consensus conference that developed guidelines for surgery in HPT.IO The consensus panel agreed that parathyroidectomy was indicated in all symptomatic patients as well as in all "asymptomatic" patients with risk factors for progression of their disease such and marked hypercalcemia, hypercalciuria, or renal insufficiency, marked bone mineral density (BMD) loss, and those younger than 50 years.!" In a reconvening of the NIH consensus panel in 2002, very little had changed. The new guidelines reduced the limits of hypercalcemia to 0.25 mmol above the normal reference, and altered the criteria of BMD loss from z scores to t scores. lOa The panel continued to recommend surgical intervention for all symptomatic patients and those who demonstrated end-organ physiologic effects of the disease. The controversy lies in the NIH consensus panel's definition of an asymptomatic patient. If one limits the definition of symptomatic HPT to the classic symptoms, including nephrolithiasis, significant myopathy, and evidence of osteitis fibrosis cystica, it is true that the majority of patients today with 1 HPT (over 80%) are asymptomatic.S'P" Asymptomatic, however, implies free of symptoms and complications of the disorder. Today, there is considerable evidence that many patients with HPT suffer from vague, nonspecific, but nonetheless real manifestations of the disease. 6,15-23 Surgeons have long observed improvement in many of these nonspecific symptoms following parathyroidectomy. Furthermore, many patients with 10 HPT do not realize until after parathyroid surgery just how severe their symptoms were. 15,17,18,24,25 Jobom and colleagues investigated psychiatric symptoms in 59 consecutive patients with 10 HPT.26 Utilizing a Comprehensive Psychopathological Rating Scale, they found that the majority of patients with HPT had considerable 0

0

419

420 - - Parathyroid Gland psychiatric symptoms compared with healthy control subjects. The most pronounced symptoms were fatigue, lassitude, failing memory, difficulty concentrating, sadness, and inner tension. After successful parathyroidectomy, there was a marked improvement in the mental health of these patients. This was one of the first surgical studies that tried to quantify the nonclassic symptoms and the surgical effect in patients with 10 HPT. In a population-based screening study from Sweden, Lundgren and coworkers found that fewer than 24% of their 10 HPT patients suffered from the classic symptoms. However, the patients with 10 HPT had more psychiatric complaints of lassitude, fatigue, irritability, and lack of sexual interest than their age-matched control subjects." Others have demonstrated similar results, with the HPT patients' experiences with more symptoms than population norms. Chan and colleagues reported a case-control series of 121 patients from 1986 to 1991 with 10 HPT utilizing a preoperative symptom questionnaire that was filled out at their first visit to the surgeon and again when they were recalled in June 1991. They found that the majority of the 10 HPT patients were indeed symptomatic preoperatively (95%) and that most patients experienced a subjective improvement in their preoperative symptoms following parathyroidectomy. 18 More recently, Hasse and associates'> set out to answer the question of just "how asymptomatic is asymptomatic 10 HPT?" In their cohort study of 582 consecutive patients with 10 HPT, 86 patients who were considered asymptomatic preoperatively participated in the follow-up questionnaire given at a median of 72 months postoperatively. The follow-up assessment consisted of the Short Form 36-item (SF-36) quality of life (QOL) instrument and a graded questionnaire that included 19 classic and nonclassic symptoms. They found that in retrospect only 9.3% of the asymptomatic patients were truly asymptomatic. Postoperatively, 81% of the asymptomatic patients reported an improvement in their preoperative state. From this study, it would appear that apparently asymptomatic 10 HPT patients realized symptoms only in retrospect and that these symptoms could not be predicted preoperatively, because they become apparent only after treatment. These studies all suggest that asymptomatic 10 HPT patients might have the same subjective benefit from parathyroidectomy as symptomatic patients. Asymptomatic 10 HPT patients treated conservatively have no frame of reference to validate whether or not they are truly asymptomatic. In an observational study by Silverberg and colleagues of 121 10 HPT patients, they claimed that 101 (83%) were asymptomatic." Patients were randomly assigned. Half (61) underwent parathyroidectomy with a normalization of their biochemical values and an increase in their BMD. The remaining 60 patients underwent observation and, during the 1O-yearfollow-up period, 22 (37%) demonstrated a progression of their disease. Despite these results, they concluded that with clinical follow-up most asymptomatic patients with 10 HPT could be monitored safely without parathyroidectomy. The authors commented that the nonspecific manifestations of 10 HPT were not included in their criteria for symptomatic disease because quantitative measures of these manifestations were not yet available. It is, therefore, likely that the number of patients who were symptomatic in

their observation group and the number of patients who demonstrated progression of their disease were underestimated. Silverberg's study, like many others in the literature, illustrates the need for validated instruments that can measure the impact of intervention on these nonspecific manifestations of HPT.24

Utilization of Outcome Patient-Based Instruments In the past, the vague, nonspecific nature of these nonclassic symptoms in HPT limited the ability of clinicians and investigators to quantitate these symptoms with validated outcome tools. Today, patient-based outcome instruments are utilized to provide a better understanding of the impact of a disease on a patient's well-being and of the effectiveness of intervention on a disease process.P-" Several authors have demonstrated an improvement in the ability to concentrate, in cognitive function, and in some of the psychiatric symptoms such as depression following parathyroidectomy by utilizing generic neuropsychiatric assessment toolS. 19,23,25,26 Others have attempted to illustrate the effect that 10 HPT has on the patient's functional health status and well-being as well as demonstrate the impact of surgical intervention on these parameters utilizing a generic QOL instrument, the SF-36 form.21.32-34 The SF-36 form defines eight domains of health status: general health, physical function, physical and emotional role limitations, social function, mental health, bodily pain, and energy or fatigue. Burney and colleagues were the first to utilize the SF-36 form and demonstrate that 10 HPT patients had a marked impairment in their health status and QOL scoring significantly lower in seven of the eight measured domains compared with population norms before parathyroldectomy.P'" Sustained improvement in six of the eight domains was demonstrated following parathyroidectomy. Talpos and coworkers randomly assigned 53 asymptomatic patients to surgery versus observation alone." The authors demonstrated a statistically significant improvement in two of the eight domains of the SF-36 health survey, those of social functioning and emotional role limitations, in the surgically treated group. These studies give insight into the impact of the nonclassic symptoms of HPT on a patient's well-being and how parathyroidectomy can affect the patient's overall health. Although these observations are important, the generic nature of the SF-36 outcome tool makes it less responsive to clinical changes that may have occurred after parathyroidectomy. 3D A disease-specific outcome measurement tool would be more responsive to the subtle clinical changes that have been observed retrospectively by patients and their surgeons.'? A disease-specific outcome tool for HPT has been validated. This instrument, including both the classic and nonclassic symptoms, has been utilized at the University of Calgary as well as in a multicenter trial studying the impact of parathyroidectomy on patients with HPT.16,17,35 Parathyroidectomy Assessment of Symptoms (PAS) scores were obtained for 13 disease-specific items preoperatively, 7 to 10 days postoperatively, at 3 months, and at 1 year. The higher the PAS score, the higher the patients ranked their

Asymptomatic Primary Hyperparathyroidism - -

experience of the symptom. We found that the 10 HPT patients were more symptomatic preoperatively than the thyroid comparison group. Following surgical intervention, the HPT patients experienced a significant decrease in their PAS scores in the first study period and this decreasing trend continued out to 1 year. 16•17,35 In contrast, the thyroid comparison group demonstrated no change in their PAS scores throughout the study (Fig. 44-1). In a further subset analysis of the University of Calgary's patients, Sywak and coworkers found that 22 of 117 patients with 10 HPT who underwent successful parathyroidectomy had none of the NIH criteria for parathyroidectomy and by definition were free of all classic symptoms." The preoperative PAS scores were equally high in both the 22 patients without NIH criteria for surgery and the 95 patients in whom at least one of the NIH criteria was present. More important, both of these 10 HPT groups were significantly more symptomatic preoperatively than the nontoxic thyroid comparison group. AlII HPT patients reported a significant improvement in their symptom scores after parathyroidectomy (Fig. 44-2). Looking specifically at the nonclassic symptoms of fatigue, depression, irritability, mood swings, and forgetfulness, we found that all of these symptoms improved at l-year follow-up in the 10 HPT patients, in contrast to no change demonstrated in these symptoms in the thyroid comparison group (Fig. 44-A and B). We concluded that the so-called asymptomatic patients were indeed suffering from reversible, nonspecific manifestations of the disease and felt the guidelines for parathyroidectomy should be broadened to include the nonclassical manifestations of 1 HPT. 0

0

Treatment of Asymptomatic Hyperparathyroidism The changing presentation of 10 HPT is a result of the increased recognition of a milder form of the disease. The intention of the NIH consensus guidelines for parathyroidectomy was to

FIGURE 44-1. The Parathyroidectomy Assessment of Symptoms (PAS) scores for primary hyperparathyroidism (HPT).The HPT patients were significantly more symptomatic than the thyroid comparison group preoperatively (P < .05). After surgery, the HPT patients demonstrated a significant decrease in their PAS scores (P < .05). The thyroid comparison group demonstrated no change in their PAS scores throughout the study.

421

FIGURE 44-2. The Parathyroidectomy Assessment of Symptoms (PAS) scores for primary hyperparathyroidism (HPT). Group A had at least one of the National Institutes of Health (NIH) criteria for parathyroidectomy present preoperatively. Group B patients had none of the NIH criteria present and were "asymptomatic." Group C consisted of the thyroid comparison group. Groups A and B were significantly more symptomatic than group C preoperatively (P < .05). After surgery, there was no difference in the PAS scores between any of the three groups.

help guide the clinician to the appropriate treatment for patients with mild 10 HPT.1O Parathyroidectomy remains the only definitive treatment of HPT, reversing the manifestations of the disease and correcting the biochemical abnormalities in over 95% of patients. 9•36,37 There is little debate about the need for parathyroidectomy in overtly symptomatic patients. Other criteria developed at the NIH conference included age younger than 50, marked hypercalcemia (>2.85 mmollL), marked hypercalciuria (>10 mmol/ day), reduction in creatinine clearance, and bone loss more than 2.5 standard deviations compared to healthy controls. These criteria were thought to reflect the physiologic end-organ effects of HPT and thus were likely to identify the patients at risk for developing complications of the disease. Additional criteria for surgery that are utilized by some authors include vertebral bone osteopenia, vitamin D deficiency, recent fracture history, and perimenopausal status for women.F Although rare, there are patients with 10 HPT in whom vertebral osteopenia is more marked than cortical bone loss. Parathyroidectomy has been shown to result in a significant improvement in vertebral bone density and only a modest increase in cortical bone density at lO-year follow-up.P-'? It appears that the patients with significant vertebral osteopenia would benefit the most from parathyroidectomy. Receptors for vitamin D metabolites in the parathyroid glands have been shown to suppress parathyroid hormone (PTH) secretion. It has been postulated that vitamin D deficiency results in even higher PTH levels in patients with HPT. Correcting the vitamin D deficiency may be associated with a worsening hypercalcemia, and thus these patients would benefit from parathyroidectomy before addressing their vitamin D deficiency.P'" Although the increased risk of fracture in HPT is not clearly established in the literature, fractures, particularly cortical fractures, suggest an accelerated course of the disease and therefore

422 - - Parathyroid Gland

FIGURE 44-3. The item-specific Parathyroidectomy Assessment of Symptoms (PAS) scores for the nonspecific symptoms of hyperparathyroidism (HPT). A, PAS scores of the HPT patients, ~emonsr:ating a s~gnifi~ant improvement i~ all five items at I-year follow-up (P < .05). B, PAS scores of the thyroid patients, demonstratmg no difference m their scores for all five Items at I-year follow-up.

have been utilized as an indication for surgery by some authors. 12,41-44 Using the NIH definition of symptomatic disease, approximately 50% of patients with 10 HPT have at least one of the NIH criteria for parathyroidectomy," For the remaining 50% of patients, some authors have suggested conservative management with yearly monitoring of physiologic parameters such as serum calcium, BMD, and renal function. 6,11,13.28,45 In the prospective trial involving 10 HPT patients randomly assigned to surgery versus observation, Silverberg and colleagues found that 37% (22 of 60) of the observation group demonstrated progression of their disease." The majority of these patients were found to have a decrease in their BMD over time, in contrast to the parathyroidectomy group, who demonstrated a significant increase in their BMD. Of the 60 patients in the observation arm, 52 were considered asymptomatic. At 10-year follow-up, 38 of these asymptomatic patients demonstrated no significant progression of their disease. This study illustrated that there is a subgroup of patients with 10 HPT that, when followed closely, demonstrates little progression in the physiologic parameters affected by HPT, such as BMD and renal function. It is, however, likely that the investigators have underestimated the population of symptomatic patients and failed to study the impact of the nonspecific symptoms on the patients overall. There continues to be considerable debate among surgeons and endocrinologists concerning the appropriate treatment of mild, nonprogressive 10 HPT. Outcome studies that assess the impact of parathyroidectomy beyond the physiologic parameters of the disease have clearly demonstrated an improvement in the patients' well-being and general health. These studies, however, have been for the most part surgical studies and, because of the inherent referral basis, still do not clearly resolve the debate. Until a randomized study is performed that includes both classic and nonclassic symptoms and measures not only the impact on the physiologic parameters but also the impact on the patient's healthrelated QOL, the debate over the management of 10 HPT will continue.

Summary The clinical manifestations of 10 HPT have evolved during the past 4 decades. Today, fewer than 20% of patients suffer from the classic symptoms of 10 HPT initially described in the 1920s to 1940s. Many patients today suffer from vague, nonspecific, but nonetheless real manifestations of the disease. It appears from the data achieved with patient-based outcome instruments that very few patients suffering from 10 HPT are truly asymptomatic. More important, many of these nonclassic symptoms improve after parathyroidectomy. It, therefore, becomes important for the primary care clinician not only to assess the physiologic parameters of 1 HPT but also to be aware of the expanding definition of symptoms associated with this disease. With the broadened guidelines for parathyroidectomy, it appears that the majority of patients with 10 HPT require parathyroidectomy and, more important, benefit from such intervention. 0

REFERENCES 1. Welboum RB. The History of Endocrine Surgery. New York, Praeger, 1990. 2. Mandl F. Therapeutischer Veruch bei Osteitis fibrosa generalisata mittels Exstirpation enies Epithelkorperchen tumors. Wien Klin Wochenschr 1925;50:1343. 3. Albright F. A page out of the history of hyperparathyroidism. J Clin Endocrinol 1948;8:637. 4. Sivula A, Ronni-Sivula H. The changing picture of primary hyperparathyroidism in the years 1956-1966. Ann Chir Gynaecol 1984; 73:319. 5. Heath H III, Hodgson SF, Kennedy MA. Primary hyperparathyroidism. Incidence, morbidity, and potential economic impact in a community. N Engl J Med 1980;302:189. 6. Silverberg SJ, Bilezikian JP, Bone HG, et aI. Therapeutic controversy therapeutic controversies in primary hyperparathyroidism. J Clin Endocrinol Metab 1999;84:7:2275. 7. Walgenbach S, Hommel G, Junginger T. Outcome after surgery for primary hyperparathyroidism: Ten-year prospective follow-up study. World J Surg 2000;24:564. 8. SoreideJA, van Heerden JA,Grant CS, La CY.Characteristicsof patients surgically treated for primary hyperparathyroidism with and without renal disease. Surgery 1996;120:1033.

Asymptomatic Primary Hyperparathyroidism - - 423 9. Eigelberger MS, Clark OH. Surgical approaches to primary hyperparathyroidism. Endocrinol Metab Clin North Am 2000;29:479. 10. Diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus development conference statement. Ann Intern Med 1991;114:593. lOa. Bilezikian JP, Potts IT, Fuleihan G, et aI. Summary statement from workshop on asymptomatic primary hyperparathyroidism: A perspective for the 21st century. J Clin Endocrinol Metab 2002;87:5353-5361. II. Rao OS. Parathyroidectomy for asymptomatic primary hyperparathyroidism (PHPT): Is it worth the risk? J Endocrinol Invest 200 I; 24: 131. 12. Bilezikian JP. Primary hyperparathyroidism. When to observe and when to operate. Endocrinol Metab Clin North Am 2000;29:465. 13. Silverberg SJ, Bilezikian JP. Evaluation and management of primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81:2036. 14. Silverberg SJ, Bilezikian JP. Primary hyperparathyroidism: Still evolving? J Bone Miner Res 1997;12:856. 15. Hasse C, Sitter H, Bachmann S, et al. How asymptomatic is asymptomatic primary hyperparathyroidism? Exp Clin Endocrinol Diabetes 2000; 108:265. 16. Pasieka JL, Parsons LL, Demeure MJ, et al. A patient-based surgical outcome tool demonstrating improvement of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942. 17. Pasieka JL, Parsons LL. Prospective surgical outcome study of relief of symptoms following surgery in patients with primary hyperparathyroidism. World J Surg 1998;22:513. 18. Chan AK, Duh Q, Katz MH, et al. Clinical manifestations of primary hyperthyroidism before and after parathyroidectomy. Ann Surg 1995;222: I. 19. Prager G, Kalaschek A, Kaczirek K, et al. Parathyroidectomy improves concentration and retentiveness in patients with primary hyperparathyroidism. Surgery 2002; 132:930. 20. Colliander EB, Strigard K, Westblad P, et al. Muscle strength and endurance after surgery for primary hyperparathyroidism. Eur J Surg 1998;164:489. 21. Burney RE, Jones KR, Christy B, Thompson NW. Health status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels. Surgery 1999;125:608. 22. Sywak MS, Knowlton ST, Pasieka JL, et al. Do the National Institutes of Health consensus guidelines for parathyroidectomy predict symptom severity and surgical outcome in patients with primary hyperparathyroidism? Surgery 2002;132:1013. 23. Solomon BL, Schaaf M, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med 1994;96:101. 24. Okamoto T, Gerstein HC, Obara T. Psychiatric symptoms, bone density and non-specific symptoms in patients with mild hypercalcemia due to primary hyperparathyroidism; A systematic overview of the literature. Endocr J 1997;44:367. 25. Ronni-Sivula H, Sivula A. Long-term effect of surgical treatment on the symptoms of primary hyperparathyroidism. Ann Clin Res 1985;17:141. 26. Joborn C, Hetta J, Johansson H, et al. Psychiatric morbidity in primary hyperparathyroidism. World J Surg 1988;12:476.

27. Lundgren E, Ljunghall S, Akerstrom G, et al. Case-control study on symptoms and signs of 'asymptomatic' primary hyperparathyroidism. Surgery 1998;124:980. 28. Silverberg SJ, Shane E, Jacobs TP, et al. A IO-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249. 29. Maloney K, Chaiken BP. An overview of outcomes research and measurement. J Healthc Qual 1999;21:4. 30. Lohr KN. Health Outcomes methodology symposium: Summary and recommendations. Med Care 2000;38(9 Suppl):1Il94. 31. Wright JG. Outcomes research: What to measure. World J Surg 1999; 23:1224. 32. Talpos GB, Bone HG III, Kleerekoper M, et aI. Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: Patient description and effects on the SF-36 health survey. Surgery 2000;128:1013. 33. Burney RE, Jones KR, Coon JW, et al. Assessment of patient outcomes after operation for primary hyperparathyroidism. Surgery 1996;120:1013. 34. Burney RE, Jones KR, Peterson M, et al. Surgical correction of primary hyperparathyroidism improves quality of life. Surgery 1998;124:987. 35. Pasieka JL, Parsons LL. A prospective surgical outcome study assessing the impact of parathyroidectomy on symptoms in patients with secondary and tertiary hyperparathyroidism. Surgery 2000; 128:531. 36. Kearns AE, Thompson GB. Medical and surgical management of hyperparathyroidism. Mayo Clin Proc 2002;77:87. 37. Howe JR. Minimally invasive parathyroid surgery. Surg Clin North Am 2000;80:1399. 38. Silverberg SJ, Gartenberg F, Jacobs TP, et al. Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism. J Clin Endocrinol Metab 1995;80:729. 39. Silverberg SJ, Locker FG, Bilezikian JP. Vertebral osteopenia. A new indication for surgery in primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81:4007. 40. Silverberg SJ, Shane E, Dempster Ow. The effects of vitamin 0 insufficiency in patients with primary hyperparathyroidism. Am J Med 1999;107:561. 41. Larsson K, Ljunghall S, Krusemo UB, et al. The risk of hip fractures in patients with primary hyperparathyroidism. J Intern Med 1993;234:585. 42. Kenny AM, MacGillivary DC, Pibeam CC, et al. Fracture incidence in postmenopausal women with primary hyperparathyroidism. Surgery 1995;118: 109. 43. Melton LJ, Atkinson EJ, O'Fallon WM, Heath H. Risk of age related fractures in patients with primary hyperparathyroidism. Arch Intern Med 1992;152:2269. 44. Vestergaard P, Molerup C, Frokjaer V, et al. Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 2000;321 :598. 45. Davies M, Fraser w.o, Hosking OJ. The management of primary hyperparathyroidism. Clin Endocrinol (Oxf) 2002;57:145.

Normocalcemic Hyperparathyroidism Jack M. Monchik, MD, FACS

Hypercalcemia as manifested by an elevated total serum calcium has traditionally been an important parameter in the diagnosis of primary hyperparathyroidism (PHPT). Initial studies of patients with PHPT stressed the rather constant elevation of the total serum calcium in this entity. Intermittent or no elevation of the total calcium was considered to be rare, if not impossible.l' Subsequent reports have identified patients with PHPT with subtle hypercalcemia defined as intermittent, minimal, or no elevation of the total calcium. For the purpose of this chapter, these patients are considered to have normocalcemic hyperparathyroidism. Most of these patients have renal stone disease and, to a much lesser degree, skeletal abnormalities.f" The introduction of bone densitometry with dual energy x-ray absorptiometry (DEXA) scans for screening for osteoporosis has identified an additional group of patients with normocalcemic hyperparathyroidism. This diagnosis of normocalcemic hyperparathyroidism is a challenge that must be considered in all patients with metabolic complications of PHPT. Solving this diagnostic problem is dependent on an understanding of calcium metabolism.

Distribution of Calcium in the Body Bone accounts for 98% of the calcium content in the body. Calcium in bone is present largely in the form of hydroxyapatite crystals, which are relatively insoluble. One percent of the total body calcium is in a soluble form in extracellular and intracellular fluid compartments, and another 1% is freely exchangeable within extracellular fluid." Calcium in serum is present in three distinct fractions in equilibrium. Figure 45-1 graphically displays the approximate distribution of calcium in serum. The ionized and complexed calcium together make up the ultrafiltrable fraction. Ultrafiltrable calcium represents about 50% of the total serum calcium. Ionized calcium accounts for 90% of the ultrafiltrable calcium and about 45% of the total serum calcium.

424

Complexed calcium is that fraction of the ultrafiltrable component that is ionically bound to citrate, phosphate, and carbonate, which represents approximately 10% of the ultrafiltrable calcium." Protein-bound calcium dependent on pH and temperature represents about 50% of the total serum calcium. Eighty percent of the protein-bound calcium is bound to albumin and 20% is bound to globulin; therefore, hypoalbuminemia can significantly lower the total serum calcium. The total serum calcium is reduced 0.8 to 1.0 mg/dL for each I-g/IOO mL reduction in the serum albumin. to

Calcium Homeostasis Calcium homeostasis is maintained by the complex interrelationship of parathyroid hormone (PTH), vitamin D and its derivatives, and calcitonin. The polypeptide PTH contains 84 amino acids. Once secreted by the parathyroid glands, it undergoes immediate degradation into the amino (N) and carboxyl (C) terminal fragments. The N-terminal fragment is biologically active but is rapidly cleared from the circulation, whereas the C-terminal fragment is biologically inert and is predominantly cleared from the circulation by the kidney. This fragment persists for a longer period in the circulation, particularly in patients with renal failure. 11-13 Intact PTH (iPTH), the 1-84 molecule, is the major circulating form of biologically active PTH. Most of the currently used serum PTH assays measure iPTH.14 The secretion of PTH is regulated by serum ionized calcium acting through a sensitive calcium-sensing receptor that is highly expressed on the surface of the parathyroid cells. Activation of this receptor by a small increase in ionized calcium activates second messengers such as intracellular calcium and inositol through one or more guanine nucleotidebinding (G) proteins to inhibit PTH secretion. Deactivation of this receptor by a small decrease in serum ionized calcium results in stimulation of PTH. Ionized calcium is, therefore, considered to be the physiologically active component of the total serum calcium. IS The parathyroid cells also have a

Normocalcemic Hyperparathyroidism - - 425

PROTEIN BOUND 50%

Bound to Globulin 20%

ULTRAFILTRABLE 50%

IONIZEDCALCIUM 45%

Complexed 10%

FIGURE 45-1. Distribution of calciumin serum.

vitamin D receptor. The binding of calcitriol (l,25-dihydroxyvitamin D) inhibits PTH secretion." Hyperphosphatemia stimulates PTH secretion primarily through induction of hypocalcemia but to a lesser extent through direct stimulation, particularly in patients with advanced renal failure. The major target organs for PTH are the kidneys, skeletal system, and intestine. PTH functions by binding to receptor sites in bone and kidney, resulting in stimulation of production of cyclic adenosine monophosphate (cAMP), which acts to carry out the cellular response of that specific target tissue.'? The predominant response by the kidney to PTH is to increase the tubular resorption of calcium and to decrease the tubular resorption of phosphorus.P:'? The other important function of PTH on the kidney is to increase the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which acts to increase the intestinal absorption of calcium." The action of PTH on the bone to regulate serum calcium is through the remodeling effect of osteoclast and osteoblast activity. The osteoblasts and their precursor cells in bone have a PTH receptor site, and binding to this site results in the production of cAMP. The osteoclasts do not have a PTH receptor site but are stimulated indirectly through the cAMP response in the osteoblasts." Coordinated actions of PTH on bone, kidney, and intestine result in an increase flow of calcium into the extracellular fluid and an increase in the serum calcium. PTH provides the predominant means of immediate regulation of the extracellular calcium. Although physiologically important, vitamin D action affects day to day calcium balance as opposed to the more immediate direct action of PTH.17 Calcitonin has a much smaller role in calcium homeostasis. Calcitonin is secreted by the parafollicular cells of the thyroid and inhibits bone resorption. Extremely high levels of calcitonin found in medullary carcinoma of the thyroid do not result in hypocalcemia.P

Ionized Calcium The measurement of ionized calcium appears to have a major role in the identification of symptomatic patients with PHPT with minimal, intermittent, or no elevation of the total calcium. 6,7,23 Ionized calcium is measured with a calciumselective ion flow-through electrode system.>' This system for measuring ionized calcium was first introduced in 1967 and has since undergone several design changes that have resulted in improved precision. Previous articles and continuing experience indicate that the serum ionized calcium is superior to total calcium in detecting PHPT in patients with intermittent, minimal, or no elevation of the total calcium. Ionized calcium is of no added benefit for diagnostic purposes in patients with elevated total serum calcium. Hypersecretion of PTH increases serum calcium by increasing the tubular resorption of calcium, increasing the net bone resorption and, to a lesser extent, increasing the intestinal absorption of calcium. One can justifiably question why total calcium is not increased in all patients with PHPT, assuming a normal serum albumin and no pancreatitis, increased phosphate intake, or hypomagnesemia, factors known to cause a decrease in the total serum calcium. Some authors have attributed the normal total serum calcium in normocalcemic hyperparathyroidism to an increased ratio of ionized and ultrafiltrable calcium to total calcium compared to normal individuals. Elevated serum PTH has been postulated to decrease the binding of calcium to protein and therefore increases ionized calcium at the expense of the protein-bound fraction. 6,23.25 An alternative explanation postulated for normocalcemia in patients with PHPT is a generalized resistance to the action of PTH on bone and kidney."

Ultrafiltrable Calcium Ultrafiltrable calcium has also been used for identification of normocalcemic PHPT. A comparative study of ultrafiltrable ionized and total calcium in symptomatic patients with intermittent or no elevation of the total calcium showed that ionized calcium was a more sensitive indicator of PHPT in this group of patients.F In this study, ultrafiltrable calcium was a more sensitive indicator of hypercalcemia than total calcium but did not reach statistical significance.

Renal Calculi Most patients with normocalcemic hyperparathyroidism are identified because of renal calculi and many of these patients have hypercalciuria. Most patients with renal calculi and hypercalciuria, however, have idiopathic hypercalciuria, a condition also associated with normocalcemia. Patients with idiopathic hypercalciuria have 24-hour urinary calcium values of 250 mg per 24 hours or higher in females, 300 mg per 24 hours or higher in males, or 4 mg/kg in males or females on a daily intake of 1000 mg of calcium.i" These criteria are useful even when diet is uncontrolled because urine calcium excretion varies only slightly in normal

426 - - Parathyroid Gland

FIGURE 45-2. Concurrent values of ionized and total calcium in a patient with renal calculi and intermittent elevation of the total calcium level. A parathyroidadenomaweighing 200 mg was removed at surgery. (From McLeod MK, Monchik JM, Martin HE The role of ionized calcium in the diagnosis of subtle hypercalcemia in symptomatic primary hyperparathyroidism. Surgery 1984;95:667.)

CONSECUTIVE CONCURRENT VALUES (different days)

individuals when dietary calcium intake is widely altered.P A small fraction of these patients with hypercalciuria have normocalcemic HPTH.3o Figure 45-2 shows concomitant ionized and total calcium values in a patient with nephrolithiasis and intermittent elevation of the total calcium, and Figure 45-3 demonstrates a patient with renal calculi with no elevation of the total calcium. Since the original description of idiopathic hypercalciuria by Albright and associates in 1953, several hypothesis have been advanced to explain this entity." Increased intestinal absorption, diminished tubular resorption of calcium resulting in a renal calcium leak, and a primary phosphate leak have been postulated.P'>' In practice, the classification of idiopathic hypercalciuria stone formers into renal calcium leak, primary intestinal hyperabsorption, or primary phosphate leak is time consuming, expensive, not reproducible, and does not appear to influence the outcome of treatment. The differentiation of hypercalciuric stone formers with normocalcemic hyperparathyroidism from those with one of the subtypes of idiopathic hypercalciuria is of prime importance because of the success of parathyroid surgery in

preventing further stone formation. Failure to accurately separate stone-forming patients with normocalcemic hyperparathyroidism from those with idiopathic hypercalciuria has led to inappropriate neck exploration. Parathyroid surgery in patients with idiopathic hypercalciuria has resulted in finding no abnormal parathyroid tissue and continued stone formation." The renal calcium leak subtype of idiopathic hypercalciuria can have an elevated serum PTH secondary to compensation by the parathyroid glands to increased renal loss of calcium. The serum ionized or total calcium is not elevated in this or other subtypes of idiopathic hypercalciuria." The absence of an elevated serum ionized or total calcium makes further testing necessary to distinguish this entity from normocalcemic hyperparathyroidism. This subtype of idiopathic hypercalciuria can sometimes be separated from normocalcemic hyperparathyroidism by treatment with a thiazide diuretic. The thiazide diuretic reduces the excessive loss of urinary calcium, causing the serum calcium to rise slightly but not above, the normal range, and resulting in a decrease of the serum PTH into the normal range.F-"

TOTAL CALCIUM (mg %)

12.0 11.0 10.0

9.0~ 8.0

FIGURE 45-3. Concurrent values of ionized and

IONIZED CALCIUM (mg %)

PATH.: Adenoma

7.0

6.0

•

•

•

5.0~~R_~_[E2ill~~_R

4.0

3.0..l....--+---+---I----I--~I--~I--~-__+-__+-~

•

• NORMAL RANGE

•

•

•

1 2 3 4 5 6 7 8 CONSECUTIVE CONCURRENT VALUES (different days)

• 9

~

• 10

total calcium levels in a patient with renal calculi and all normal total calcium levels. A parathyroid adenoma weighing 440 mg was removed at surgery. (From McLeod MK, Monchik JM, Martin HE The role of ionized calcium in the diagnosis of subtle hypercalcemia in symptomatic primary hyperparathyroidism. Surgery 1984;95:667.)

Normocalcemic Hyperparathyroidism - - 427

I have shown that ionized calcium is more sensitive than total calcium in diagnosing PHPT in patients with nephrolithiasis and minimal or no elevation of the total calcium.i-" We recommend three consecutive days of ionized and total calcium as a screening study for hyperparathyroidism in patients with nephrolithiasis with minimal or no elevation of the serum total calcium. A serum iPTH should be done on at least one day. An elevated iPTH may be the only clue to the diagnosis of normocalcemic hyperparathyroidism.26

Bone Disease Although historically most patients with normocalcemic hyperparathyroidism were identified because of renal calculi, an increasing number of patients have recently been identified by screening patients for osteoporosis with dual-energy x-ray absorptiometry (DEXA) scans. Traditionally, hyperparathyroidism was associated with overt bone disease in a significant number of patients. This traditional bone disease was frequently symptomatic and associated with radiologic findings such as bone cysts, brown tumors of the long bones, subperiosteal resorption of the distal phalanges and clavicles, and "salt and pepper" demineralization of the skull. The increased awareness of the diagnosis of PHPT and multichannel blood screening studies have resulted in an earlier diagnosis of this condition and considerably fewer patients with these classic bone findings. The introduction of screening for osteoporosis with DEXA scans has identified an increasing number of patients with severe osteopenia or osteoporosis." Hyperparathyroidism is considered an important cause of osteoporosis as a consequence of its known catabolic effect promoting osteoclast activity and bone resorption. The human skeleton consists of cortical and trabecular bone. Cortical bone is the compact layer, which predominates in the shafts of the long bones. Trabecular bone is composed of a series of thin plates, which form the interior meshwork of bones, particularly the vertebrae, pelvis, and end of long bones. The major site of bone mineral loss in PHPT appears to be cortical bone; therefore, the DEXA scan of the distal radius is more sensitive than that of the spine or hip in detecting bone loss due to PHPT. 4o The diagnosis of PHPT should be pursued in patients with severe osteopenia or osteoporosis because of the favorable outcome of parathyroid surgery. Correction of PHPT results in stopping the accelerated bone loss attributable to the hyperparathyroidism and a 10% to 12% increase in bone mass in trabecular as well as in cortical bone. This increase lasts at least a decade after successful parathyroid surgery.'" Patients with a low vertebral bone density demonstrated a marked increase in bone density after surgery. This group experienced a 20% increase in vertebral bone density over a 4-year period." This indicates that remineralization after surgical correction of PHPT involves a generalized increase in bone mass, not just cortical bone mass. Minimal, intermittent, or no elevation of the total calcium in patients with PHPT and osteoporosis is not uncommon. A study at Rhode Island Hospital identified 64 patients from

January 1995 to June 1999 with osteoporosis defined by a t score of 2.5 or less who underwent parathyroid surgery. Fifteen (23%) of these patients had 40% of their preoperative total calcium values within the normal range and 6 (9%) of these patients had no preoperative elevated total calcium, These 6 patients had a total of 44 concomitant serum ionized and total calcium measurements; 42 of the ionized calcium values were elevated and 2 were normal. Each of these patients had at least one elevated value for iPTH.43 Patients with severe osteopenia or osteoporosis who do not have an elevated serum total calcium should be screened on 3 consecutive days for serum ionized and total calcium and a serum iPTH on at least 1 day to minimize the risk of missing the diagnosis of normocalcemic hyperparathyroidism.

Diagnostic Studies All patients with recurrent renal calculi and or severe osteopenia or osteoporosis should be screened for PHPT because of the benefits provided by surgical correction. Patients with the combination of an elevated serum ionized calcium and an elevated iPTH have hyperparathyroidism, even in the absence of elevated serum total calcium. An elevated serum iPTH in the absence of elevated ionized or total calcium does not confirm the diagnosis of normocalcemic hyperparathyroidism. The iPTH can be elevated in the absence of an elevated ionized or total calcium in the renal leak form of idiopathic hypercalciuria and vitamin D deficiency.36.44 The iPTH may return to normal with treatment with a thiazide diuretic in the renal leak form of idiopathic hypercalciuria. Patients with vitamin D deficiency have a low 25-hydroxyvitarnin D level, and their serum PTH cannot be corrected by vitamin D replacement. In patients in whom the combination of 3 consecutive days of concomitant serum ionized and total calcium and intact parathyroid hormone screening cannot provide a definitive diagnosis, the oral calcium loading study may be helpful. 26.44 An elevated serum iPTH with no elevation in the ionized or total calcium is not uncommon. In a study of 178 patients with PHPT 27 patients (15%) had no elevation of the total or ionized calcium. The diagnosis in these patients was established by an oral calcium loading study showing the serum ionized calcium increasing to a supranormal value with only a minimal decrease in iPTH. 26 An oral calcium loading study can be accomplished in an office setting. The patient is given an oral dose of 1000 mg of elemental calcium. A baseline serum iPTH is obtained prior to giving the oral calcium load, and subsequent serum iPTH values are obtained at 30, 60, and 120 minutes after giving the oral calcium load. Figure 45-4 illustrates the suppression of iPTH in 18 normal controls, which shows that all but 2 of these patients exhibited suppression to 70% or more of the baseline level of iPTH at 60 minutes after the oral calcium load. Figure 45-5 shows the results of the oral calcium loading study in 6 patients with recurrent renal calculi with normocalcemic or subtle hyperparathyroidism. Five of these 6 patients did not suppress to less than 70% of the baseline iPTH. These results and our continuing

428 - - Parathyroid Gland IRMA PTH (Percent of Baseline)

140 120

100

IRMA PTH (Percent of Baseline) 140120 100

80

80

60

60

40

40

20

20

0-L...--+-------1f------+--------i BASE LINE 30 60 120 TIME (Minutes)

0-4----1-------l.----..+-------j BASE LINE 30 60 120 TIME (Minutes)

FIGURE 45-4. Percentage of change in intact parathyroid hormone values expressed as a percentage of the baseline values during the oral calcium loading test in 18 normal control subjects. IRMA PTH = immunoradiometric assay of parathyroid hormone, (From Monchik JM, Lamberton RP, Roth U. Role of the oral calcium loading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. Surgery 1992;112:1103.)

FIGURE 45-5. Percentage of change in intact parathyroid hormone values expressed as a percentage of the baseline values during oral calcium loading in six patients with nonnocalcemic hyperparathyroidism. IRMA PTH = immunoradiometric assay of parathyroid hormone. (FromMonchikJM, LambertonRP, Roth U. Role of the oral calcium-loading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. Surgery 1992;112:1103.)

experience with the oral calcium-loading study emphasize that no single test can be expected to reliably identify all patients with normocalcemic hyperparathyroidism. Subsequent unpublished data from our institution have provided further confirmation that a completely normal suppression of iPTH can occur with oral calcium loading in patients with PHPT.

ionized calcium. All patients with recurrent renal calculi, severe osteopenia, or osteoporosis should be screened for PHPT because of the benefits of surgical correction. We suggest screening these patients with three consecutive days of serum ionized and total calcium and intact parathyroid hormone on one day.

Summary This chapter focuses on the physiology of calcium metabolism and the static and dynamic testing pertinent to the diagnosis of normocalcemic hyperparathyroidism in symptomatic patients with renal calculi or osteoporosis. An important group of patients with PHPT and recurrent renal calculi or severe osteopenia or osteoporosis has minimal, intermittent, or no elevation of the serum total calcium. The ionized calcium has been shown to be a more sensitive indicator of PHPT in this situation than total calcium. Patients with an elevated serum ionized calcium and iPTH have PHPT even in the absence of elevated serum total calcium. Treatment with a thiazide diuretic or correction of vitamin D deficiency may be necessary to separate patients with normocalcemic hyperparathyroidism from those with the renal leak form of idiopathic hypercalciuria or vitamin D deficiency. The oral calcium loading study can be helpful in identifying normocalcemic hyperparathyroidism in patients with normal or no elevation of the total calcium or

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28.

Duncan's Diseases of Metabolism. Philadelphia, WB Saunders, 1974, P 1225. Habener JF, Segre GV, Powell D, et al. Immunoreactive parathyroid hormone in circulation of man. Nature 1972;238: 152. Segre GV, Habener JF, Powell D. et al. Parathyroid hormone in human plasma: Immunochemical characterization and biological implications. J Clin Invest 1972;51:3163. Nussbaum SR, Zabradnik RI, Lavigne JR, et al. Highly sensitive twosite immunoradiometric assay of parathyrine and its clinical utility in evaluating patients with hypercalcemia. Clin Chem 1987;33:1364. Brown EM, Pollak M, Seidman CE, et al. Calcium ion-sensing cellsurface receptors. N Engl J Med 1995;333:234. Neveh-Many T, Friedlaender MM, Mayer H, Silver J. Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not calcitonin mRNA in vivo in the rat: Dominant role of 1,25dihydroxyvitarnin D. Endocrinology 1989;125:275. Nordin BEC, Marshall DH, Peacock M, et al. Plasma calcium homeostasis. In: Talmage RV, Owen M, Parsons JA (eds), CalciumRegulating Hormones. New York, Excerpta Medica, 1975, P 239. Spiegel AM, Gierchik P, Levine MA, et al. Clinical implications of guanine nucleotide-binding proteins as receptor-effector couplers. N Engl J Med 1985;312:26. Michelangoli VP, Hung NH, Martin TJ. States of activation of chick kidney adenylate cyclase induced by parathyroid hormone and guanyl nucleotides. J Endocrinol 1977;72:69. Mawer EB, Backhouse J, Hill LF, et al. Vitamin D metabolism and parathyroid function in man. Clin Sci Med 1975;48:349. McSheehy PMJ, Chambers TJ. Osteoblastic cells mediate osteoclastic responsiveness to parathyroid hormone. Endocrinology 1986;118:824. Friedman J, Raisz LG. Thyrocalcitonin inhibitor of bone resorption in tissue culture. Science 1965;150:1465. Monchik JM, Martin HE Ionized calcium in the diagnosis of primary hyperparathyroidism. Surgery 1980;88: 185. Moore EW. Ionized calcium in normal serum ultrafiltrate and whole blood determined by ion exchange electrodes. J Clin Invest 1976;42:318. Yendt ER, Gange RJA. Detection of primary hyperparathyroidism with special reference to its occurrence in hypercalciuric females with normal or borderline serum calcium. Can Med Assoc J 1968;98:331. Maruani G, Hertig A, Paillard M, Houillier P. Normocalcemic primary hyperparathyroidism: Evidence for a generalized target-tissue resistance to parathyroid hormone. J Clin Endocrinol Metab 2003;88:4641. Forster J, Monchik JM, Martin HE A comparative study of serum ultrafiltrable, ionized, and total calcium in the diagnosis of primary hyperparathyroidism in patients with intermittent or no elevations in total calcium. Surgery 1988;104:1137. Hodgkinson A, Pynah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stones of renal origin. Br J Surg 1958;46:10.

29. Peacock M, Hodgkinson A, Nordin BEC. Importance of dietary calcium in the definition of hypercalciuria. BMJ 1967,3:469. 30. Johansson H, Thoran L, Werner L, et al. Normocalcemic hyperparathyroidism, kidney stones, and idiopathic hypercalcuria. Surgery 1975:77:691. 31. Albright F, Henneman P, Benedict PH, et al. Idiopathic hypercalciuria: A preliminary report. Proc R Soc Med 1953;46:1077. 32. Bordier P, Ryckewart A, Gueris J, et al. On the pathogenesis of so-called idiopathic hypercalcuria. Am J Med 1977;63:398. 33. Broadus AE, Dominquez M, Barter FC. Pathophysiological studies in idiopathic hypercalcuria: Use of an oral calcium tolerance test to characterize distinctive hypercalciuric subgroups. J Clin Endocrinol Metab 1978;47:751. 34. Pak CYC, Kaplan R, Bone H, et al. A simple test for the diagnosis of absorptive, resorptive, and renal hypercalciurias, N Engl J Med 1975;292:497. 35. Poole GV, Albertson DA, Myers RT. Normocalcemic hyperparathyroidism revisited. Am Surg 1983;49:668. 36. Coe FL, Caterbury JM, Firpo JJ, et al. Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J Clin Invest 1973; 52:134. 37. Edwards BR, Baer PG, Sutton RAL, et al. Micropuncture study of diuretic effects on sodium and calcium reabsorption in the dog nephron. J Clin Invest 1973;52:2418. 38. Clark OH. Endocrine Surgery of the Thyroid and Parathyroid Glands. St. Louis, CV Mosby, 1985, P 202. 39. Silverberg SJ, Bilezikian JP. Clinical presentation of primary hyperparathyroidism in the United States. In: Bilezikian JP, Marcus R, Levine MA (eds), The Parathyroids, 2nd ed. New York, Academic Press, 2001, p 349. 40. Silverberg SJ, Shane E, Jacobs TP, et al. The natural history of treated and untreated asymptomatic primary hyperparathyroidism: A ten-year prospective study. N Engl J Med 1999;341: 1249. 41. Silverberg SJ, Locker FG, Bilezikian JP. Vertebral osteopenia: A new indication for surgery in primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81:4007. 42. Ledger GA, Burritt, MF, Kao PC, et al. Abnormalities of parathyroid hormone secretion in elderly women that are reversible by short term therapy with 1,25-dihydroxyvitamin D 3 • J Clin Endocrinol Metab 1994;79:211. 43. Monchik JM, Gorgun E. Normocalcemic hyperparathyroidism in patients with osteoporosis. Surgery 2004;136:1242. 44. Monchik JM, Lamberton RP, Roth U. Role of the oral calcium-loading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. Surgery 1992;112:1103.

Localization Studies in Persistent or Recurrent Hyperparathyroidism Jose M. Rodriguez, MD • P. Parrilla, MD

The surgical management of patients with hyperparathyroidism (HPT) is successful in more than 90% of cases.l-' Furthermore, in specialized centers, the morbidity rate of parathyroidectomy is lower than 1%.4-8 Patients with persistent HPT (hypercalcemia persists or recurs within 6 months after surgery) or, less commonly, recurrent HPT (hypercalcemia recurs after >6 months of nonnocalcemia) necessitate reoperation. In these cases, the morbidity rate increases up to 10% for permanent recurrent laryngeal nerve injury and to 35% for hypoparathyroidism.tP A successful neck exploration for HPT is primarily dependent on the experience of the surgeon, the anatomic location of the parathyroid glands (normal or ectopic sites), and the presence of a single adenoma as opposed to multiglandular disease or carcinoma.l" The most common causes of recurrent or persistent disease are unlocated parathyroid adenoma (80%),15,16 undiagnosed second adenoma (~9% of cases),'? misdiagnosis of parathyroid hyperplasia as adenomatous disease, and parathyroid carcinoma. 18 Supernumerary glands account for 15% to 25% of failed cases. 19-21 We found ectopic parathyroid tumors in 5% to 11% of failures (thymus, intrathyroid, undescended, in the retroesophageal space and in the carotid sheath).IO,15,22,23 In these cases of persistent or recurrent HPT, surgical intervention is most difficult because of the loss of normal tissue planes (as also occurs after extensive thyroid surgery) and the possibility that the missed parathyroid gland is situated in an ectopic position. Localization studies in these patients reduce operating time, avoid unnecessary dissection, reduce operative morbidity, and improve the success rate. I,24 In cases of persistent or recurrent HPT, one must first confirm the diagnosis of HPT and review previous surgical and pathology reports. With this information, we can usually determine whether the patient has a single adenoma, a double adenoma, parathyroid hyperplasia or, rarely, a carcinoma. Localization studies can be selected according to availability, cost, and experience.P Surgery for persistent or recurrent HPT should be performed only after positive localization studies. Various localization techniques that are 430

no longer used include esophageal fluoroscopy." cineradi-

ography.'? and thermography-" Currently, we classify localization methods as preoperative (invasive or noninvasive) and intraoperative (Table 46-1),

Noninvasive Preoperative Methods Ultrasonography High-resolution ultrasonography (US) (7.5 or 10 MHz) was introduced by Edis and Evans in 1979. 29 It enables exploration of the thyroid, carotid, and jugular areas and the cervical area between the thyroid cartilage and the sternal margin (Fig, 46-1). The advantages are that it is easy to perform, is well tolerated by the patient, does not require the injection of contrast medium, does not emit radiation, and can be done quickly and inexpensively. Unfortunately, the retroesophageal, retrotracheal, retrosternal, and deep cervical glands are difficult to locate by US. However, intrathyroid adenomas can be localized better with US than with other techniques although they can also be confused with a thyroid nodule. 30-32 The sensitivity of US varies according to the ultrasonographer's experience, the frequency of the transducer, the resolution of the image, and the size of the parathyroid gland.P The sensitivity of US reported in the literature varies greatly, from 22% to 82%.1,10,11,13,15,18,34-42 False-positive results are caused by thyroid nodules (6% to 15% of patients with HPT have associated thyroid lesions),3,33 adenopathy, and even esophageal lesions. Metal clips can make interpretation more difficult. The percentage of false-positive results is usually about 15% to 20%.10,15,30,36,37 Only Carlson and associatesf reported 4% false-positive results, but with a sensitivity of only 22%. Endoscopic US has also been used to locate posterior glands adjacent to the esophagus. Henry" diagnosed 52% of parathyroid tumors using endoscopic US, Catargi and colleaguesv reported the sensitivity of endoscopic US was 71 %, In both studies, endoscopic US was better than

Localization Studies in Persistent or Recurrent Hyperparathyroidism - -

431

usually more frequent than with other techniques and may reach up to 50%.1,34,51

Magnetic Resonance Imaging

conventional US. Color Doppler US has been used in an attempt to differentiate thyroid from parathyroid tumors, depending on vascularity (thyroid lesions and large parathyroid tumors are more vascular). However, as Gooding and Clar06 have reported, no clear differentiation can be established by Doppler US alone.

Computed Tomography Computed tomography (CT) is a less sensitive method than magnetic resonance imaging (MRI). It is relatively expensive, exposes the patient to radiation, and requires the administration of contrast material to obtain the best results. It is useful for ectopic parathyroid glands (retrotracheal, retroesophageal, and mediastinal) but is less effective for those in a normal location. Metal clips can also distort the image. Furthermore, peri thyroid lymphadenopathy and even the existence of tortuous or arteriosclerotic vessels may make localizing abnormal parathyroid glands difficult." The sensitivity of CT reported in the literature ranges from 16% to 70%.10,13,15.18.35-37,39-41,48-50 False-positive results are

FIGURE 46-1. Ultrasonogram showing intrathyroidal parathyroid adenoma.

Although CT and MRI both provide excellent anatomic details, MRI is preferable because it does not require the administration of contrast material, there are no artifacts from the clips left in the neck, and shoulder artifact is not a problem. However, MRI is expensive, A parathyroid tumor usually has a low signal intensity in Tl-weighted imaging (similar to muscle or thyroid) and a high signal intensity (more than or the same as fat) in T2-weighted imaging (Fig. 46_2).48 Not all adenomas have the same image characteristics.P MRI is especially useful for identifying ectopic parathyroid glands. Of 121 patients undergoing reoperation for HPT, MRI located 79% of the ectopic glands and only 59% ofthose were situated in a normal position" Superior parathyroid glands are more difficult to localize because they usually lie posterior to the thyroid at the level of the cricoid cartilage. 53 The sensitivity for MRI is greater than for CT scanning, ranging from 50% to 88%.1,13,15,18,34-38,41,49,54,55 Thyroid abnormalities and enlarged lymph nodes are a frequent cause of false-positive results. 55,56 The most common discernible causes for false-negative MRI imaging were adenomas situated closely adjacent to a thyroid goiter and cases of parathyroid hyperplasia. The results obtained for hyperplasia are worse than parathyroid adenomas, probably because of the size of the gland,35,41.53,57 although not all authors agree." Gadolinium can also improve the differential contrast with the adjacent tissues. 59,60

Thallium 201-Technetium Tc 99m Pertechnetate Scanning Thallium uptake by parathyroid adenomas was initially reported by Fukunaga and associates.s' The clinical application was performed using technetium 99m together with thallium 201. 62,63 Subtraction of the two images obtained help locate the abnormal parathyroid gland or glands. The advantages of thallium 20l-technetium 99m pertechnetate (TI-Tc) scanning are its availability, low risk, minimum

FIGURE 46-2. T2-weighted magnetic resonance image with left upper parathyroid adenoma (arrow).

432 - - Parathyroid Gland irradiation, and low operator dependence. Tumors located in perithyroid areas, especially next to the inferior pole, are localized more effectively.'" Conversely, no more than 50% of glands in the mediastinum are localized. False-negative results also depend on the size of the parathyroid glands, because parathyroids weighing less than 0.5 g are usually not detected. The most common cause of false-positive results was patient motion during examination. Also, thyroid lesions such as adenomas, carcinomas, multinodular goiters, or enlarged lymph nodes also cause false-positive results.f Price,66 in a 1993 review of 1432 patients requiring parathyroid reoperation in whom Tl-Tc scanning was used, found an average sensitivity of 55% (range, 45% to 68%); 12% ofresults were false positive. The sensitivity of Tl-Tc was even lower than 25% in the studies by Miller,36 Doherty," and their coworkers. Tl-Tc scintigraphy was a widely used localization study for parathyroid glands until the introduction of sestamibi scanning.

Technetium 99m Sestamibi Scintigraphy In 1988, Coakley and associates'" reported using technetium 99m sestamibi for cardiac function studies. Chiu and colleagues'< demonstrated the incorporation of technetium 99m into the cytoplasm and mitochondria of mouse fibroblasts in response to certain stimuli. Parathyroid cells have a large amount of mitochondria, which enables technetium 99m sestamibi to enter more intensely into the neighboring thyroid tissue.s? O'Doherty and coworkers" compared technetium 99m sestamibi and thallium 201 uptake and observed a greater uptake per gram of sestamibi in the parathyroid tissue. Recent studies relate the sestamibi uptake with the absence of P-glycoprotein in parathyroid adenomas," or even with the cellular proliferation ratio.P There are three different technetium scanning methods. 1. Single-isotope dual-phase scan. The simplest procedure was described by Taillefer and associates as the double-phase study.73 A single radioisotope scan is performed with cervicothoracic planar imaging at 10 to 15 minutes and also at 2 to 3 hours. For the cervical area, a pinhole collimator can be used selectively to improve the resolution. The late phase (2 to 3 hours) is usually preferable for detecting abnormal parathyroid glands because the thyroid clears the uptake faster than the parathyroid adenomas. 2. Dual-isotope subtraction scan. Tc 99m sestamibi is used in conjunction with another radionuclide specific to the thyroid. Iodine 123 or Tc 99m pertechnetate (low cost and quicker) are used for the thyroid subtraction.Y" 3. Three-dimensional studies. The major drawback of anterior planar views (the most frequently used) is the lack of spatial localization of the uptake. A combination of lateral or oblique planar views may help to find abnormal parathyroid glands from adjacent and/or superimposed strucrures.F:" With the help of the computed reconstruction of sagittal or transverse scans or even with three-dimensional images, single-photon emission computed tomography (SPECT) allows better localization of the uptake. 79-81 This is especially useful in case of a mediastinal location. 82

FIGURE 46-3. Tc 99m sestamibi: left lower parathyroid adenoma and thyroid adenoma follicular (false positive).

The sensitivity reported for sestamibi in persistent or recurrent HPT ranges from 57% to 85%,13.15,18.37-43,50,54,55,83 but most of the series are close to 80%, There are not significant differences between the use of the single-isotope dual-phase and the dual-isotope subtraction scan, but SPECT improves the results. 84 The most common cause of false-positive results is the coexistence of benign thyroid disease (adenomas or multinodular goiter) (Fig. 46-3).85 Also, the presence of follicular,86 papillary," and Hurthle cell thyroid carcinomas." primary thyroid lymphomas." and lymph nodes?" account for false-positive sestamibi results (see Fig. 46-3). Falsenegative results, as in our own experience, are related more to the smaller size of the gland. Intrathyroid, mediastinal (Fig. 46-4), or deep cervical parathyroids can be localized using technetium 99m sestamibi (i.e., its accuracy is not

FIGURE 46-4. Tc 99m sestamibi scan demonstrating a mediastinal parathyroid adenoma.

Localization Studies in Persistent or Recurrent Hyperparathyroidism - -

433

FIGURE 46-5. Undescended parathyroid adenoma in a Tc 99m sestamibi scan.

related to location) (Figs 46-5 to 46-8; see also Figs. 46-3 and 46-4). Sestarnibi is inaccurate in patients with multiple adenomas or parathyroid hyperplasia because often only one of the multiple abnormal glands is identified. Tc 99m tetrofosrnin is another isonitrile derivative of pertechnetate. The uptake of tetrofosrnin in parathyroid tissue is similar to sestarnibi, but the thyroid washout rate is slower.90-93 The diagnostic sensitivity of tetrofosrnin is identical to sestamibi using a dual-tracer subtraction method but is markedly lower with the single-tracer method." Tc 99m furifosrnin is also a useful tracer in parathyroid tumors, but the experience reported is limited."

FIGURE 46-7. Intrathyroid adenoma (Tc 99m sestamibi scan).

In some cases, positron emission tomography (PET) (lsF-fluorodeoxyglucose or lie-methionine) has been used because of its increased uptake in neoplastic tissue. 96-98 The results are good; however, there are a limited number of studies published and the cost of PET scanning is high. The characteristics of the most common noninvasive localization methods are shown in Table 46-2.

Invasive Preoperative Methods Invasive localization studies are indicated when the combined results of the noninvasive tests are negative, equivocal, or conflicting.

FIGURE 46-6. Recurrent hyperparathyroidism in hyperfunctioning parathyroid cyst adenoma in a patient with multiple endocrine neoplasia type 1 (Tc 99m sestamibi scan).

FIGURE 46-8. Sestamibi scan with thymic parathyroid adenoma.

434 - - Parathyroid Gland

Fine-Needle Aspiration Fine-needle aspiration (FNA) of the parathyroid tumor performed under sonographic guidance can improve the results obtained with US. FNA enables cytologic examination of parathyroid hormone (PTH) measurement in the aspirate. When the aspiration is positive for PTH, it confirms the diagnosis of a parathyroid tissue." PTH determination is more helpful than cytologic examination for diagnosing parathyroid lesions because cytologists often have difficulty in differentiating between a parathyroid gland and thyroid tissue, and the sample may also be insufficient.l'" Karstrup and associates'?' diagnosed 100% of the cases by bioassay but only 60% by cytologic examination. McFarlane and colleagues 102 also published excellent results for PTH assay (specificity 100% and sensitivity 70%). Some clinicians have recommended injection of 95% ethanol into parathyroid neoplasms to produce necrosis. Unfortunately, the tumor may recur after the ethanol injection, and recurrent laryngeal nerve injury also occurs. Furthermore, parathyroid tissue is also unavailable for histologic examination or for cryopreservation.

Parathyroid Arteriography Proper parathyroid arteriography includes examination of both thyrocervical trunks (to look for parathyroid glands in the superior mediastinum, tracheoesophageal groove, or intrathyroid or juxtathyroid location glands), the internal mammary arteries (glands in the thymus and anterior mediastinum) and carotids (juxtathyroid or undescended glands), and sometimes the selective catheterization of the superior thyroid artery. Parathyroid adenomas appear highly vascularized and oval or round (see Fig. 46-9). The sensitivity obtained with digital subtraction arteriography is around 60% to 65%; it is a difficult and expensive technique. 15,102,103 In selected cases, it is possible to do an angiographic embolization of the localized adenoma (Fig, 46-9),104

because this helps document the exact location of the parathyroid tumor.I'" Nilsson and coworkers.l'" however, published significant results with sampling from large veins such as the jugular vein, innominate vein, and superior cava. A twofold gradient between the intact parathyroid hormone (iPTH) concentration in peripheral blood and that in the selective venous sample (SVS) establishes the site of the venous drainage of the tumor. The problem arises in cases in which this gradient is not attained and localization is uncertain.l'" The sensitivity of the SVS ranges from 63% to 83%.13,15.37,50,53,83.102,108 Jones and coworkers.l'" from the University of California-San Francisco, reported 64 patients with an exact location in 75% of cases, and the SVS was not useful for the surgeon in only 17% of the cases. This technique is the most sensitive and lateralizes about 80% of parathyroid tumors. 37,107.109 Furthermore, it is just as accurate for mediastinal glands as for cervical glands and depends on gland function rather than gland size. It is also helpful when there is more than one abnormal parathyroid gland and can convert an equivocal noninvasive study into a positive one. The reported sensitivity of localizing studies for persistent or recurrent HPT is shown in Table 46-3. In cases of recurrent HPT after total parathyroidectomy with autotransplant in the forearm, the first localizing study to do is the iPTH gradient. PTH assay in the basilic vein of both arms draining the graft, with or without ischemic

Selective Venous Sampling for Parathyroid Hormone Assay Angiography is performed primarily to outline the ve?ous drainage, and it can obtain a sample for PTH assay. It IS an expensive technique and requires an expert radiologist because it is technically difficult. The samples must be taken as selectively as possible from the smallest venous branches

FIGURE 46-9. Ectopic mediastinal adenoma is shown in an internal mammary arteriogram.

Localization Studies in Persistent or Recurrent Hyperparathyroidism - - 435

blockade, is usually diagnostic when there is at least a twofold increase in relation to the other arnl.llO.lll It is recommended to do at least two positive studies before surgery. Sestamibi, CT scan or MRI, and clinical palpation of the arm may also be necessary. 112 In parathyroid carcinoma, CT and MRI are especially useful for detecting mediastinal and thoracic recurrences." US can be used for detecting cervical parathyroid carcinoma recurrence. Sestamibi allows for whole-body scanning and therefore may detect distant metastases.

Intraoperative Localization Methods Intraoperative Ultrasonography High-resolution intraoperative US may be useful once the peak of the learning curve has been reached and operating time can be reduced significantly. Kern and colleagues" found it to be more effective than any other preoperative technique for intrathyroid or perithyroid glands. The benefit of the routine use of intraoperative US in reoperative parathyroid surgery has not been established.

Radio-Guided Parathyroid Surgery Tc 99m sestamibi is the most common localization test in recurrent parathyroid disease. It is possible to use an intraoperative gamma probe to detect abnormal parathyroid tissue. This method permits minimally invasive surgery (including video-assistedparathyroidectomy). Some authors report excellent resultsll3 ·117; however, longer follow-up and more studies are necessary before this procedure can be applied routinely.

The problems of this approach are false-positive results (thyroid disease), cost, and longer operative time.

Intraoperative PTH Determination of intraoperative PTH (IOPTH) may confirm the removal of the hyperfunctioning parathyroid tissue, thus reducing the operative time. 1I8 . 119 If the basal levels of IOPTH drop more than 50% 10 minutes after parathyroid resection, it is indicative of successful surgery. Irvin and coworkers 120.121 reported a sensitivity of 93% with this method. These results have been confirmed by others," but most patients had single adenomas. Perhaps, in persistent parathyroid hyperplasia or double adenomas, the interpretation of the results is more difficult. Occasionally, the IOPTH drop is less than 50%, especially if the initial basal iPTH levels are not very high. For these reasons, this method needs a careful interpretation by the surgeon, considering also the previous sestamibi imaging and the surgical findings. 113 Injection of methylene blue or toluidine blue is of little value and is not used.

Conclusions Positive localization studies are necessary before neck explorations for persistent or recurrent HPT. Noninvasive imaging methods should be used first, and Tc 99m sestamibi is the most accurate localizing study. Localization studies should be used complementarily, such that the results obtained individually improve significantly if the studies are combined or concordant. Sestamibi and US may be useful and inexpensive initial imaging studies. SVS, an excellent invasive method, must be used if the rest of the

436 - - Parathyroid Gland

imaging studies are negative or discordant. IOPTH may be useful in some cases but does not replace good surgical experience and interpretation.

REFERENCES I. Levin KE, Gooding GAW, Okerlund M, et al. Localization studies in patients with a persistent or recurrent hyperparathyroidism. Surgery 1987;102:917. 2. Thompson NW. Localization studies in patients with primary hyperparathyroidism. Br J Surg 1988;75:97. 3. Auguste U, Attie IN, Schanap D. Initial failure of surgical exploration in patients with primary hyperparathyroidism. Am J Surg 1990;160:333. 4. Clark OH, Wilkes W, Siperstein AE, et al. Diagnosis and management of asymptomatic hyperparathyroidism: Safety, efficacy, and deficiencies in our knowledge. J Bone Miner Res 1991;6:25. 5. Lundgren E, Rastad J, Ridefelt P, et al. Long-term effects of parathyroid operation on serum calcium and parathyroid hormone values in sporadic primary hyperparathyroidism. Surgery 1992;112:1123. 6. Uden P, Chan AK, Duh QY, et al. Primary hyperparathyroidism in younger and older patients: Clinical symptoms and outcome of surgery. World J Surg 1992;16:791. 7. Kjellman M, Sandelln K, Famebo 1.0. Primary hyperparathyroidism: Low surgical morbidity supports liberal attitude to operation. Arch Surg 1994;129:237. 8. Sosa JA, Powe NR, Levine MA, et al. Thresholds for surgery and surgical outcomes for patients with primary hyperparathyroidism: A national survey of endocrine surgeons. J Clin Endocrinol Metab 1998;83:2658. 9. Brennan ME, Norton JA. Reoperation for persistent and recurrent hyperparathyroidism. Ann Surg 1985;120:40. 10. Grant CS, Van Heerden JA, Charboneau EM, et al. Clinical management of persistent and/or recurrent primary hyperparathyroidism. World J Surg 1986;10:555. II. Carty SE, Norton JA. Management of patients with persistent or recurrent primary hyperparathyroidism. World J Surg 1991;15:716. 12. Jarhiilt J, Nordestrom J, Perbeck L. Reoperation for suspected primary hyperparathyroidism. Br J Surg 1993;80:453. 13. Shen W, Duren M, Morita E, et al. Reoperation for persistent and recurrent primary hyperparathyroidism. Arch Surg 1996;131:861. 14. Wells SA, Debenedetti MK, Doherty GM. Recurrent or persistent hyperparathyroidism. J Bone Miner Res 2002;17:158. 15. Jaskowiak N, Norton JA, Alexander HR, et al. A prospective trial evaluating a standard approach to reoperation for missed parathyroid adenoma. Ann Surg 1996;224:308. 16. Hasse C, Sitter H, Brunne M, et al, Quality of life and patient satisfaction after reoperation for primary hyperparathyroidism: Analysis of long-term results. World J Surg 2002; 13:26. 17. Tezelman S, Shen W, Shaver JK, et al. Double parathyroid adenomas: Clinical and biochemical characteristics before and after parathyroidectomy. Ann Surg 1993;218:300. 18. Kebebew E, Arici C, Duh QD, Clark OH. Localization and reoperations results for persistent and recurrent parathyroid carcinoma. Arch Surg 2001;136:878. 19. Wang C-A. The anatomic basis of parathyroid surgery. Ann Surg 1976;183:271. 20. Liechtty RD. Parathyroid anatomy in hyperplasia. Arch Surg 1992;127:813. 21. Henry JF, Denizot A, Audiffret J, France G. Results of reoperations for persistent or recurrent secondary hyperparathyroidism in hemodialysis patients. World J Surg 1990;14:303. 22. Fraker DL, Doppman JL, Shwaker TH, et al. Undescended parathyroid: An important etiology for failed operations for primary hyperparathyroidism. World J Surg 1990;14:342. 23. Conn lM, Gongalves MA, Mansour KA, McGarity WC. The mediastinal parathyroid. Am Surg 1991;57:62. 24. Patow CA, Norton JA, Bennan ME. Vocal paralysis and reoperative parathyroidectomy: A prospective study. Ann Surg 1986;203:282. 25. Roe SM, Bums P, Graham LD, et al. Cost effectiveness of preoperative localization studies in primary hyperparathyroidism disease. Ann Surg 1994;219:582. 26. Wyman SM, Robbins LL. The roentgen recognition of parathyroid adenoma. AJR Am J Roentgenol1954;71 :777.

27. Stevens AC, Jackson CEo Localization of parathyroid adenoma by oesophageal cineroentgenography. AJR Am J Roentgenol 1967; 99:223. 28. Samuels BJ, Dowdy AH, Lecky Jw. Parathyroid termography. Radiology 1972;104:575. 29. Edis AJ, Evans PC. High-resolution real-time ultrasonography and preoperative localization of parathyroid tumors. N Engl J Med 1979;301:532. 30. Levin K, Clark OH. The reasons of failure in parathyroid surgery. Arch Surg 1989;124:91 I. 31. Liburty SK, Bartlett DL, Jaskowiak NT, et al, The role of the thyroid resection during reoperation for persistent or recurrent hyperparathyroidism. Surgery 1997;122:1183. 32. McIntyre RC, Eisenach JH, Pearlman NW, et al. Intrathyroidal parathyroid glands can be a cause of failed cervical exploration for hyperparathyroidism. Am J Surg 1997;174:750. 33. Gooding GAW. Sonography of the thyroid and parathyroid. Radiol Clin North Am 1993;31:967. 34. Erdman WA, Breslav NA, Weinreb JC, et al. Noninvasive localization of parathyroid adenomas: A comparison of x-ray, computerized tomography, ultrasound, scintigraphy, and MRI. Magn Reson Imaging 1989;102:917. 35. Kurbskack AJ, Wilson SD, Lawson TL, et al, Prospective comparison of radionuclide, computed tomography, sonographic, and magnetic resonance localization of parathyroid tumors. Surgery 1989;106:639. 36. Miller DL, Doppman JL, Shawker TH, et al. Localization of parathyroid adenomas in patients who have undergone surgery: 1. Noninvasive imaging methods. Radiology 1987;162:133. 37. Rodriguez 1M, Tezelman S, Siperstein AE, et al. Localization procedures in patients with persistent or recurrent hyperparathyroidism. Arch Surg 1994;129:870. 38. Numerow LM, Morita ET, Clark OH, et al. Persistent/recurrent hyperparathyroidism: A comparison of sestamibi scintigraphy, MRI and ultrasonography. 1 Magn Res Imaging 1995;5:702. 39. Peeler BB, Martin WH, Sandler MP, Goldstein RE. Sestarnibi parathyroid scanning and preoperative localization studies for patients with recurrent/persistent hyperparathyroidism or significant comorbid conditions: Development of an optimal localization. Am Surg 1997;63:37. 40. Thompson JB, Grant CS, Perrier NO, et al. Reoperative parathyroid surgery in the era of sestamibi scanning and intraoperative parathyroid hormone monitoring. Arch Surg 1999;134:699. 41. De Feo ML, Colagrande S, Biagini C, et al. Parathyroid glands: Combination of 99mTc MIBI scintigraphy and US for demonstration of parathyroid glands and nodules. Radiology 2000;214:393. 42. Feingold DL, Alexander HR, Chen CC, et al. Ultrasound and sestamibi scan as the only preoperative imaging test in reoperation for parathyroid adenomas. Surgery 2000; 128: 1103. 43. Carlson GL, Famdon GL, Clayton B, Rose PG. Thallium isotope scintigraphy and ultrasonography: Comparative studies of localization techniques in primary hyperparathyroidism. Br 1 Surg 1990;77:327. 44. Henry JF, Audifret J, Denizot A. Endosonography in the localization of parathyroid tumours: A preliminary study. Surgery 1990;108:1021. 45. Catargi B, Raymond 1M, Lafarge-Gense V, et al, Localization of parathyroid tumours using endoscopic ultrasonography in primary hyperparathyroidism. J. Endocrinol Invest 1999;22:688. 46. Gooding GAW, Clark OH. Use of color Doppler imaging in the distinction between thyroid and parathyroid lesions. Am J Surg 1992;164:51. 47. Kohri K, Ishikawa Y, Mitsumasa K, et al. Comparison of imaging methods for localization of parathyroids tumors. Am J Surg 1992;164:140. 48. Auffermann W, Gooding GAW, Okerlund MD, et al. Diagnosis of recurrent hyperparathyroidism: Comparison of MR imaging and the other techniques. AJR Am J RoentgenoI1988;150:1027. 49. Doherty GM, Doppman JL, Miller DL, et al. Results of a multidisciplinary strategy for management of mediastinal parathyroid adenoma as a cause of persistent hyperparathyroidism. Ann Surg 1992;215: 10 I. 50. Mariette C, Pelliser L, Combemale F, et al. Reoperation for persistent or recurrent primary hyperparathyroidism. Langenbecks Arch Surg 1998;383: 174. 51. Kem KA, Shawker TH, Jones BL. Intraoperative ultrasound on reoperative parathyroid surgery: An initial evaluation. World 1 Surg 1986; 10:631. 52. Aufferman W, Guis M, Tavares NJ, Higgins CB. MR signal intensity of parathyroid adenomas: Correlation with histopathology. AJR Am J Roentgenol 1989;153:873.

Localization Studies in Persistent or Recurrent Hyperparathyroidism - - 437 53. Higgins CB. Role of magnetic resonance imaging in hyperparathyroidism. Radiol Clin North Am 1993;31:1017. 54. Fayet C, Hoeffel C, Fulla Y, et al. Technetium-99m sestamibi scintigraphy, magnetic resonance imaging, and venous sampling in persistent and recurrent hyperparathyroidism. Br 1 Radiol 1998;71:108. 55. Gotway MB, Reddy GP, Webb R, et al. Comparison between MR imaging and 99ffiTc-MIBI scintigraphy in the evaluation of recurrent or persistent hyperparathyroidism. Radiology 2001 ;218:783. 56. Higgins CB, Aufferman W. MRI imaging of thyroid and parathyroid: A review of current status. AJR Am 1 RoentgenoI1988;151:1095. 57. Ishibashi M, Nishida H, Hiromatsu Y, et al. Comparison of technetium99m-MIBI, technetium 99m-tetrofosmin, ultrasound, and MRI for localization of abnormal parathyroid glands. 1 Nucl Med 1998;39:320. 58. McDermott VG, Fernandez RJM, Meaken TJ, et al. Preoperative MR imaging in hyperparathyroidism: Results and factors affecting parathyroid detection. AJR Am 1 RoentgenoI1996;166:705. 59. Seelos KC, De Marco R, Clark OH, Higgins CB. Persistent and recurrent hyperparathyroidism assessment with gadopentetate dimeglumineenhanced MR imaging. Radiology 1990;177:373. 60. Kang YS, Resen K, Clark OH, Higgins CB. Localization of abnormal parathyroid glands of the mediastinum with MR imaging. Radiology 1993;189:137. 61. Fukunaga M, Morita R, Yokenuga Y. Accumulation of 201TI chloride in a parathyroid adenoma. Clin Nucl Med 1979;4:229. 62. Ferlin G, Borsato N, Camerani M, et al. New perspectives in localizing enlarged parathyroids by technetium-thallium subtraction scan. 1 Nucl Med 1983;24:438. 63. Young AE, Gaunt 11, Croft DN, et al. Localization of parathyroid adenomas by thallium 201 and technetium 99m. BMI 1983;286:1384. 64. Chan TY, Serpell lW, Chan 0, et al. Misinterpretation of the upper parathyroid adenoma on thallium-20Iltechnetium-99m subtraction scintigraphy. Br 1 Radiol 1991;64: I. 65. Attie IN, Khan A, Rumanck WM, et al. Preoperative localization of parathyroid adenomas. Am 1 Surg 1988;156:323. 66. Price DC. Radioisotopic evaluation of the thyroid and the parathyroids. Radiol Clin North Am 1993;31:991. 67. Coakley AJ, Kettle AG, Wells CP, et al. 99m-Technetium sestamibi: A new agent for parathyroid imaging. Nucl Med Commun 1989; 10:791. 68. Chiu ML, Kronange JF, Piwnica Worms D. Effect of mitochondrial and plasma membrane potentials on accumulation of hexakis (2-methoxyisobutylisonitrile) technetium in cultured mouse fibroblasts. 1 Nucl Med 1990;31:1646. 69. Sandrock D, Merino Ml, Norton lA, et al. Light and electromicroscopic analyses of parathyroid tumours explain results ofTI201 Tc99m parathyroid scintigraphy. Eur 1 Med 1989;15:410. 70. O'Doherty Ml, Kettle AG, Collins REC, Coakley AI. Parathyroid imaging with technetium 99m sestamibi: Preoperative localization and tissue uptake studies. 1 Nucl Med 1992;33:313. 71. Mitchel BK, Cornelius EA, Zoghbi S, et al. Mechanism of technetium 99m sestamibi parathyroid imaging and the possible role of p-glycoprotein. Surgery 1996; 120: 1039. 72. Pinero A, Rodriguez 1M, Martinez-Barba E, et al. Tc-99m sestamibi scintigraphy and cell proliferation in primary hyperparathyroidism: A causal or casual relationship? Surgery 2003; 134:41. 73. Taillefer R, Boucher Y, Potvin C, Lambert R. Detection and localization of parathyroid adenomas in patients with hyperparathyroidism using a single radionuclide imaging procedure with technetium 99m sestamibi (double-phase study). 1 Nucl Med 1992;33:1801. 74. Wei IP, Burke Gl, Mansberger AR. Prospective evaluation of the efficiency of technetium 99m sestamibi and iodine 123 radionuclide imaging of abnormal parathyroid glands. Surgery 1992; 112: 1111. 75. Wei IP, Burke GJ, Mansberger AD. Prospective imaging of abnormal parathyroid glands in patients with hyperparathyroidism disease using combination Tc99m-pertechnetate and Tc99m sestamibi radionuclide scans. Ann Surg 1994;219:568. 76. Hindie E., Melliere D, Simon D, Perlemuter L, et al. Primary hyperparathyroidism: Is technetium 99m sestamibi/iodine subtraction scanning the best procedure to locate enlarged glands before surgery? 1 Clin Endocrinol Metab 1995;80:302. 77. Chen CC, Skarulis MC, Fraker DL, et al. Technetium-99m sestamibi imaging before reoperation for primary hyperparathyroidism. 1 Nucl Med 1995;36:2186. 78. leanguillaume C, Hindle E, Meignan-Debray S, et al. Tc-99m sestamibi and 1-123 detection of a parathyroid adenoma in the presence of cold thyroid nodule. Clin Nucl Med 1997;22:258.

79. Sfakianakis GN, Irvin GL ill, Foss 1, et al. Efficient parathyroidectomy guided by SPECT-MIBI and hormonal measurements. 1 Nucl Med 1996;88:798. 80. Neumann DR, Esselstyn CB, Kim EY, et al. Primary experience with double-phase SPECT using Tc-99m sestamibi in patients with hyperparathyroidism. Clin Nucl Med 1997;22:217. 81. Chen CC, Holder LE, Scovill WA, et at. Comparison of parathyroid imaging with technetium-99m-pertechnetate/sestamibi subtraction, double-phase technetium-99m sestamibi and technetium-99m sestamibi SPECT. 1 Nucl Med 1997;38:834. 82. Teigen EL, Kilgore EJ, Cowan RJ, et al. Technetium-99m sestamibi SPECT localization of mediastinal parathyroid adenomas. 1 Nucl Med 1996;37:1535. 83. Irvin GL, Molinari AS, Figueroa C, et al. Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Ann Surg 1999;229:874. 84. Pattou F, Huglo D, Proye C. Radionuclide scanning in parathyroid diseases. Br 1 Surg 1998;85: 1605. 85. Pinero A, Rodriguez 1M, Ortiz S, et al. Influence of thyroid pathology on the results of parathyroid gammagraphy with Tc99m sestamibi. Clin Endocrinol 2000;53:655. 86. Koss WGM, Brown MR, Balfour JF. A false-positive localization of parathyroid adenoma with technetium Tc99m sestamibi scan secondary to a thyroid follicular carcinoma. Arch Surg 1996; 131:216. 87. Nakahara H, Noguchi S, Murakami N, et al. Technetium-99m sestamibi scintigraphy compared with thallium-201 in evaluation of thyroid tumours. 1 Nucl Med 1996;37:901. 88. Balon HR, Fink-Bennet D, Stoffer SS. Technetium-99m sestamibi uptake by recurrent Hiirthle cell carcinoma of the thyroid. 1 Nucl Med 1992;33: 1393. 89. Scott AM, Kostakoglu L, O'Brien IP, et al. Comparison of technetium-99m-MIBI and thallium-Zul-chloride uptake in primary thyroid lymphoma. 1 Nucl Med 1992;33:1396. 90. Aigner RM, Fueger GF, Nicoletti R. Parathyroid scintigraphy: Comparison of technetium-99m methoxyisobutylisonitrile and technetium-99m-tetrophosmin studies. Eur 1 Nucl Med 1996;23:693. 91. Pattou F, Oudar C, Huglo D, et al. Localization of abnormal parathyroid glands with jugular sampling for parathyroid hormone, and subtraction scanning with sestamibi or tetrophosmin. Aust N Z 1 Surg 1998;68: 108. 92. Ishibashi M, Nishida H, Strauss W, et al. Localization of parathyroid glands using technetium-99m-tetrofosmin imaging. 1 Nucl Med 1997; 38:706. 93. Pattou F, Huglo D, Proye C. Radionuclide scanning in parathyroid disease. Br 1 Surg 1998;85:1605. 94. Giordano A, Meduri G, Rubini G, et al. Italian multicenter study on 99m-Tc-tetrophosmin in parathyroid scintigraphy: Results in 133 subjects. Eur 1 Nucl Med 1998;25:9. 95. Aigner RM, Fueger GF, Wolf G. Parathyroid scintigraphy: First experiences with technetium(ill)-99m-QI2. Eur 1 Nucl Med 1997; 24:326. 96. Arslan N, Rydzewski B. Detection of a recurrent parathyroid carcinoma with FDG positron emission tomography. Clin Nucl Med 2002;27:221. 97. Neumann DR, Esselstyn CB, Macintyre WI, et al. Regional body FOG-PET in postoperative recurrent hyperparathyroidism. 1 Comput Assist Tomogr 1997;21:25. 98. Cook Gl, Wong lC, Smelie WI, et al. [11C]Methionine positron emission tomography for patients with persistent or recurrent hyperparathyroidism after surgery. Eur 1 Endocrinol 1998;139:195. 99. Marcocci C, Mazzeo S, Bruno-Bossio G, et al. Preoperative localization of suspicious parathyroid adenomas by PTU assay in the needle aspiration. Eur 1 Endocrinol 1998;139:72. 100. Tikkakosky T, Stenfors LE, Typpo T, et al. Parathyroid adenomas: Preoperative localization with ultrasound combined with fine-needle biopsy. 1 Laryngol OtoI1989;62:981. 101. Karstrup S, Glenthoj A, Hainau B, et al. Ultrasound-guided, histological, fine-needle biopsy from suspect parathyroid tumours: Success rate and reliability of histological diagnosis. Br 1 Radiol 1989;62:981. 102. McFarlane MP, Fraker DL, Shawker TH, et al. Use of preoperative fine-needle aspiration in patients undergoing reoperation for primary hyperparathyroidism. Surgery 1994; 116:959. 103. Miller DL. Preoperative localization and interventional treatment of parathyroid tumours. When and how? World 1 Surg 1991;15:706.

438 - - Parathyroid Gland 104. McIntyre RC, Kumpe DA, Liechty D. Reexploration and angiographic ablation for hyperparathyroidism. Arch Surg 1994; 129:499. 105. Miller DL. Endocrine angiography and venous sampling. Radiol Clin NorthAm 1993:31:1051. 106. Nilsson BE, Tissell LE, Janson S, et al. Parathyroid localization by catheterization of large cervical and mediastinal veins to determine serum concentrations of intact parathyroid hormone. World Surg 1994;18:605. 107. Sugg SL, Fraker DL, Alexander R, et al. Prospective evaluation of selective venous sampling for parathyroid hormone concentrations in patients undergoing reoperations for primary hyperparathyroidism. Surgery 1993;114:1004. 108. Billingsley KG, Fraker DL, Doppman JL, et al. Localization and operative management of undescended parathyroid adenomas in patients with persistent primary hyperparathyroidism. Surgery 1994; I 16:982. 109. Jones 11, Brunaud L, Dowd CF, et al. Accuracy of selective venous sampling for intact parathyroid hormone in difficult patients with recurrent or persistent hyperparathyroidism. Surgery 2002; 132:944. I 10. Casanova D, Safati E, De Francisco A, et al. Secondary hyperparathyroidism: Diagnosis of site of recurrence. World J Surg 1991;15:546. I I I. Demeter JG, De Jong SA, Lawrence AM, Paloyan E. Recurrent hyperparathyroidism due to parathyroid autografts: Incidence, presentation, and management. Am Surg 1993;59:178. 112. Fong-Fu C, Chiang Hsuan L, Hue-Yon C, et al. Persistent and recurrent hyperparathyroidism after total parathyroidectomy with autotransplantation. Ann Surg 2002;235:99. 113. Alexander HR, Chen CC, Shawker T, et al. Role of preoperative localization manoeuvers including intraoperative PTH assay determination

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I 17. 118.

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for patients with persistent or recurrent hyperparathyroidism. J Bone Miner Res 2002;17: 133. Norman JG, Jaffray CE, Chheda H. The false-positive parathyroid sestamibi: A real or perceived problem and a case for radio-guided parathyroidectomy. Ann Surg 2000;23 I :31. Huang GU, Wu HS, Tsai SC, et al. Recurrent hyperfunctioning parathyroid gland demonstrated radionuclide imaging and an intraoperative gamma probe. Clin Nucl Med 2000;25:348. Geissler B, Grober S, Zugel N, Lindemann F. [Radio-guided parathyroidectomy: Successful intraoperative parathyroid localization diagnosis with 99mTc sestamibi in primary and recurrent hyperparathyroidism.] Chirurg 2001;72:1179. Navarra G, Feggi L, Ascanelli S, et al. Role of radio-guided surgery in recurrent secondary hyperparathyroidism. Nephron 2001;88:36. Proye CA, Goropoulos A, Franz C, et al. Usefulness and limits of quick intraoperative measurements of intact (1-84) parathyroid hormone in the surgical management of hyperparathyroidism: Sequential measurements in patients with multiglandular disease. Surgery 1991;110: 1035. Irvin GL III, Prudhomme BS, Deriso GT, et al. A new approach to parathyroidectomy. Ann Surg 1994;2 I 9:574. Irvin GL III, Dembrow VD, Prudhomme DL. Clinical usefulness of an intraoperative "quick parathyroid hormone" assay. Surgery 1993;114:1019. Irvin GL, Molinari AS, Figueroa C, Carneiro DM. Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Ann Surg 1999;226:874.

Technique of Parathyroidectomy H. Jaap Bonjer, MD, PhD • Hajo A. Bruining, MD, PhD

One of the pioneers of parathyroid surgery, Edward D. Churchill, stated in 1931 that "the success of parathyroid surgery must lie in the ability of the surgeon to know a parathyroid gland when he sees it, to know the distribution of the glands, where they hide, and also to be delicate enough in technique to be able to make use of this knowledge,"! More than half a century later, this statement still describes perfectly the fundamentals of successful parathyroid surgery. Therefore, the embryology and anatomy of parathyroid glands are discussed before the description of the technique of parathyroidectomy.

Embryology of Parathyroid Glands The parathyroid glands develop from the third and fourth pharyngeal pouches.? The upper parathyroid glands originate from the dorsal tips of pharyngeal pouch IV.3 The ventral portion of pharyngeal pouch IV consists of the ultimobranchial body, which is incorporated into the lateral part of the developing thyroid and eventually supplies the parafollicular or C cells. The common embryologic origin of the lateral part of the thyroid and the upper parathyroids accounts for the occasional intrathyroidal location of upper parathyroids, although this is a rare observation." The lower parathyroid glands arise from the dorsal part of pharyngeal pouch III. The thymus, which originates from the ventral part of pharyngeal pouch III, and the lower parathyroid gland descend as a complex in a plane ventrally to pharyngeal pouch IV. Therefore, the lower parathyroids are usually found in a more anterior position than the upper parathyroids. At the caudal descent, the lower parathyroid usually dissociates from the thymus and is ultimately located near the lower pole of the thyroid. The caudal migration of the complex of the lower parathyroid and thymus can vary widely. In the case of absence of migration, the lower parathyroid gland is found cranially to the upper pole of the thyroid, mimicking a superior parathyroid. Thymic tissue surrounding the undescended parathyroid can clarify the

true origin of the ectopic parathyroid gland. The absence of thymic tissue caudally to the thyroid is another indicator of an undescended lower parathyroid. When the lower parathyroid remains attached to the thymus during caudal migration, it becomes positioned in the anterosuperior mediastinum.

Anatomy of Parathyroid Glands Number of Parathyroid Glands The presence of four parathyroid glands is most common in humans. In dissection studies of 428 human subjects by Gilmour, four parathyroid glands were found in 87% of all patients and three parathyroids in 6.3%.5 Akerstrom and colleagues reported comparable rates in an autopsy study of 503 cases." Four parathyroids were found in 84% and three parathyroids in 3% of all patients in this study. The occurrence of supernumerary parathyroid glands is a rare entity that nevertheless has important clinical consequences, particularly in patients with hyperparathyroidism resulting from multiple-gland disease. In a series of 2015 patients who were operated on for primary hyperparathyroidism, a hyperfunctioning supernumerary fifth parathyroid caused hypercalcemia in 15 patients (0.7%).7 Nine of these patients required reoperations to reveal the parathyroid tumor. The majority of these fifth gland tumors were located in the mediastinum, either in the thymus (n = 7) or related to the aortic arch (n = 3). Edis and Levitt" reported a rate of persistent hyperparathyroidism of 10% resulting from an enlarged supernumerary parathyroid in patients with secondary hyperparathyroidism. In a series of 762 patients with primary hyperparathyroidism, Wang and coworkers documented 6 patients with persistent hyperparathyroidism caused by hyperfunctioning supernumerary glands (0.6%), all of which were located in or in close association with the thymus." In a dissection study of 428 cases, Gilmour found supernumerary parathyroid glands in 29 cases (6.7%).5 Five parathyroids were observed in 25 cases (5.8%),6 parathyroids in 2 cases (0.05%),8 parathyroids in 1 case, and 12 parathyroids in another case. Akerstrom and 439

440 - - Parathyroid Gland colleagues concluded in an autopsy study that most supernumerary glands were either rudimentary or divided." When supernumerary parathyroids weighing less than 5 mg were excluded, there were 24 cases of supernumerary glands (5%). These supernumerary parathyroids were most frequently found in the thymus or in relation to the thyrothymic ligament.

Location of Parathyroid Glands The location of parathyroid glands varies widely as a result of differences in degree of migration during embryologic development. Superimposed on the various locations of parathyroid glands are the displacements of parathyroid glands that become enlarged in the process of ensuing hyperparathyroidism. Enlarged parathyroid glands tend to migrate in an areolar plane, which offers little resistance as a result of gravity and perhaps swallowing and lower intrathoracic pressures.!" In some patients, these migrations result in considerable displacement of parathyroid tumors. Awareness of the common "pathways" of migration is invaluable in parathyroid surgery. Eighty percent of the upper parathyroid glands are found at the cricothyroid junction, about 1 em cranial to the intersection of the recurrent laryngeal nerve and the inferior thyroid artery (Fig. 47-1).6 The upper parathyroids, which are tucked posteriorly to the upper pole of the thyroid, are usually covered by a fascial sheath connecting the thyroid to the pharynx. More anteriorly situated upper parathyroids are located on the surface of the thyroid, frequently underneath the capsule of the thyroid. The unique feature of these subcapsular parathyroids is the freedom of movement of the parathyroids within the capsule. This feature distinguishes

FIGURE 47-1. Locations of the upper parathyroid glands. The more common locations are indicated by darker shading. The numbers represent the percentages of glands found at the different locations. (From Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95:17.)

parathyroids from thyroid nodules, which cannot move freely. The occurrence of intrathyroidal parathyroids is rare and controversial. A subcapsular parathyroid is easily confused with a true intrathyroidal parathyroid, which is surrounded by thyroid tissue. Akerstrom and colleagues noted true upper intrathyroidal parathyroid glands in three cases (0.2%) among 503 autopsies.f Wang considered the upper parathyroid gland the most likely to be intrathyroidal because of the close embryologic relationship of the primordium of the upper parathyroid gland with the lateral complex of the thyroid. 1I However, Wheeler and coauthors'? reported eight intrathyroidal parathyroid tumors in 7 patients (3.5%) in a series of 200 patients undergoing exploration of the neck for hyperparathyroidism. Seven of these eight intrathyroidal parathyroids were considered to be lower parathyroid glands. The incidence of intrathyroidal parathyroids ranges from 0.5% to 3% in the literature.l':'>" Normal upper parathyroid glands are found in the retroor paraesophageal space in I % of all cases. IS This space is the site where enlarged upper parathyroids descend to the superoposterior mediastinum. The importance of this ectopic location of upper parathyroid glands is illustrated in Figure 47-2. In a series of 104 patients with persistent hyperparathyroidism, 34 parathyroid tumors were found in the superoposterior mediastinum.'?

34 21 19 13 10 5 1 1

SUPERIOR POSTERIOR MEDIASTINUM ANTERIOR MEDIASTINUM BEHIND UPPER POLE OF THYROID BEHIND CLAVICLE WITHIN THYMIC TONGUE BEHIND LOWER POLE OF THYROID BEHIND ESOPHAGUS BEHIND ANGLE OFTHE JAW INTRATHYROIDAL

FIGURE 47-2. Sites of 104 missing parathyroid tumors. (From Wang CA. Parathyroid re-exp1oration: A clinical and pathological study of 112 cases. Ann Surg 1977;186:142.)

Technique of Parathyroidectomy - -

The distribution of locations of the lower parathyroid glands varies more widely (Fig. 47-3). More than half of the lower parathyroids are located around the lower pole of the thyroid. Twenty-eight percent of the lower parathyroids are found in the thyrothymic ligament or within the thymus. A rare location of lower parathyroids is high in the neck at the carotid bifurcation, resulting from absence of embryologic migration. When lower parathyroid glands become enlarged, they tend to migrate into the anterior mediastinum. Figure 47-2 shows that one third of all missed parathyroid tumors were found in the thymus or in the anterior mediastinum.

Gross Features of Parathyroid Glands It is essential in parathyroid surgery to distinguish between normal and hyperfunctioning parathyroid glands. Hyperfunctioning parathyroid glands are enlarged. Therefore, definition of the normal size of a parathyroid gland is crucial. The size of normal parathyroids varies considerably because parathyroids are easily molded as a result of their soft consistency. The shape of the parathyroid gland is dependent on its anatomic position. Parathyroids that are located in loose tissue have an oval, bean, or teardrop shape. When parathyroids lie underneath a capsule, their shape is flat with sharp edges. Although a particular shape of a parathyroid gland is not associated with hyperfunction, a spherical shape often indicates hyperactivity of the parathyroid.P

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Because the shape of parathyroids is diverse, the parenchymal weight of parathyroid glands is the most reliable parameter for parathyroid function.P The weight of parathyroid glands attains its maximum in men in the third decade of life. 22 In women, there is a progressive rise until about the age of 50 years. The weights of parathyroid glands are lower in patients with chronic illnesses, except renal disease, and lower in women than in men.P The weights of the lower parathyroids are greater than those of the upper parathyroids. The normal weight of a parathyroid gland remains uncertain. An upper limit of normal parenchymal weight of 38 mg for a single gland was reported by Gilmour and Martin." Dufour and Wilkerson found an upper normal limit of 49 mg for the parenchymal weight of a single gland.P Akerstrorn and colleagues found a maximal normal glandular weight of 59 mg in an autopsy study of 368 cases without evidence of hyperparathyroidism." Dufour and Wilkerson demonstrated that 95% of the individual glands weighed between 8.2 and 75.0 mg. It should be noted that an overlap of the weights of normal and abnormal parathyroid glands exists. In our series of 1080 patients with hyperparathyroidism, several patients became normocalcemic after removal of abnormal parathyroid glands weighing only 60 mg. Underestimation of the weight of parathyroid glands can easily occur when the parathyroid lies underneath the capsule of the thyroid and only part of the parathyroid can be examined. Therefore, the entire parathyroid should be exposed before assessing its weight. Alternatively, the weights of parathyroid glands, which are surrounded by an abundance of fat, can be overestimated. The color of normal parathyroid glands ranges from yellowish brown to reddish brown. The color depends on the amount of fat, number of oxyphil cells, and degree of vascularity.P Enlarged parathyroid glands display colors varying from dark brown to light yellow. In secondary or tertiary hyperparathyroidism, the enlarged parathyroids sometimes have a typical gray color. Parathyroid carcinomas can also have a grayish white surface.

Blood Supply of Parathyroid Glands Preservation of the blood vessels supplying the parathyroid glands in parathyroid surgery is essential to prevent damage to normal parathyroid glands. Most parathyroid glands have a single artery (80%).26 The length of the parathyroid artery can vary from I to 40 mm. In general, the parathyroid glands derive their arterial branches from the inferior thyroid artery. However, 20% or more of the upper parathyroid glands are vascularized by the superior thyroid artery. Delattre and coworkers" found in an autopsy study that 10% of the lower parathyroid glands were dependent on an anterior branch of the superior thyroid artery. In most of these cases, the inferior thyroid artery was absent, which is not unusual at the left side. Mediastinal parathyroids often have an artery that is a thymic branch of the internal mammary artery." The venous return of parathyroid glands runs almost parallel to the arterial vessels. 0.2 FIGURE 47-3. Locations of the lower parathyroid glands. The more common locations are indicated by darker shading. The numbers represent the percentages of glands found at the different locations. (From Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95:17.)

Technique of Parathyroidectomy The diagnosis of hyperparathyroidism should be confirmed by the assessment of an elevated serum parathyroid hormone

442 - - Parathyroid Gland

level using a two-site immunoassay.P" Localization studies of enlarged parathyroid glands are necessary only in patients having exploration of the neck for persistent or recurrent hyperparathyroidism and in patients undergoing parathyroidectomy with local anesthesia.P-" We believe that pre- and postoperative laryngoscopy to assess vocal cord function is mandatory in (para)thyroid surgery.P

Anesthesia Exploration of the neck is performed preferentially under general anesthesia with endotracheal intubation. In patients who are unfit for general anesthesia, an enlarged parathyroid gland can be removed under local anesthesia when localization studies have demonstrated the exact site of the parathyroid tumor. 33 Positioning of the patient on the operating table is of paramount importance. The patient's neck should be extended dorsally to provide optimal access to the neck. Care should be taken not to overextend the neck to prevent postoperative occipital head pain. The arms of the patient should lie alongside the body to allow the surgeon and the assistant to stand on both sides of the neck. Long ventilation tubes facilitate placement of the ventilator at some distance from the operating table, which creates space for the operating team. The ventilation tubes can be fixed on the head of the patient using a sheet or a special Velcro band (Fig. 47-4). The second assistant can stand at the head of the table. Replacement of the endotracheal tube in the case of rupture of the cuff is difficult when the patient's head is covered with drapes. Therefore, we recommend packing of the oropharynx with a gauze strip to prevent gas leakage from any cause.

Exploration of the Neck The use of magnifying glasses (2x) facilitates exploration of the neck. Fine bipolar forceps are a valuable asset to prevent diathermic injury of the recurrent laryngeal nerve. The ligation of small vessels is best done with a fine right-angled dissection clamp. A symmetrical collar incision is made,

FIGURE 47-4. Positioning of the patient on the operating table for (para)thyroid surgery. The neck is hyperextended, and the ventilation tubes are fixed on the head.

preferentially in a natural skin crease, 3 to 4 em cranially to the suprasternal notch. An incision that is located too close to the suprasternal notch is likely to become a hypertrophic scar. The incision should not extend beyond the sternocleidomastoid muscles. After incising the platysma, the cranial skin-platysma flap is dissected upward to the notch of the thyroid cartilage and downward to the suprasternal notch. A self-retaining retractor is used to withdraw the upper and lower skin-platysma flaps. A midline incision is made in the cervical fascia from the cricoid cartilage down to the suprasternal notch. The sternohyoid and sternothyroid muscles are separated from the underlying thyroid and thymus. If present, the middle thyroid vein must be divided to allow the thyroid lobe to be retracted anteriorly and medially. Transection of the strap muscles is unnecessary because they can be retracted sufficiently by a wide blunt retractor, held by the second assistant standing at the head of the operating table, who has the second best view of the operating field, which is important for surgical education. The thyroid lobe can be retracted by an Allis clamp or stitch. It is essential to free the thyroid and thymus from the strap muscles, from the cricoid cartilage to the suprasternal notch, to obtain complete exposure of the lateral aspects of the thyroid and the thymus. Fascial sheaths covering the thyroid should be removed until the surface of the thyroid is shiny; otherwise, subcapsular parathyroid glands can easily be overlooked. The fascia between the common carotid artery and the thyroid should be opened alongside the carotid artery to have access to the retroesophageal space. On the right side, care should be taken to avoid injury to a nonrecurrent laryngeal nerve at this step because this anomaly is more common on the right side.34 Throughout the entire procedure, the surgical field should be kept as bloodless as possible to prevent discoloring the parathyroid glands, which impedes their identification. Parathyroid glands are often (partially) surrounded by fat. Therefore, any lobule of fat at the predilection sites of parathyroids should be inspected. When the thin fascia that covers the fat lobule is carefully opened, the parathyroid gland usually "pops" out. Normal parathyroid glands have a basic light brown color. The color is important to differentiate parathyroid glands from fat, which is more yellow, and from thyroid nodules, which are more red in color. Another important feature of parathyroid glands is their freedom of motion in relation to the thyroid gland. When looking for a parathyroid, it can be helpful to strike along the thyroid with a peanut sponge to find moving structures. A thyroid nodule can mimic a parathyroid gland but is more firmly attached to the thyroid and does not have a distinct vascular stalk. In the thyrothymic ligament or in the thymus, parathyroid glands can easily be confused with lymph nodes. However, the consistency oflymph nodes is firmer than that of parathyroids. Lymph nodes are also grayer than parathyroids. Palpation is another valuable method to detect parathyroid tumors. In particular, enlarged upper parathyroids, which have descended dorsally to the inferior thyroid artery, can often be more readily palpated than seen. On the other hand, a negative palpation does not exclude the presence of a parathyroid tumor because the consistency of parathyroids can be similar to that of the surrounding tissue. A sense of abnormal local "fullness" may indicate the presence of a parathyroid tumor.

Technique of Parathyroidectomy - -

During the dissection of parathyroid glands, the vascular anatomy should be kept in mind. Dissection of the upper parathyroid gland should be started at the dorsal tip of the upper parathyroid to prevent injury to the parathyroid vessels, which usually ascend from the inferior thyroid artery. The dissection of the lower parathyroid gland should start at the caudal end of the parathyroid because the vascular hilus is on the cranial side of the lower parathyroid. When a normal parathyroid gland becomes devitalized during dissection, it should be cut with a razor knife in small fragments of I mm! and replanted in the sternocleidomastoid muscle. The recurrent laryngeal nerve is not exposed routinely because the risk of injury to this nerve is very low when delicate dissection is performed.'? However, the surgeon should realize that the nerve can be embedded in the anterior or medial capsule of an enlarged upper parathyroid gland or in the dorsal capsule of an enlarged lower parathyroid. The parathyroid exploration is usually started by searching for the right upper parathyroid gland. The right upper parathyroid is usually located behind or on the dorsum of the thyroid cranial to the inferior thyroid artery. The posterior aspect of this part of the thyroid can be visualized adequately when the thyroid is retracted medially, the upper part of the strap muscles retracted cranially, and the middle part of the strap muscles retracted laterally. Retraction of the strap muscles is best done by the second assistant with blunt retractors while standing at the head of the operating table. Gentle dissection of the fat lobules and fibrous attachments of the thyroid reveals the majority of the upper parathyroid glands. The dissection should be constantly done under direct vision to prevent injury of the recurrent laryngeal nerve, which runs anteriorly and medially to the upper parathyroid gland. When the upper parathyroid cannot be found in its usual site, the para- and retroesophageal space dorsal to the inferior thyroid artery should be palpated. In the case of a descended upper parathyroid tumor, dissection is facilitated when the assistant pushes the descended parathyroid in a ventrocranial direction. When considerable descent of an upper parathyroid has taken place, the tumor can usually be moved upward by gentle digital teasing. If regular dissection and digital exploration have proved negative, the capsule of the upper pole of the thyroid gland should be opened eventually to inspect for a subcapsular-intrathyroidal parathyroid. After this step, the exploration should proceed to the right lower parathyroid gland. The search for the lower parathyroid gland should start with thorough inspection of the lower pole of the thyroid, the thyrothymic ligament, and the thymus. When the lower parathyroid is not visualized at inspection, the junction of the thyrothymic ligament and the lower pole of the thyroid should be dissected. In many cases, the lower parathyroid hides in the fat between the inferior thyroid veins. Subsequently, the posterior aspect of the lower thyroid lobe should be inspected. If the lower parathyroid has not been identified after these steps, the thin sheath covering the thymus should be incised. Rarely, a parathyroid tumor on the anterior surface of the thyroid gland has been described. After this procedure, the other side of the neck should be explored in a similar fashion.

443

Biopsies of Parathyroid Glands The role of biopsies during parathyroid surgery is limited." Some authors rely on the microscopic features of parathyroids to distinguish adenomas from hyperplastic glands.36-39 However, no single criterion has proved irrefutable in making this differentiation.w" In a study of the histology of parathyroid glands in 236 patients with primary hyperparathyroidism, significantly different morphologic features in adenomas and primary hyperplasias could not be demonstrated." Therefore, the surgeon should assess the size and color of the parathyroid glands and determine which parathyroid glands are abnormal. Description of the disease of hyperparathyroidism as "single-glanddisease" or "multiplegland disease" is a consequence of lack of microscopic distinction between adenomas and hyperplasia. The role of the pathologist intraoperatively is limited to the identification of parathyroid tissue." Taking biopsy specimens of parathyroid glands routinely increases the incidence of postoperative transient hypocalcemia/" Kaplan and coworkers'? compared the rates of postoperative transient hypocalcemia in one group of patients with hyperparathyroidism having biopsies of all parathyroids with those of another group having occasional biopsies. The rates of postoperative transient hypocalcemia were 48% and 26%, respectively. In our series of patients with nonfamilial hyperparathyroidism operated on before 1989, I of 156 patients with single-gland disease developed permanent hypoparathyroidism, probably as a result of routine biopsies of all parathyroid glands. An alternative method to differentiate between normal and abnormal parathyroid glands is the density test, as proposed by Wang and Rieder.48 The density test measures the difference in total fat content of two parathyroid glands. A low intercellular fat content indicates hormonal hyperfunction. However, detailed studies of normal parathyroid glands have shown wide variations in the amounts of intercellular fat. Seventy-five percent of normal glands have been shown to have less than 30% intercellular fat and 50% of normal glands less than 10% intercellular fat. With these data, estimations of intercellular fat content have become practically useless as a parameter of normality.f'-" Tibblin and colleagues used the amount of intracellular fat to delineate normal and abnormal parathyroid glands." Normal parathyroid glands contain easily detectable amounts of intracellular fat, whereas in abnormal glands intracellular fat is decreased or absent. However, these are not consistent findings. Approximately 10% of parathyroid adenomas have significant amounts of intracellular fat, and hyperplastic glands can stain for varying amounts of intracellular fat."

Resection of Parathyroid Tissue In patients with nonfamilial hyperparathyroidism and patients with multiple endocrine neoplasia (MEN) type 2 syndromes, only enlarged parathyroid glands with an estimated weight greater than 40 mg should be removed.44 •53,54 In patients with a solitary enlarged parathyroid gland, the vascular stalk of the tumor should be ligated and the tumor removed. At the dissection of the parathyroid tumor, the capsule of the parathyroid should not be opened to prevent

444 - - Parathyroid Gland seeding of parathyroid tissue, which can cause recurrent hyperparathyroidism.v-" The removed parathyroid tumor should be weighed on precise scales before formalin fixation and sent to the pathologist for frozen section confirmation of the presence of parathyroid tissue. The normal-sized parathyroid glands should be marked with a fine nonabsorbable suture to facilitate identification of the parathyroid glands when a reoperation for recurrent hyperparathyroidism is necessary. In the case of enlargement of two or three parathyroid glands, the enlarged glands should be removed. In our series of 179 patients with multiple-gland disease, 120 patients had two enlarged parathyroid glands, 40 had three enlarged glands, 18 had four enlarged glands, and 1 had five enlarged glands. After selective removal of the enlarged glands, irrespective of their microscopic appearances, the rate of recurrent hyperparathyroidism was 1.8% after an average follow-up of 13.5 years.f If all parathyroid glands are enlarged, the left and right thymus should be removed because supernumerary parathyroid glands are frequently located in the thymusf To prevent postoperative hypoparathyroidism, a remnant of approximately 50 mg of parathyroid tissue should be left behind. An easily (re)accessible parathyroid gland with a reliable vascular stalk should be chosen for this purpose. In patients with secondary hyperparathyroidism, familial hyperparathyroidism, or MEN 1 syndrome, all parathyroid glands are involved. The rate of recurrent hyperparathyroidism in these patients ranges from 10% to 50%.58-60 A subtotal parathyroidectomy should be performed, leaving behind a well-vascularized remnant of a lower parathyroid with the dimensions of a normal gland. The thymus should be removed bilaterally because a supernumerary parathyroid gland is located in the thymus in 3% to 5% of all patients."I,62 An alternative for subtotal parathyroidectomy is total parathyroidectomy with autotransplantation of parathyroid tissue into the forearm muscles, combined with cryopreservation of some parathyroid tissue. 63

derivative) should be added to the oral medication. Symptoms of muscular cramps and "tetany" must be promptly countered with administration of intravenous calcium. In some patients, symptoms of tetany may develop while the serum calcium level is normal. This is probably due to a rapid decrease in serum calcium after removal of the parathyroid tumor, causing increased neural excitability, but may also persist after calcium replacement resulting from an accompanying hypomagnesemia.v'

Troubleshooting for a Missing Parathyroid Gland The enlarged parathyroid gland can remain undiscovered after routine exploration of the neck in some patients. Several of such "classic" situations are described next. It is of great importance to identify the normal parathyroid glands during the exploration of the neck because a parathyroid missed at its normal localization can indicate the site of the migrated enlarged parathyroid. Situation 1. Three normal parathyroid glands have been identified but the (right) upper parathyroid gland cannot be localized (Fig. 47-5). In this circumstance, the space dorsal to the thyroid gland and the esophagotracheal groove should be explored. The space between the esophagus and the vertebrae should be opened. Digital palpation for the parathyroid tumor can be helpful. Situation 2. Three normal parathyroids have been identified, but the (right) lower gland is absent at the lower pole of the thyroid and in the thyrothymic ligament (Fig. 47-6). The thymus on the side of the missing lower parathyroid should be exposed. The thymus is lighter in color and smoother than the surrounding fat. The retrosternal part of the thymus can be mobilized by applying light tension on the thyrothymic ligament while freeing the thymus by delicate blunt dissection with a peanut sponge.s" As the extraction of the thymus

Closure of the Neck Incision After completion of the parathyroidectomy, the operative field is thoroughly checked for hemostasis. A low-pressure suction drain can be used. The strap muscles and the platysma muscle are closed with an absorbable suture. The skin is closed intracutaneously.

Postoperative Care A successful parathyroidectomy results in a decrease in the serum calcium level, which usually reaches its nadir 48 hours after the operation. Postoperative hypocalcemia is most frequent in patients with severe skeletal depletion of calcium, resulting in "bone hunger." The manifestations of hypocalcemia include numbness around the mouth, tingling of the fingertips, muscle cramps, carpopedal spasms, anxiety, convulsions, main d'accoucheur (Trousseau's sign), and opisthotonos.f If symptoms appear, calcium should be administered. Patients with hypocalcemia should be given a maximum of 3 g of calcium orally per day. In the event that this treatment is ineffective, alfacalcidol (a vitamin D

FIGURE 47-5. Situation 1. (Modified from Thompson NW, EckhauserE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)

Technique of Parathyroidectomy - - 445

FIGURE 47-6. Situation 2. (Modified from Thompson NW, Eckhauser E, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)

FIGURE 47-7. Situation 3. (Modified from Thompson NW, Eckhauser E, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)

proceeds, a small clamp can be moved downward on the thymus to extract the thymus out of the mediastinum. Use of careful blunt dissection prevents injury of the large mediastinal vessels. When the parathyroid tumor has not been found after performing the steps described in situations I and 2, an intrathyroidal parathyroid tumor should be considered. Incision of the thyroid capsule can reveal an intrathyroidal parathyroid. If a parathyroid tumor has not been found at this point, the carotid sheath should be opened from the level of the carotid bifurcation to the base of the neck. When this step has also proved negative, the superior or inferior pole of the thyroid gland should be excised for a missing upper or lower parathyroid gland, respectively. Situation 3. Three normal parathyroids have been localized, but the (left) lower gland is missing (Fig. 47-7). At the level of the superior thyroid artery and anterior to the carotid bulb, an enlarged parathyroid gland with a thymic remnant is encountered. A maldescended fourth pharyngeal pouch is likely, resulting in a cranial position of the upper parathyroid gland. This has been described by Edis and colleagues as an undescended "parathymus,"? Situation 4. Four normal parathyroids have been visualized (Fig. 47-8). Increased levels of parathyroid hormone rule out another cause of hypercalcemia. This situation is not uncommon and can be due to a tumor originating from a supernumerary (fifth) parathyroid gland located in the thymus. Resection of the left and right thymus is indicated. Situation 5. One parathyroid is missing and a contralateral (left lower) gland seems slightly enlarged; the other parathyroids are normal (Fig. 47-9). This is an awkward situation because it is impossible to determine intraoperatively whether this slightly enlarged parathyroid is hyperfunctioning. In the case of moderate hypercalcemia with a mild clinical picture, the slightly enlarged parathyroid can be removed and the procedure completed. In severe disease, the steps in situations I and 2 should be followed. Also, a concomitant

other cause of hypercalcemia may be present (e.g., sarcoidosis or malignancy). Situation 6. On one side, two normal parathyroids are demonstrated; on the other side, a normal parathyroid has been found just below the crossing of the recurrent laryngeal nerve and the inferior thyroid artery (Fig. 47-10). In this situation, it is unclear whether an upper or lower parathyroid is missing; consequently, there is uncertainty about the localization of the parathyroid tumor. In such a case, a virtual coronal plane should be drawn through the recurrent laryngeal nerve.f When the normal parathyroid is located anterior to this plane, the normal parathyroid is the lower parathyroid. If the normal parathyroid is located dorsal to the coronal plane, it is the upper parathyroid.

FIGURE 47-8. Situation 4. (Modified from Thompson NW, Eckhauser E, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)

446 - - Parathyroid Gland

FIGURE 47-9. Situation 5. (Modified from Thompson NW, EckhauserE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)

Normal parathyroid glands should never be removed when a parathyroid tumor cannot be found at an exploration of the neck for hyperparathyroidism. Removal of normal parathyroids never decreases hypercalcemia. On the contrary, it can cause permanent hypoparathyroidism when a successful reoperation is performed. A primary sternotomy should be considered only in patients with life-threatening hypercalcemia.

Mediastinotomy A mediastinotomy should be undertaken only after thorough exploration of the neck, including inspection of the para- and retroesophageal space and the left thymus and right thymus.

The anterior mediastinum is exposed through an additional vertical incision from the suprasternal notch to the second or third intercostal space on either the right or left side. A complete sternotomy is done when the posterior mediastinum is explored. Appropriate care should be taken not to injure the internal mammary vessels or the pleura. The left innominate vein can be retracted or divided to inspect the anterior mediastinum. In a series of 400 patients with primary hyperparathyroidism, 84 mediastinal parathyroid tumors were observed/" Only 19 (5%) parathyroid tumors had to be removed through a mediastinotomy. Conn and coworkers reported that only 22% of all mediastinal parathyroid tumors required splitting of the sternum to remove the tumors." In this study, a mediastinal parathyroid tumor was not found when thallium-technetium scanning, computed tomography scanning, magnetic resonance imaging, or angiography of the mediastinum did not detect a parathyroid tumor. In a large series of 2770 patients with primary hyperparathyroidism, only 38 patients (1.4%) had a mediastinotomy to remove an enlarged parathyroid gland." Thoracoscopy has been reported to be a successful minimally invasive technique to remove parathyroid tumors located deep in the mediastinum.F The parathyroid glands that require a mediastinotomy for removal are either ectopic lower parathyroids, which descended into the anterior mediastinum during embryologic development, or supernumerary parathyroids. The blood supply of these mediastinal parathyroids is usually derived from the internal mammary vessels. Approximately 70% of the mediastinal parathyroid glands are found within or attached to the thymus. 69,71 Other locations of mediastinal parathyroids are at the ascending aorta, aortic arch, and its major branches and occasionally on the pericardium.

Lateral Approach for Parathyroid Exploration The lateral approach for parathyroidectomy was first described by Peind." This approach involves dissection between the anterior border of the sternocleidomastoid muscle and the posterior border of the strap muscles." The omohyoid muscle is usually divided. Retraction of the sternocleidomastoid muscle and the carotid sheath laterally and the strap muscles medially exposes the lateral aspect of the thyroid gland, the tracheoesophageal groove, the recurrent laryngeal nerve, and the parathyroid glands. The lateral approach is preferable in parathyroidectomy under local anesthesia because the limited dissection and moderate retraction of the neck muscles are well tolerated by patients.s" Another indication for the lateral approach is parathyroidectomy after previous neck surgery. The lateral approach in these patients provides a dissection plane more likely to be devoid of scar tissue from the previous operation."

Summary FIGURE 47-10. Situation 6. (Modified from Thompson NW, Eckhauser E, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)

An understanding of the embryology of the parathyroid glands and the ability to distinguish between a normal and an abnormal parathyroid gland are essential for successful

Technique of Parathyroidectomy - - 447

parathyroid surgery. A systematic approach knowing the routine and unusual locations for parathyroid glands results in successful parathyroidectomy in more than 95% of patients with primary hyperparathyroidism. Normal parathyroid glands should not be removed, and biopsy should be done selectively. Routine biopsy of normal parathyroid glands results in more hypoparathyroidism.

REFERENCES I. Cope O. The story of hyperparathyroidism at the Massachusetts General Hospital. N Engl 1 Med 1966;274: 1174. 2. Boyd JD. Development of the thyroid and parathyroid glands and the thymus. Ann R Coli Surg Engl 1950;7:455. 3. Mansberger AR, Wei JP. Surgical embryology and anatomy of the thyroid and parathyroid glands. Surg Clin North Am 1993;73:727. 4. Wang CA. Surgical management of primary hyperparathyroidism. Curr Probl Surg 1985;12:1. 5. Gilmour lR. The gross anatomy of the parathyroid glands. 1 Pathol 1938;46: 133. 6. Akerstrom G, Malmaeus 1, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95:14. 7. Russell CF, Grant CS, van Heerden lA. Hyperfunctioning supernumerary parathyroid glands. Mayo Clin Proc 1982;57:121. 8. Edis AJ, Levitt MD. Supernumerary parathyroid glands: Implications for the surgical treatment of secondary hyperparathyroidism. World 1 Surg 1987;11:398. 9. Wang CA, Mahaffey JE, Axelrod L, Perlman lA. Hyperfunctioning supernumerary parathyroid glands. Surg Gynecol Obstet 1979;148:711. 10. Cope O. Surgery of hyperparathyroidism: The occurrence of parathyroids in the anterior mediastinum and the division of the operation into two stages. Ann Surg 1941;114:706. II. Wang CA. Hyperfunctioning intrathyroid parathyroid gland: A potential cause of failure in parathyroid surgery. 1 R Soc Med 1981;74:49. 12. Wheeler MH, WIlliams ED, Path FRC, Wade lSH. The hyperfunctioning intrathyroidal parathyroid gland: A potential pitfall in parathyroid surgery. World 1 Surg 1987;11:110. 13. Black EM, Zimmer lE Hyperparathyroidism, with particular reference to treatment. Arch Surg 1956;72:830. 14. Hellstrom 1, Ivemark BI. Primary hyperparathyroidism: Clinical and structural findings in 138 cases. Acta Chir Scand 1962;294S:1. 15. Coffey RJ, Potter IF, Canary 11. Diagnosis and surgical control of hyperparathyroidism. Ann Surg 1965;161:732. 16. Katz AD, Hopp D. Parathyroidectomy: Review of 338 consecutive cases for histology, location and reoperation. Am 1 Surg 1982; 144:411. 17. Thompson NW. The techniques of initial parathyroid exploration and reoperative parathyroidectomy. In: Thompson NW, Vinik AI (eds), Endocrine Surgery Update. New York, Grune & Stratton, 1983, p 365. 18. Wang CA. The anatomic basis of parathyroid surgery. Ann Surg 1975;183:271. 19. Wang CA. Parathyroid re-exploration: A clinical and pathological study of 112 cases. Ann Surg 1977;186:140. 20. Bruining HA. Operative strategy in primary hyperparathyroidism. In: Kaplan EL (ed), Surgery of the Thyroid and Parathyroid Glands. Assen, The Netherlands, Van Gorcum, 1983, p 158. 21. Grimelius L, Johansson H, Ljunghall S, et al. Controversies in the treatment of hyperparathyroidism. Acta Chir Scand 1979;145:355. 22. Gilmour JR, Martin Wl. The weight of the parathyroid glands. 1 Pathol Bacteriol 1937;44:431. 23. Dufour R, Wilkerson SY. Factors related to parathyroid weight in normal persons. Arch Pathol Lab Med 1983;107:167. 24. Akerstrom G, Grimelius L, Johansson H, et al. The parenchymal cell mass in normal human parathyroid glands. Acta Pathol Microbiol Scand 1981;89:367. 25. Castleman B, Roth SI. Tumors of the Parathyroid Glands (Atlas of Tumor Pathology, 2nd series). Washington, DC, Armed Forces Institute of Pathology, 1978, p 14. 26. Delattre JF, Flament JB, Palot lP, Pluot M. Les variations des parathyroides. Nombre 2, situation et vascularisation arterielle. Etude anatomique et applications chirurgicales. 1 Chir (Paris) 1982;1l9:633.

27. Hackeng WHL, Lips P, Netelenbos rc, Lips C1M. Clinical implications of estimation of intact parathyroid hormone (PTH) versus total immunoreactive PTH in normal subjects and hyperparathyroid patients. 1 Clin Endocrinol Metab 1986;63:447. 28. Blind E, Schmidt-Gayk H, Armbruster FP, Stadler A. Measurement of intact human parathyrin by an extracting two-site immunoradiometric assay. Clin Chern 1987;33:1376. 29. Frolich M, Walma ST, Paulson C, Papapoulos SE. Immunoradiometric assay for intact parathyroid hormone: Characteristics, clinical application and comparison with a radio-immunoassay. Ann Clin Biochem 1990;27:69. 30. Brennan MF, Doppman Jl., Kurdy AG, et al. Assessment of techniques for preoperative parathyroid gland localization in patients undergoing reoperation for hyperparathyroidism. Surgery 1981;91:6. 31. Edis AJ, Sheedy PF II, Beahrs OH, van Heerden lA. Results of reoperation for hyperparathyroidism, with evaluation of preoperative localization studies. Surgery 1978;84:384. 32. Patow CA, Norton lA, Brennan ME Vocal cord paralysis and reoperative parathyroidectomy. Ann Surg 1986;203:282. 33. Pyrtek U, Belkin M, Bartus S, Schweizer R. Parathyroid gland exploration with local anaesthesia in elderly and high-risk patients. Arch Surg 1988;123:614. 34. Lore 1M. An Atlas of Head and Neck Surgery. Philadelphia, WB Saunders, 1988, p 729. 35. Bruining HA. Surgical Treatment of Hyperparathyroidism. Springfield, Ill, Charles C Thomas, 1971, p 44. 36. Cooke TJC, Boey JH, Sweeney EC, et al. Parathyroidectomy: Extent of resection and late results. Br 1 Surg 1977;64:153. 37. Paloyan E, Lawrence AM, Baker WH, et al. Near total parathyroidectomy. Surg Clin North Am 1969;43:49. 38. Rudberg C, Akerstrorn G, Palmer M, et al. Late results of operation for primary hyperparathyroidism in 441 patients. Surgery 1986;99:643. 39. Haff RC, Armstrong RG. Trends in the current management of primary hyperparathyroidism. Surgery 1974;75:715. 40. Badder EM, Graham WP III, Harrison TS. Functional insignificance of microscopic parathyroid hyperplasia. Surg Gynecol Obstet 1977; 145:863. 41. Lawrence DAS. A histological comparison of adenomatous and hyperplastic parathyroid glands. 1 Clin Pathol 1978;31 :626. 42. Nishiyama RH. Pathology of parathyroid tumors. In: Thawley SE, Panje WR (eds), Comprehensive Management of Head and Neck Tumors. Philadelphia, WB Saunders, 1987, p 1650. 43. Bonjer H1. Single and Multiple Gland Disease in Primary Hyperparathyroidism [thesis]. Rotterdam, The Netherlands, Erasmus University, 1992, p 57. 44. Bonjer HJ, Bruining HA, Birkenhager lC, et al. Single and multigland disease in primary hyperparathyroidism: Clinical follow-up, histopathology, and flow cytometric DNA analysis. World 1 Surg 1992;16:737. 45. Nishiyama RH. The intraoperative diagnosis of parathyroid lesions. Acta Chir Aust 1994;112:8. 46. Edis AJ, Beahrs OH, van Heerden lA, Akwari OE. "Conservative" versus "liberal" approach to parathyroid neck exploration. Surgery 1977;82:466. 47. Kaplan EL, Bartlett S, Sugimoto 1, Frediand A. Relation of postoperative hypocalcemia to operative techniques: Deleterious effect of excessive use of parathyroid biopsy. Surgery 1982;92:827. 48. Wang CA, Rieder SV. A density test for the intraoperative differentiation of parathyroid hyperplasia from neoplasia. Ann Surg 1978;187:63. 49. Dekker A, Dunsford HA, Geyer Sl, The normal parathyroid gland at autopsy. The significance of stromal fat in adult patients. 1 Pathol 1979;128:127. 50. Dufour DR, Wilkerson SY. The normal parathyroid revisited: Percentage of stromal fat. Hum PathoI1982;13:717. 51. Tibblin S, Bondeson AG, Ljungberg O. Unilateral parathyroidectomy in hyperparathyroidism due to single adenoma. Ann Surg 1982;195:245. 52. Bondeson AG, Bondeson L, Ljungberg 0, Tibblin S. Fat staining in parathyroid disease. Diagnostic value and impact on surgical strategy: Clinicopathologic analysis of 191 cases. Hum PathoI1986;17:1255. 53. Thompson NW, Sandelin K. Technical considerations in the surgical management of primary hyperparathyroidism caused by multiple gland disease (hyperplasia). Acta Chir Aust 1994;112S:16. 54. Wells SA, Leight GS, Hensley M, Dilley WG. Hyperparathyroidism associated with the enlargement of two or three parathyroid glands. Ann Surg 1985;202:533.

448 - - Parathyroid Gland 55. Akerstrorn G, Rudberg C, Grimelius L, Rastad 1. Recurrent hyperparathyroidism due to parathyroid tissue. Acta Coo Scand 1988;154:549. 56. Rattner DW, Marrone GC, Kasdon E, Silen W. Recurrent hyperparathyroidism due to implantation of parathyroid tissue. Am 1 Surg 1985;149:745. 57. Bonjer HI, Bruining HA, Bagwell CB, et al. Primary hyperparathyroidism: Pathology, flow cytometric DNA analysis, and surgical treatment. Crit Rev Clin Lab Sci 1992;29:1. 58. Lamers CBHW, Froeling PGAM. Clinical significance of hyperparathyroidism in familial multiple endocrine adenomatosis type 1 (MEA I). Am 1 Med 1979;66:422. 59. Clark OH, Way LW, Kunt TK. Recurrent hyperparathyroidism. Ann Surg 1976;184:391. 60. Marsden P, Day JL. Hyperparathyroidism: The risk of recurrence. Clin Endocrinol (Oxf) 1973;2:9. 61. Palmer JA, Sutton FR. Importance of a fifth parathyroid gland in the surgical treatment of hyperparathyroidism. Can J Surg 1978;21 :350. 62. Goretzki PE, Dotzenrath C, Rocher 00. Management of primary hyperparathyroidism caused by multiple gland disease. World J Surg 1991;15:693. 63. Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy versus total parathyroidectomy versus total parathyroidectomy and autotransplantation in secondary hyperparathyroidism: A randomized study. World J Surg 1991;15:745. 64. Clark OH, Siperstein AE. The hypercalcemic syndrome: Hyperparathyroidism. In: Friesen SR, Thompson NW (eds), Surgical Endocrinology: Clinical Syndromes, 2nd ed. Philadelphia, JB Lippincott, 1990, p 311.

65. Granberg PO, Cederrnark B, Farnebo LO, et al. Parathyroid tumors. Curr Probl Cancer 1985;9:32. 66. Ahlers J, Rothmund M. Die cervicale Thymektomie als erweitertes Operationsverfahren beim prirnaren und sekundaren Hyperparathyroidismus. Chirurg 1980;51:629. 67. Edis AJ, Purnell DB, van Heerden lA. The undescended "parathymus": An occasional cause of failed neck exploration for hyperparathyroidism. Ann Surg 1979:190:64. 68. Pyrtek U, Painter RL. An anatomic study of the relationship of the parathyroid glands to the recurrent laryngeal nerve. Surg Gynecol Obstet 1964;9:509. 69. Nathaniels EK, Nathaniels AM, Wang CA. Mediastinal parathyroid tumors: A clinical and pathological study of 84 cases. Ann Surg 1970;171:165. 70. Conn JM, Goncalves MA, Mansour KA, McGarity WC. The mediastinal parathyroid. Am Surg 1991;57:62. 71. Russel CF, Edis AI, Scholz DA, et al. Mediastinal parathyroid tumors: Experience with 38 tumors requiring mediastinotomy for removal. Ann Surg 1981;193:805. 72. Prinz RA, Lonchyna V, Camaille B, et al. Thoracoscopic excision of enlarged mediastinal parathyroid glands. Surgery 1994;116:999. 73. Feind CR. Re-exploration for parathyroid adenoma. Am J Surg 1964; 108:543. 74. Stevens JC. Lateral approach for exploration of the parathyroid gland. Surg Gynecol Obstet 1979;148:431. 75. Kadowski MH, Fulton N, Shark C, et al. Difficulties of parathyroidectomy after previous thyroidectomy. Surgery 1989; I06: 1018.

Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) Quan-Yang Duh, MD

Surgery offers the only definitive treatment for patients with primary hyperparathyroidism. I The success of parathyroidectomy depends on the skill and judgment of the surgeon. The best surgical approach should give the highest rate of cure with the lowest rate of complications. In this chapter, issues that influence surgical strategy are discussed. A strong case is made for surgeons to have a good understanding of the embryologic development of the parathyroid glands and to have experience in exploring thoroughly both sides of the neck during the initial operation for primary hyperparathyroidism. Advances in localization studies and intraoperative parathyroid hormone (PTH) monitoring allow the surgeon to limit the extent of exploration in some patients. Bilateral exploration of all four parathyroid glands, however, remains the "gold standard," against which the results of other approaches are evaluated. Bilateral exploration is necessary in patients who are at high risk for having multiple-gland disease, such as those with familial syndromes and those with negative localization studies. When in doubt, bilateral exploration, identifying all four parathyroid glands, is most likely to result in the highest success rate.

Indications for Parathyroidectomy Primary hyperparathyroidism is a common disease in nontropical areas of the world. It is found in 1 in 2000 men and in 1 in 500 women after menopause and is more common in elderly people. Because hypercalcemia is frequently detected by routine laboratory studies and because of the availability of specific, sensitive, and accurate assays for intact PTH, most patients are diagnosed now at an early stage. Thus, it is uncommon to see patients with severe

primary hyperparathyroidism with osteitis fibrosa cystica or nephrolithiasis with renal dysfunction.

Etiology of Primary Hyperparathyroidism About 80% of patients with primary hyperparathyroidism have a single adenoma, 15% have hyperplasia of all four glands, and 5% have double adenomas.? The cause of parathyroid adenoma or hyperplasia is not known. Head and neck irradiation increases the risk of primary hyperparathyroidism by 11% per centigray.v' Ten percent of parathyroid adenomas have a PRAD-I oncogene (cyclin D gene activated by PTH promoter). Mutations in the calcium sensor protein appear not to be an important cause of primary hyperparathyroidism.' although decreased calcium receptor has been described in parathyroid adenomas and in hyperplastic parathyroid glands in patients with chronic renal failure. Retinoblastoma tumor suppressor gene is found to be frequently mutated in parathyroid cancers," whereas p53 mutations are rare.' Two thirds of apparently sporadic parathyroid cancers have mutations in the HRPT2 gene, the gene responsible for the hyperparathyroidism-jaw tumor syndrome.! Patients with multiple endocrine neoplasia (MEN) types 1 and 2A are more likely to have hyperparathyroidism, as are family members of patients with familial hyperparathyroidism. In the mouse, deletion of the MEN 1 tumor suppressor gene in the parathyroid gland results in parathyroid neoplasia and hypercalcemic hyperparathyroidism." Patients with Cowden's disease'? (breast cancer, thyroid neoplasm, and gastrointestinal polyps) and McCune-Albright syndrome!' (caused by activating mutations of the stimulating guanosine triphosphate-binding protein) are also at higher risk for developing primary hyperparathyroidism.

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450 - - Parathyroid Gland

Diagnosis of Primary Hyperparathyroidism The biochemical diagnosis of primary hyperparathyroidism is made by documenting an elevated serum PTH in a patient with hypercalcemia (serum calcium> to.5 mg/dL) without hypocalciuria. Patients with benign familial hypocalciuric hypercalcemia (BFHH) are also hypercalcemic and have an inappropriately high PTH. Virtually all patients with other causes of hypercalcemia have a suppressed serum PTH level. Patients with BFHH have elevated levels of PTH in the presence of hypercalcemia because of mutations in the gene encoding the extracellular calcium sensor protein, making the parathyroid cells less sensitive to hypercalcemia.P BFHH can be suspected on the basis of a family history and identified by low urinary calcium excretion (calcium clearance less than 1% of creatinine clearance). Cancer is the other most common cause of hypercalcemia." Patients with hypercalcemia of malignancy can be diagnosed by a thorough history and physical examination. Many solid tumors associated with hypercalcemia secrete parathyroid hormone-related protein (PTHrP); others cause hypercalcemia through cytokines or by direct bone destruction. With the exception of some very rare renal cell carcinomas and ovarian carcinomas that secrete PTH, none of these patients have elevated serum PTH levels. Other laboratory findings consistent with primary hyperparathyroidism include a low serum phosphorus level «2.5 mg/dL), elevated serum chloride level (> 107 mmol!L), and elevated serum chloride-to-phosphate ratio (>33). Some patients have elevated serum levels of alkaline phosphatase and uric acid. Subperiosteal resorption can be demonstrated in hand radiographs of patients with elevated alkaline phosphatase levels. It is rare in other patients with primary hyperparathyroidism.

Mild Primary Hyperparathyroidism The symptoms and signs of mild primary hyperparathyroidism can be more subtle and less specific, such as fatigue, weakness, lethargy, depression, memory loss, personality changes, constipation, and decreased bone density. It is controversial whether to operate on patients with few or no symptoms or metabolic problems and minimal hypercalcemia. A prospective study of patients with primary hyperparathyroidism showed, however, that truly asymptomatic patients are uncommon: less than 5% of patients." Many patients with these nonspecific symptoms improved after a successful parathyroid operation compared with a control group of patients who underwent thyroidectomy. Ninety-five percent had improvement of one or more symptoms after parathyroidectomy, and 55% felt better overall (compared with 30% after thyroidectomyj.P The severity of hypercalcemia did not correlate with the presence of these symptoms before parathyroidectomy; neither did it correlate with the improvement in symptoms after successful surgery.l-!"

Benefits of Parathyroidectomy in Patients with Primary Hyperparathyroidism Patients with untreated primary hyperparathyroidism have an increased risk of death from cardiovascular disease and cancers. This increased risk of death is similar in magnitude to that associated with smoking, and the risk appeared to correlate with parathyroid tumor size and the peak calcium level. 17,18 Parathyroidectomy benefits most patients with primary hyperparathyroidism. Muscle strength and fine motor function'? as well as psychiatric symptoms'" improve within 1 month after parathyroidectomy. The incidence of renal colic decreases from 66% to 2% per year 1 year after parathyroidectomy." Left ventricular hypertrophy also improves within 1year after parathyroidectomy.P Bone mineral density improves after parathyroidectomy in patients with asymptomatic primary hyperparathyroidism, and the improvement is sustained for at least 4 years after parathyroidectomy.-' Quality of life measurement also improves after parathyroidectomy.t'

Surgical Strategy in Patients with Primary Hyperparathyroidism The primary goal of parathyroidectomy for patients with primary hyperparathyroidism is to cure the primary hyperparathyroidism and to achieve normocalcemia. The best surgical strategy should achieve this goal with minimal complications, such as persistent hyperparathyroidism, recurrent hyperparathyroidism, postoperative hypoparathyroidism, and recurrent laryngeal nerve injury, and with efficient use of operating time and resources. The most important variable that influences the success of parathyroidectomy is the experience of the surgeon. The success rate for parathyroidectomy reported by most endocrine surgery centers is 95% or better. The rate of persistent hyperparathyroidism can be as high as 30% in less experienced hands." Persistent hyperparathyroidism is usually caused by missing an ectopic tumor or missing one of the multiple abnormal glands." Recurrent hyperparathyroidism usually occurs in patients with familial disease, such as those with familial hyperparathyroidism and MEN 1.26 It is more cost-effective to have a higher success rate in the initial operation than to rely on reoperation when the initial operation fails. Although reoperation for hyperparathyroidism can be successful 90% of the time.i? it costs twice as much because of the need for preoperative localization studies.l" and the risk of recurrent nerve injury is higher. The general principles that my colleagues and I follow for surgical exploration in patients with primary hyperparathyroidism are listed in Table 48-1.

Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) - -

451

Double adenomas are more common in older patients; the incidence is about 9% for patients older than 60 years." Finding only a minimally enlarged parathyroid gland in a patient who has severe hypercalcemia should also raise the suspicion that another larger parathyroid tumor is present and should be found and resected. When frozen section reveals an oxyphil adenoma, one should also identify at least four parathyroid glands because some oxyphil adenomas are nonfunctional. Interestingly, double adenomas are not distributed randomly; it is much more likely to have bilateral upper gland double adenomas than would be predicted by random distribution.P

Initial Operation No routine localization study is necessary before the initial neck exploration for patients with primary hyperparathyroidism.29.30 A small, low cervical incision along the skin crease is made. The strap muscles are dissected and separated but are not divided. The surgical plane of dissection is different for parathyroidectomy and thyroidectomy. For thyroidectomy, I dissect as close to the thyroid gland as possible, taking individual branches of the thyroid vessels on the thyroid gland and leaving the parathyroid glands lateroposteriorly in the surrounding tissue to preserve vascularity when the thyroid gland is removed. For parathyroidectomy, I dissect more laterally along the carotid sheath, leaving the parathyroids on the posterior surface of the thyroid gland, thus making them easier to find. Both sides of the neck are explored, and all four glands are tentatively identified before any gland is resected. I rarely perform mediastinotomy during initial operation unless the patient is severely hypercalcemic (serum calcium> 14 mg/dL after optimal medical treatment) because many of these can be removed by thoracoscopy or mediastinoscopy."

Single Adenoma When a single large parathyroid tumor is found, the remaining three parathyroid glands are identified. The large tumor is then excised and confirmed by frozen section. If there is doubt about the nature of the normal-appearing parathyroid glands, a biopsy of one of them can be performed by placing a titanium clip at the tip of the gland away from the hilum to avoid devascularizing the gland. The risk of postoperative hypoparathyroidism is increased if biopsies of all normal parathyroid glands are performed routinely, so routine biopsy of all normal parathyroid glands should be discouraged.l? An experienced surgeon can accurately identify 95% of normal parathyroid glands, even without frozen section.

Double Adenomas When two enlarged parathyroid glands are found, the remaining two normal glands should also be identified. One or both of the normal-appearing glands should be biopsied, marked with a titanium clip, and confirmed by frozen section. This avoids leaving two hyperplastic glands should the patient have parathyroid hyperplasia and asymmetrically enlarged glands. The two tumors should then be excised and confirmed by frozen section.

Hyperplasia When all the glands are enlarged (>7 mm in largest dimension), the patient has hyperplasia. A subtotal parathyroidectomy is indicated. My routine procedure is to identify all four glands and then perform a biopsy on the one that appears the least abnormal and is away from the recurrent laryngeal nerve, leaving a 50-mg remnant marked by a titanium clip. After the parathyroid tissue is confirmed by frozen section and the remnant appears to be well vascularized and viable, the remaining three abnormal glands can be excised and confirmed by frozen section. If the remnant appears dusky and its viability is questionable, with a high risk of postoperative hypoparathyroidism, it is completely excised, and a second gland should be chosen for subtotal resection, and so on. Performing the subtotal resection first before removing the rest of the abnormal glands gives four chances to leave a perfect remnant. Bilateral cervical thymectomy should be a routine part of the operation in patients with hyperplasia because supernumerary glands occur in 20% of patients and are usually situated in the thymus or perithymic fat. Some parathyroid tissue, preferably that from the least abnormal hyperplastic parathyroid gland, should be cryopreserved. If the patient becomes hypoparathyroid later, the tissue can then be autotransplanted. Total parathyroidectomy with autotransplantation to the forearm is an alternative that I do not usually use. It has a lower risk of recurrence but a higher risk of hypoparathyroidism than subtotal parathyroidectomy for parathyroid hyperplasia. Total parathyroidectomy is indicated in children with severe neonatal hypercalcemia because of the high risk of persistent hyperparathyroidism after a subtotal parathyroidectomy. Parathyroid tissue should also be cryopreserved. Parathyroid hyperplasia occurs in 15% to 20% of cases in various published series. When hyperplasia is found, one should be suspicious of familial hyperparathyroidism or MEN. Patients with a family history of hyperparathyroidism tend to have a more severe presentation clinically, are more likely to have multiple gland disease, and are at higher risk for persistent or recurrent hyperparathyroidism after parathyroidectomy. Thyroid anomalies may also be associated with parathyroid hyperplasia. 34 If thyroid hemiagenesis or agenesis of the isthmus is found in a patient with primary hyperparathyroidism, parathyroid hyperplasia should be suspected.

452 - - Parathyroid Gland

Multiple Endocrine Neoplasia and Familial Hyperparathyroidism Patients with MEN 1 and familial hyperparathyroidism without other endocrine disorders usually, but not inevitably, have hyperplasia; the gland size can vary significantly. When all glands are enlarged, a subtotal parathyroidectomy or a total parathyroidectomy with autotransplantation as well as bilateral thymectomy is indicated; some parathyroid tissue should be cryopreserved. In patients with MEN 1 who have one or two enlarged parathyroid glands, resection of only these glands with biopsy of the normal-appearing glands is an adequate operation with a higher risk of recurrent hyperparathyroidism over the patient's lifetime.P One alternative is a unilateral clearance of all parathyroid tissues from the affected side of the neck, including a unilateral cervical thymectomy, so that if hyperparathyroidism recurs in the remaining glands, the reoperation will be needed only on the contralateral side." Patients with MEN 2A can also have hyperparathyroidism. All of these patients warrant total thyroidectomy and possible central neck node dissection to treat or prevent medullary thyroid cancer. In contrast to patients with MEN I, those with MEN 2A are likely to develop hypoparathyroidism after a subtotal parathyroidectomy. One should, therefore, resect only the enlarged glands and biopsy and mark the normal-appearing glands. Patients with MEN 2A are much less likely to develop recurrent hyperparathyroidism than those with MEN I or familial hyperparathyroidism without MEN.35 Total parathyroidectomy with autotransplantation is more aggressive than necessary for these patients.

Location of Parathyroid Glands An ectopically situated parathyroid tumor is a common cause of persistent hyperparathyroidism (Fig. 48-1). This is one reason why an experienced surgeon achieves a 95% success rate for the initial parathyroid operation, by knowing where the parathyroid glands are commonly found, whereas an inexperienced surgeon has only about a 70% success rate.25 The inferior parathyroid glands and the thymus develop embryologicallyfrom the third branchial pouch. They descend from the upper neck down to the anterior mediastinum. Ectopic lower parathyroid glands can, therefore, be found anywhere along this long path of descent. The lower parathyroid glands are usually on the surface of the lower pole of the thyroid gland or in the thyrothymic ligament. They are frequently found within or adjacent to the thymus in the upper anterior mediastinum and are rarely found in the carotid sheath. The most common position of the inferior parathyroid gland is anteroinferior to the junction of the inferior thyroid artery and the recurrent laryngeal nerve. The superior parathyroid glands develop from the fourth branchial pouch. They descend less than the third branchial pouch and, therefore, become the superior glands. The superior glands vary less in position than the inferior glands. The most common location for the superior gland is just superoposterior to the junction of the inferior thyroid artery and the recurrent laryngeal nerve at the level of the cricoid cartilage. The superior parathyroid gland is frequently found in the

FIGURE 48-1. Locations of parathyroid tumors found at reoperation after a failed initial operation. Most of these parathyroid tumors can be excised through a neck incision, and most would have been found at the initial operation if the common ectopic locations were thoroughly explored in both sides of the neck. (From Shen W, Duren M, Morita E, et aI. Reoperation for persistent or recurrent primary hyperparathyroidism. Arch Surg 1996;131:861. © 1996, American Medical Association.)

tracheoesophageal groove posteriorly and may descend along the esophagus into the posterior mediastinum. Intrathyroidal parathyroid glands occur in about I % of patients and may originate from a superior or an inferior parathyroid gland. Intrathyroidal parathyroid glands account for about 12% of failed initial operations. Ultrasonography helps identify these tumors."

Focused or Unilateral Neck Exploration Versus Bilateral Neck Exploration for Primary Hyperparathyroidism Rationale for Focused or Unilateral Exploration Currently, there are three different approaches to parathyroidectomy; they differ in the extent of exploration. For the bilateral approach, the surgeon explores and identifies all four parathyroid glands. For the unilateral approach, the surgeon identifies two glands on the same side of the neck. For the focused approach, only one gland (the presumed single adenoma) is identified. There are potential advantages of a focused or unilateral approach for parathyroidectomy. In theory at least, not having to find all the other parathyroid glands when a parathyroid adenoma is already identified can shorten the operating time and lower the risk of injury to the recurrent laryngeal nerve and other normal parathyroid glands. A focused approach

Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) - - 453

requires localization studies to pinpoint the most likely location of the adenoma. In the past, my colleagues and I used the focused approach routinely only in patients undergoing reoperations to avoid unnecessary dissection in scarred tissue; this is possible with the aid of multiple localization studies.'? With the widespread use of preoperative localization studies in patients undergoing the initial operation, the focused approach has gained popularity. Several techniques have been described; many are called "minimally invasive parathyroidectomy," including small lateral incision, local anesthesia, gamma probe guidance, and video-assisted techniques. In general, for a successful focused approach to parathyroidectomy, the surgeon needs to know where to start the operation (localization studies) and when to stop (intraoperative PTH monitoring or by calculation of probabilityl.P'-" If bilateral exploration is planned for the initial operation, no localization studies or intraoperative monitoring of PTH is necessary because 95% of the abnormal glands can be found by the surgeon without these studies. There is controversy regarding whether routine use of localization studies for initial parathyroid surgery is economically justifiable or necessary. If a focused or unilateral approach is planned, a localization study is necessary to help the surgeon decide where to start the exploration. In the traditional unilateral approach, the surgeon chooses the side of initial exploration randomly and does not use localization studies or PTH monitoring.t" One side of the neck is chosen randomly for the initial exploration. If a localization study has been done and it is positive, the side of the neck where the adenoma is expected is explored. If an abnormal gland and a normal gland are found and confirmed by frozen section, the abnormal gland is presumed to be the only adenoma that is causing the patient's primary hyperparathyroidism. The contralateral side is not explored. If the initial side shows two normal parathyroid glands, the contralateral side is then explored to look for the adenoma. If two abnormal glands are found on the initial side, hyperplasia is presumed, and the contralateral side is explored to perform a subtotal parathyroidectomy. If only one gland is found on the initial side, the contralateral side is also explored/? For focused exploration, localization studies are used to direct where the exploration should be started. Intraoperative PTH is used to monitor the drop in PTH; a greater than 50% drop from either the baseline or preexploration level (whichever is higher) 10 minutes after excising the adenoma predicts a successful operation." Once the adenoma is found and the intraoperative PTH confirms that there are no more pathologic parathyroid glands remaining, which occurs in almost all cases of patients with a single adenoma, the operation is concluded. There is controversy, however, regarding the accuracy of intraoperative PTH monitoring to predict the presence of a second adenoma or hyperplasia." It has been shown that double adenomas are found in fewer patients when focused exploration is used than when bilateral exploration is used. The discrepancy is caused by some large glands that are either "nonsecreting large parathyroid glands" or "latent adenomas." Long-term follow-up is needed to distinguish between the two possibilities. There is an alternative way to perform a focused parathyroidectomy without using intraoperative PTH monitoring. Both sestamibi scanning and ultrasonography are performed.

In two thirds of patients, both studies show a single adenoma and are concordant in location. Focused exploration in this subgroup of patient is successful in 96% without using intraoperative PTH monitoring.F Although it may seem obvious that complications should occur less with a focused or unilateral approach compared with a bilateral approach, it remains to be proved. Studies comparing the results of a focused or unilateral approach with those of a bilateral approach have not compared them by intent." Series of bilateral explorations routinely include complicated cases of multiple adenomas and hyperplasia, whereas series of focused or unilateral approaches have selected the patients who are likely to have a single adenoma and thus less likely to have failure or complications. Operating time perhaps should be shorter for the more limited approaches, but it is mostly surgeon dependent." Some proponents of bilateral exploration argue that exploring the remaining normal glands should not take longer than the time spent waiting for the results of intraoperative PTH. There are no prospective randomized studies comparing these approaches.

Incidence of Multiple-Gland Disease and the Accuracy of Localization Studies and Intraoperative PTH Monitoring Determine the Success of the Focused or the Unilateral Approach The most serious potential problem of the focused or unilateral exploration is failure to identify a second adenoma or hyperplasia. This risk depends on the percentage of patients with multiglandular disease, the accuracy of localization studies to identify multiglandular disease, and the accuracy of intraoperative PTH monitoring to identify a residual pathologic parathyroid gland.r' The long-held belief that 15% to 20% of patients have multiglandular disease is being challenged by some series with excellent short-term results after a focused approach aided by preoperative sestarnibi scanning and intraoperative PTH monitoring showing that only 5% of patients have multiglandular disease.f Most studies have shown that localization studies are much less accurate for multiple-gland disease than for a single adenoma. The sensitivity of most studies is greater than 80% for a single adenoma but much lower for multiglandular disease. 46,47 A rule of thumb is that one third of patients with multiglandular disease would have a negative scan, one third would have a scan consistent with a single adenoma, and one third would have a scan showing more than one abnormal gland.f The accuracy of intraoperative PTH monitoring for multiglandular disease also remains controversial."

Difficulty in Determining Whether a Parathyroid Tumor is an Adenoma or Hyperplasia Inherent in the strategy of focused or unilateral exploration is the assumption that one can identify an abnormal parathyroid gland as an adenoma or as part of generalized hyperplasia. Most endocrine surgeons and experienced endocrine pathologists believe that one cannot make a definitive diagnosis of adenoma versus hyperplasia by examining only the

454 - - Parathyroid Gland abnormal gland. Characteristics other than size of the gland can help distinguish between an adenoma or a hyperplastic parathyroid gland and a normal gland. Abnormal or hypercellular parathyroid tissue is darker, firmer, and more vascular; sinks in saline; and has a low fat content and high cellularity. A compressed rim of normal parathyroid tissue is suggestive of an adenoma, but there are many exceptions. Data from physiologic and molecular studies support the existence of double adenomas. Intraoperative PTH monitoring shows that in some patients the PTH level does not become normal until a second adenoma is excised. 48,49 Many parathyroid tumors that are considered hyperplastic histologically can be shown to be monoclonal tumors. 50

Conclusion Primary hyperparathyroidism can be definitively diagnosed on the basis of an elevated serum PTH in hypercalcemic patients without hypocalciuria. Asymptomatic patients with minimal hypercalcemia appear to benefit from successful parathyroidectomy, and 95% of patients can be cured when treated by an experienced endocrine surgeon. Focused exploration and unilateral neck exploration are acceptable when the probability of multiglandular disease is low; the success rate is high if two preoperative localization studies show concordance or a successful localization study is combined with intraoperative PTH monitoring. Bilateral neck exploration, however, remains a safe approach with an excellent success rate. Whether the focused or unilateral exploration is superior to the bilateral approach in success rate, complication rate, or cost-effectiveness remains to be proved by a prospective randomized study.

REFERENCES 1. NIH conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus development conference statement. Ann Intern Med 1991;114:593. 2. Bartsch D, Nies C, Hasse C, et al. Clinical and surgical aspects of double adenoma in patients with primary hyperparathyroidism. BrJ Surg 1995;82:926. 3. Schneider AB, Gierlowski TC, Shore-Freedman E, et aI. Dose-response relationships for radiation-induced hyperparathyroidism. J Clin Endocrinol Metab 1995;80:254. 4. Tezelman S, Rodriguez JM, Shen W, et aI. Primary hyperparathyroidism in patients who have received radiation therapy and in patients who have not received radiation therapy. J Am Coil Surg 1995;180:81. 5. Hosokawa Y, Pollak MR, Brown EM, Arnold A. Mutational analysis of the extracellular Ca 2+-sensing receptor gene in human parathyroid tumors. J Clin Endocrinol Metab 1995;80:3107' 6. Cryns VL, Thor A, Xu HJ, et al. Loss of the retinoblastoma tumorsuppressor gene in parathyroid carcinoma. N Engl J Med 1994; 330:757. 7. Hakim JP, Levine MA. Absence of p53 point mutations in parathyroid adenoma and carcinoma. J Clin Endocrinol Metab 1994;78:103. 8. Shattuck TM, Valimaki S, Obara T, et aI. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 2003;349: 1722. 9. Libutti SK, Crabtree JS, Lorang D, et aI. Parathyroid gland-specific deletion of the mouse Menl gene results in parathyroid neoplasia and hypercalcemic hyperparathyroidism. Cancer Res 2003;63:8022. 10. Hamby LS, Lee EY, Schwartz RW. Parathyroid adenoma and gastric carcinoma as manifestations of Cowden's disease. Surgery 1995; 118:115. II. Cavanah SF, Dons RF. McCune-Albright syndrome: How many endocrinopathies can one patient have? South Med J 1993;86:364.

12. Pearce SH. Clinical disorders of extracellular calcium-sensing and the molecular biology of the calcium-sensing receptor. Ann Med 2002;34:201. 13. Deftos LJ. Hypercalcemia in malignant and inflammatory diseases. Endocrinol Metab Clin North Am 2002;31:141. 14. Eigelberger MS, Cheah WK, Ituarte PH, et al. The NIH criteria for parathyroidectomy in asymptomatic primary hyperparathyroidism: Are they too limited? Ann Surg 2004;239:528. 15. Chan AK, Duh QY, Katz MH, et aI. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: A casecontrol study. Ann Surg 1995;222:402. 16. Siperstein AB, Shen W, Chan AK, et aI. Normocalcemic hyperparathyroidism: Biochemical and symptom profiles before and after surgery. Arch Surg 1992;127:1157. 17. Hedback G, aden A, Tisell LE. Parathyroid adenoma weight and the risk of death after treatment for primary hyperparathyroidism. Surgery 1995;117:134. 18. Ogard CG, Engholm G, Almdal TP, Vestergaard H. Increased mortality in patients hospitalized with primary hyperparathyroidism during the period 1977-1993 in Denmark. World J Surg 2004;28:108. 19. Chou FF, Sheen-Chen SM, Leong CPo Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism. Surgery 1995; 117:18. 20. Solomon BL, Schaaf M, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med 1994;96:101. 21. Jabbour N, Corvilain J, Fuss M, et aI. The natural history of renal stone disease after parathyroidectomy for primary hyperparathyroidism. Surg Gynecol Obstet 1991;172:25. 22. Stefenelli T, Mayr H, Bergler-Klein J, et al. Primary hyperparathyroidism: Incidence of cardiac abnormalities and partial reversibility after successful parathyroidectomy. Am J Med 1993;95: 197. 23. Silverberg SJ, Gartenberg F, Jacobs TP, et aI. Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism. J Clin Endocrinol Metab 1995;80:729. 24. Pasieka JL, Parsons LL, Demeure MJ, et aI. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942. 25. Malmaeus J, Granberg PO, Halvorsen J, et aI. Parathyroid surgery in Scandinavia. Acta Chir Scand 1988;154:409. 26. Shen W, Duren M, Morita E, et aI. Reoperation for persistent or recurrent primary hyperparathyroidism. Arch Surg 1996;131:861; discussion 867. 27. Weber CJ, Sewell CW, McGarity We. Persistent and recurrent sporadic primary hyperparathyroidism: Histopathology, complications, and results of reo peration. Surgery 1994;116:991. 28. Doherty GM, Weber B, Norton JA. Cost of unsuccessful surgery for primary hyperparathyroidism. Surgery 1994;116:954. 29. Oertli D, Richter M, Kraenzlin M, et al. Parathyroidectomy in primary hyperparathyroidism: Preoperative localization and routine biopsy of unaltered glands are not necessary. Surgery 1995;117:392. 30. Roe SM, Bums RP, Graham LD, et al. Cost-effectiveness of preoperative localization studies in primary hyperparathyroid disease. Ann Surg 1994;219:582. 31. Prinz RA, Lonchyna V, Camaille B, et al. Thoracoscopic excision of enlarged mediastinal parathyroid glands. Surgery 1994;116:999. 32. Uden P, Chan A, Duh QY, et al. Primary hyperparathyroidism in younger and older patients: Symptoms and outcome of surgery. World J Surg 1992; 16:791. 33. Milas M, Wagner K, Easley KA, et al. Double adenomas revisited: Nonuniform distribution favors enlarged superior parathyroids (fourth pouch disease). Surgery 2003;134:995; discussion 1003. 34. Duh QY, Ciulla TA, Clark OH. Primary parathyroid hyperplasia associated with thyroid hemiagenesis and agenesis of the isthmus. Surgery 1994;115:257. 35. Kraimps JL, Duh QY, Demeure M, Clark OH. Hyperparathyroidism in multiple endocrine neoplasia syndrome. Surgery 1992;112:1080. 36. Feliciano DY. Parathyroid pathology in an intrathyroidal position. Am J Surg 1992; 164:496. 37. Rodriguez 1M, Tezelman S, Siperstein AE, et aI. Localization procedures in patients with persistent or recurrent hyperparathyroidism. Arch Surg 1994;129:870. 38. Carty SE, Worsey J, Vnji MA, et aI. Concise parathyroidectomy: The impact of preoperative SPECT 99mTc sestamibi scanning and intraoperative quick parathormone assay. Surgery 1997; 122: 1107; discussion 1114.

Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) - - 455 39. Irvin GL 3rd, Dembrow VD, Prudhomme DL. Clinical usefulness of an intraoperative "quick parathyroid hormone" assay. Surgery 1993;114: 1019; discussion 1022. 40. Wang CA. Unilateral neck exploration for primary hyperparathyroidism. Arch Surg 1990;125:985. 41. Haciyanli M, Lal G. Morita E, et al. Accuracy of preoperative localization studies and intraoperative parathyroid hormone assay in patients with primary hyperparathyroidism and double adenoma. JAm Coll Surg 2003;197:739. 42. Arici C, Cheah WK, Ituarte PH, et aI. Can localization studies be used to direct focused parathyroid operations? Surgery 2001;129:720. 43. Wei JP, Burke OJ. Analysis of savings in operative time for primary hyperparathyroidism using localization with technetium 99m sestamibi scan. Am J Surg 1995;170:488. 44. Proye CA, Carnaille B, Bizard JP, et al. Multiglandular disease in seemingly sporadic primary hyperparathyroidism revisited: Where are we in the early 1990s? A plea against unilateral parathyroid exploration. Surgery 1992;112:1118.

45. Carneiro DM, Irvin GL 3rd. Late parathyroid function after successful parathyroidectomy guided by intraoperative hormone assay (QPTH) compared with the standard bilateral neck exploration. Surgery 2000;128:925;discussion 935. 46. Heller KS, Attie IN, Dubner S. Parathyroid localization: Inability to predict multiple gland involvement. Am J Surg 1993;166:357. 47. Thompson GB, Mullan BP, Grant CS, et aI. Parathyroid iinaging with technetium-99m-sestarnibi: An initial institutional experience. Surgery 1994; 116:966. 48. Weber CJ, Ritchie JC. Retrospective analysis of sequential changes in serum intact parathyroid hormone levels during conventional parathyroid exploration. Surgery 1999;126:1139; discussion 1143. 49. Kao PC, van Heerden JA, Taylor RL. Intraoperative monitoring of parathyroid procedures by a 15-minute parathyroid hormone immunochemiluminometric assay. Mayo Clin Proc 1994;69:532. 50. Arnold A, Brown MF, Urena P, et al. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest 1995;95:2047.

Surgical Approach to Primary Hyperparathyroidism (Unilateral Approach) Anders O. J. Bergenfelz, MD, PhD • Sten A. G. Tibblin, MD, PhD

Historical Background The purpose of surgical treatment in primary hyperparathyroidism (PHPT) is to remove enough abnormal parathyroid tissue to make and keep the patient normocalcemic. Patients with PHPT caused by a solitary parathyroid adenoma are almost always cured by removal of this adenoma. To accomplish unilateral neck exploration, the side on which the adenoma is located has to be known preoperatively, and this should be a true solitary adenoma rather than hyperplasia or multiple adenomas. When Felix Mandl operated on his first patient for PHPT, the general belief was that enlarged parathyroid glands were the result of bone disease and deficiency of parathyroid activity; his patient, Albert, initially received a parathyroid homograft from a deceased patient. When the treatment failed to improve Albert's condition, Mandl had the knowledge, confidence, and courage to re-explore the patient and remove the pathologic parathyroid gland with at least temporary cure of the patient. I In the early days of parathyroid surgery,removal of the enlarged gland was usually successful. However, with the recognition of primary parathyroid hyperplasia as a distinct histopathologic entity, it became obvious that more parathyroid tissue had to be removed.' To be sure not to miss multiglandular disease, a bilateral neck exploration was advocated. Some surgeons even recommended incisional biopsy of the three normal-appearing parathyroid glands when a solitary parathyroid tumor was identified. Later, Paloyan and associates" suggested that all patients with PHPT had hyperplasia and should, therefore, be treated by subtotal parathyroidectomy. During the 1970s, when the number of patients diagnosed with PHPT rapidly increased, it became obvious that bilateral neck exploration with biopsy of all glands had its price because some patients experienced postoperative hypocalcemia. In a Scandinavian survey, including more than 600 parathyroid operations performed during 1 year, hypocalcemia occurred postoperatively in about 15% of patients." Hypocalcemia occurred

456

less often in patients undergoing only excision of the adenoma rather than biopsy and removal of more than one gland." A unilateral approach in patients with PHPT had been originally advocated in the 1970s by C. A. Wang.s He used intraoperative oil red 0 staining and the saline float test to help determine whether a parathyroid gland was normal or abnormal. Unilateral parathyroidectomy was introduced in our department in 1977, and the initial 5-year results were presented in 1982.6 The principle for the unilateral approach is to restrict the neck exploration to the side on which the solitary adenoma is located. Originally, we did not use any localization studies; consequently, about half of our patients had unilateral approaches because 50% of the solitary adenomas were found on the left side and 50% on the right side. When a parathyroid adenoma was localized intraoperatively, the ipsilateral normal-appearing parathyroid and the adenoma were both removed, thus eliminating presumably all parathyroid tissue on this side. If the wrong side happened to be explored first, the two normal parathyroids were left intact and a contralateral exploration was performed. Again, both the adenoma and the normal parathyroid glands were removed on the second side. Intraoperative frozen section histopathologic examination was used to confirm the diagnosis of a solitary adenoma and a normal-sized parathyroid gland.

Histopathologic Varieties of PHPT

A variety of pathologic conditions cause PHPT (Fig. 49-1). The most common cause of PHPT (85% to 90%) is a solitary benign parathyroid adenoma. Malignant tumors of the parathyroid gland are extremely unusual, occurring in less than 1% of cases; parathyroid cancers are sometimes difficult to distinguish from atypical adenomas. Parathyroid tumor metastases are certainly a sign of malignancy. Chief cell

Surgical Approach to Primary Hyperparathyroidism (Unilateral Approach) - -

457

HYPERPARATHYROIDISM

FIGURE 49-1. Various forms of hyperparathyroidism encountered in the surgical practice. MEN = multiple endocrine neoplasia.

hyperplasia (four-gland parathyroid hyperplasia) constitutes about 10% to 15% of all cases of PHPT. It affects all glands, but the hyperplasias may vary considerably in size, color, and configuration. Findings of microscopic areas of nodular hyperplasia have been described by Harrison and colleagues," and their biologic significance seems to be minimal. Hyperplasia is identified as primary when there is no obvious reason for it to occur. Secondary hyperparathyroidism (HPT) is usually caused by end-stage renal disease. Secondary HPT usually resolves after successful kidney transplantation. Sporadic multiple adenomas can occur synchronously or metachronously. Multiple adenomas occur much more frequently in patients with multiple endocrine neoplasia (MEN) 1 or 2 and in patients with familial HPT without other endocrinopathies. Oil red 0 staining of parathyroid tissue, as introduced by Roth and Gallagher"and modified by Ljungberg and Tibblin,9 has helped pathologists distinguish between normal and abnormal parathyroid tissue and between solitary adenoma and hyperplasia. True solitary adenomas often have a compressed rim of normal parathyroid tissue. Characteristically, the red stain is taken up by the suppressed chief cells, whereas the hyperactive adenomatous cells do not take up this fat stain. In the normal parathyroid, there is a homogeneous picture of chief cells stained red by the oil red 0 as an expression of the suppression. These criteria help differentiate between a solitary adenoma and a hyperplastic gland, although some pathologists believe that it is impossible to differentiate between a hyperplastic gland and an adenomatous gland without histologic evidence of another normal

gland. The advantageof giving the pathologista whole normalappearing parathyroid gland is to eliminate the possibility of four-gland parathyroid hyperplasia as a cause of PHPT. The cooperation of an experienced pathologist is essential. It is a great advantage for the pathologist if the suppressed rim of normal parathyroid cells can be identified. The surgeon can help the pathologist by tying a suture around the vascular pedicle of the gland because the vessels often first enter the normal compressed tissue of the adenoma. Intraoperative oil red 0 staining is performed as a complement to the conventional hematoxylin-eosin method. Although this technique improves the diagnostic accuracy and microscopic interpretation in some cases, it is still difficult to be completely sure of this diagnosis. Thus, among 165 consecutive patients with PHPT, all of whom had their parathyroid stained by hematoxylin-eosin and oil red 0 intraoperatively, 8% were judged equivocal."

Results of Unilateral Parathyroidectomy (Original Approach) When patients are considered for unilateral parathyroidectomy, it is important to exclude familial HPT because these patients usually have multiple abnormal parathyroid glands. Patients who had previous operations in their neck for either parathyroid disease or thyroid disease are not candidates for unilateral parathyroidectomy because the functional parathyroid reserve cannot be evaluated.

458 - - Parathyroid Gland Identification of a normal parathyroid gland is easy in most instances, but occasionally it is difficult or even impossible. Extensive exploration to identify normal parathyroid glands should be avoided because it might result in ischemia of the normal glands. When original exploratory principles were followed in 102 patients in which the side of the parathyroid neoplasm was unknown preoperatively, the intended operation could be performed in 88 patients (i.e., unilateral parathyroidectomy either with or without bilateral exploration). In 14 patients, various examples of atypical exploration of normal parathyroid glands were applied. I I Most commonly, one or two of the normal glands were missing.'! In a multicenter study, including five departments of surgery, unilateral neck exploration was compared to bilateral neck exploration in regard to long-term effects on the serum calcium level.P In each department, the prevailing exploratory principles were strictly defined. All patients from a 5-year period fulfilling these definitions and other inclusion criteria were analyzed postoperatively and after 8 to 9 years with regard to calcium status. Two percent of the patients who underwent unilateral operations had hypercalcemia after 8.7 years, whereas 5% of those patients who had a bilateral neck exploration had hypercalcemia after an average follow-up time of 8.0 years. Permanent hypocalcemia occurred in 2% and in 6% of those patients who had a unilateral and bilateral neck exploration, respectively. Nonnocalcemia was observed in 96% of patients who had unilateral neck exploration. In patients who had bilateral neck exploration, 89% were normocalcemic.P Also, the frequency of early postoperative hypocalcemia was significantly lower in the patients who had unilateral neck exploration as compared to patients who had bilateral neck exploration. None of the patients who had a unilateral approach had a postoperative serum calcium below 2.00 mmollL, whereas among patients who had a bilateral approach 19% had serum calcium levels below 2.00 mmollL.

Preoperative Localization Without preoperative localization, the chance of exploring the correct side in which the parathyroid adenoma is located is 50%. 6 If the adenoma is not found on the initial side, the contralateral side has to be explored, which increases operative time and possibly morbidity. The accuracy of available imaging studies for parathyroid localization depends on the size and position of the adenoma, the degree of parathyroid hyperfunction, and other unknown factors. In patients with mild PHPT and a small parathyroid adenoma, localization studies are less successful. This is one reason that preoperative localization procedures are generally considered unnecessary and costly" by most surgeons who routinely perform bilateral neck exploration. An experienced surgeon is able to find the abnormal parathyroid gland or glands in 92% to 98% of patients. 14 Ultrasonography of the neck gives good results when the adenoma is large, when it is situated in the neck, and when there is a normal thyroid gland." The accuracy of ultrasonography for localizing parathyroid neoplasm is operator and equipment dependent. When ultrasonography is combined with fine-needle aspiration biopsy and parathyroid hormone (PTH) sampling of the suspected lesion, the accuracy of the method when positive approaches 100%.16

Isotope methods for parathyroid localization studies have been used extensively during the past 20 years. Thalliumtechnetium subtraction scintigraphy was initially used but has been replaced by sestamibi scintigraphy, which has high sensitivity and positive predicted value for solitary parathyroid adenomas." By adding delayed sestamibi scans'? and single photon-emission computer tomography" or oblique views with a higher dose of Tc 99m sestamibi," an even higher accuracy might be possible. Although sensitive for localizing a solitary parathyroid adenoma, sestamibi scintigraphy is less accurate for identifying multiglandular disease. 2o-22 Furthermore, small parathyroid adenomas are localized less accurately.22,23 We have used selective venous sampling and intact PTH assay in two variations. First, we have used it preoperatively to help identify the region of the elusive parathyroid tumor.>' We have also directly punctured the jugular veins and obtained blood for PTH sampling after induction of anesthesia. For the latter studies, we used a rapid method for the analysis of intact PTH levels. A high degree of specificity (92%) could be reached with this method; the sensitivity was 64%.25 This test is more reliable when the parathyroid adenoma is the superior gland and drains directly into the jugular vein. When the parathyroid adenoma is in the lower gland position, the accuracy is lower. Hence, the ideal localization procedure has yet to be developed. Currently, we advocate the use of preoperative localization procedures in the following clinical situations: (1) in patients with previous thyroid or parathyroid surgery and (2) in patients in whom a focused parathyroid exploration is planned.

Intraoperative Monitoring ofPTH Intraoperative measurement of intact PTH concentration during parathyroidectomy was first described by Nussbaum and associates.i" A highly sensitive intact PTH assay was modified, enabling the incubation time to be shortened to about 15 minutes. After removal of a parathyroid adenoma, there is a sharp decrease in the PTH level if the PHPT was due to a solitary parathyroid adenoma (Fig. 49-2). Several groups-"!' have subsequently reported similar findings. An even shorter turnaround time is possible when the analytic equipment, including proper laboratory personnel, is situated in the operating room." When a macroscopic diagnosis is strongly suggestive of a solitary adenoma, the wound may be closed but the patient is kept under anesthesia. When the PTH level fails to drop after removal of the suspected adenoma, the removed gland either is not of parathyroid origin or is a normal parathyroid gland (Fig. 49-3). When the removed lesion is of parathyroid origin and the PTH level decreases less than 60% at 15 minutes after gland removal, parathyroid hyperplasia or double parathyroid adenoma should be suspected and a comprehensive bilateral neck exploration performed (Fig. 49-4).29 The quick intact PTH assay offers the advantage of a functional evaluation of the surgical procedure and therefore renders intraoperative histologic examination unnecessary. Some surgeons have proposed that when the same solitary parathyroid tumor is identified by both sestamibi scintigraphy

Surgical Approach to Primary Hyperparathyroidism (Unilateral Approach) - -

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and ultrasonography, a focused parathyroid exploration can be done with a 95% success rate." Other surgeons suggest that from a cost-effective standpoint, same-day PTH testing for minimal invasive parathyroidectomy is superior to intraoperative PTH monitoring.>' Clearly, these issues can only be definitively resolved by a multicenter, prospective, randomized trial.

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Surgical Treatment of PHPT under Local Anesthesia Some patients with PHPT have coexisting severe cardiovascular disease and respiratory insufficiency.Pv" Surgical removal of parathyroid adenomas under local anesthesia'r' ! was initially proposed as an attractive alternative to longterm medical treatmenr'v" or percutaneous biochemical ablatiorr'" for high-risk patients. Focused parathyroidectomy under local or regional anesthesia has been proposed as an alternative to operation under general anesthesia for most patients with PHPT.45-48 Parathyroid exploration under local anesthesia is well tolerated by patients, and heart rate and blood pressure fluctuate less than in patients having neck exploration under general anesthesia.t" For patients who have a focused parathyroidectomy under local anesthesia, accurate localization studies are of paramount importance. If noninvasive localization studies are performed, we recommend that the results of at least two tests should agree for definite localization because of a high incidence of false-positive results." As an alternative, ultrasonography combined with fine-needle aspiration for PTH sampling of the suspected lesion may be used."

10 15

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FIGURE 49-3. In a 45-year-old woman with primary hyperparathyroidism, two parathyroid glands were interpreted as being macroscopically enlarged and excised. Frozen section showed normal parathyroid tissue. The parathyroid hormone (PTH) level did not decrease until a 0.38-g parathyroid adenoma was removed. Data are shown as a percentage of baseline value.

Minimal Invasive Parathyroidectomy Owing to the advancement in preoperative localization procedures, as well as intraoperative PTH monitoring and refinement of surgical technique, endoscopic and video-assisted

460 - - Parathyroid Gland

parathyroidectomyhave recently been introduced and are proposed to improve cosmesis and reduce postoperative pain.50-55 Conversionto standard bilateral neck exploration occurs in 8% to 15% of the patients,52,56 which is close to the 7% reported with a conventional minimal invasive parathyroidectomy."

Advantages of Unilateral Parathyroidectomy Good results have been claimed by the proponents of the unilateral approach, with a decreased risk of hypocalcemia I 1,12.58,59 and vocal cord injury.58 Furthermore, focused parathyroidectomy has been suggested to lower costs, shorten hospital stay, and enhance recovery time.6°-63 In agreement with these studies, a systematic review comparing unilateral with bilateral neck exploration indicated a tendency to favor the unilateral procedure.v' Recently, the first prospective, randomized, controlled trial comparing unilateral and bilateral neck exploration for PHPT was reported.P Cure rate and costs did not differ between the two groups. However, the patients in the bilateral group had a higher incidence of early symptomatic hypocalcemia and lower serum calcium values on postoperative days I to 4 compared with patients in the unilateral group. In addition, in patients with PHPT due to a solitary parathyroid adenoma, unilateral neck exploration was associated with a shorter operative time. Complications occurred mainly in the bilateral group.P

Conclusion and Future Aspects High-quality preoperative localization procedures such as sestarnibi scintigraphy and ultrasonography as well as the introduction of intraoperative monitoring for intact PTH serum levels have facilitated the treatment of patients with solitary parathyroid adenoma. Minimal invasive parathyroidectomy is the ideal surgical treatment for patients with PHPT due to a single parathyroid adenoma. In a survey of the members of the International Association of Endocrine Surgeons, more than half of them indicated that they current!y perform minimal invasive parathyroidectomy and use the technique for an average of 44% of the patients with PHPT.65 Several questions need to be addressed in the future, such as the role of video-assisted parathyroidectomy compared to a focused conventional approach, and the precise role for parathyroidectomy under local anesthesia. Furthermore, although a 5-year follow-up has shown that measurement of intraoperative PTH can predict long-term operative success.t" long-term data from prospective, randomized trials are necessary to provide the answer to a possible difference in long-term normocalcemia between the different surgical strategies.

REFERENCES I. Mandl F. Therapeutischer Versuch bei Ostitis Fibrosa generalisata Mittels Exstirpation eines Epitehelkorperchen Tumors. Wien Clin Wochenschr 1925;50:1343. 2. Bloch MA, Frame B, Jackson CE, et al. The extent of operation for primary hyperparathyroidism. Arch Surg 1974;109:798.

3. Paloyan K, Lawrence AM, Oslapas R, et al. Subtotal parathyroidectomy for primary hyperparathyroidism: Long-term results in 292 patients. Arch Surg 1983;118:425. 4. Johansson H, Granberg PO, Tibblin S, et al. Scandinavian study of the parathyroid surgical activity in 1975. Acta Chir Scand Suppl 1979;493:66. 5. Wang CA. Surgical management of primary hyperparathyroidism. Curr Probl Surg 1985;22: I. 6. Tibblin S, Bondeson A-G, Ljungberg O. Unilateral parathyroidectomy in hyperparathyroidism due to single adenoma. Ann Surg 1982; 195:245. 7. Harrison ST, Duarte B, Reitz RE, et al. Primary hyperparathyroidism four- to eight-year postoperative follow-up demonstrating persistent functional insignificance of microscopic parathyroid hyperplasia and decreased autonomy of parathyroid hormone release. Ann Surg 1981; 194:429. 8. Roth SI, Gallagher MJ. The rapid identification of "normal" parathyroid glands by the presence of intracellular fat. Am J Pathol 1976;84:521. 9. Ljungberg 0, Tibblin S. Perioperative fat staining in frozen sections in primary hyperparathyroidism. Am J PathoI1979;95:633. 10. Bondeson A-G, Bondeson L, Ljungberg 0, Tibblin S. Fat staining in parathyroid disease: Diagnostic value and impact on surgical strategy-Clinicopathologic analyses of 191 cases. Hum Pathol 1985;16:1255. II. Tibblin S, Bondeson A-G, Bondeson L, Ljungberg O. Surgical strategy in hyperparathyroidism due to solitary adenoma. Ann Surg 1984; 200:776. 12. Tibblin S, Bizard JP, Bondeson A-G, et al. Primary hyperparathyroidism due to solitary adenoma: A comparative multicenter study of early and long-term results of different surgical regimens. Eur J Surg 1991;157:511. 13. Thompson NW. Localization studies in patients with primary hyperparathyroidism. Br J Surg 1988;75:97. 14. Thompson NW, Eckhauser FE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:814. 15. Uden P, Aspelin P, Berglund J, et al. Preoperative localization in unilateral parathyroid surgery. Acta Chir Scand 1990;156:29. 16. Bergenfelz A, Forsberg L, Hederstrom E, Ahren B. Preoperative localization of enlarged parathyroid glands with ultrasonic-guided fine-needle aspiration for parathyroid hormone assay. Acta Radiol 1991; 32:403. 17. Billotey C, Aurengo A, Najean Y, et al. Identifying abnormal parathyroid glands in the thyroid uptake area using technetium-99m sestamibi and factor analysis of dynamic structures. J Nuel Med 1994; 35:1631. 18. Taillefer R. 99mTc sestamibi parathyroid scintigraphy. In: Freeman EM (ed), Nuelear Medicine Annual, 1995. New York, Raven Press, 1995, p 51. 19. Norman J, Chheda H, Farrell C. Minimally invasive parathyroidectomy for primary hyperparathyroidism: Decreasing operative time and potential complications while improving cosmetic results. Am Surg 1998;64:391. 20. Bergenfelz A, Tennvall J, Valdemarsson S, et al. Sestamibi versus thallium subtraction scintigraphy in parathyroid localization: A prospective comparative study in patients with predominantly mild primary hyperparathyroidism. Surgery 1997;121:601. 21. McBiles M, Lambert AT, Cote MG, et al. Sestamibi parathyroid imaging. Semin Nuel Med 1995;25:221. 22. Bergenfelz A, Lindblom P, Tibblin S, Westerdahl J. Unilateral versus bilateral neck exploration for primary hyperparathyroidism: A prospective randomized controlled trial. Ann Surg 2002;236:543. 23. Lee VS, Wilkinsson RH, Leight GS Jr, et al. Hyperparathyroidism in high-risk surgical patients: Evaluation with double-phase technetium99m sestamibi imaging. Radiology 1995;197:627. 24. Bergenfelz A, Lundstedt C, Stridbeck H, Ahren B. Large vein sampling for intact parathyroid hormone in the preoperative localization of enlarged parathyroid glands. Acta Radiol 1992;33:528. 25. Bergenfelz A, Algotsson L, Roth B, et al. Side localization of parathyroid adenomas by simplified intraoperative venous sampling for parathyroid hormone. World J Surg 1996;20:358. 26. Nussbaum SR, Thompson AR, Hutcheson KA, et al. Intraoperative measurement of parathyroid hormone in the surgical management of hyperparathyroidism. Surgery 1988;104:1121.

Surgical Approach to Primary Hyperparathyroidism (Unilateral Approach) - - 461 27. Irvin GL, Dembrow VD, Prudhomme DL, et aI. A new approach to parathyroidectomy. Ann Surg 1994;219:574. 28. Bergenfelz A, Norden NE, Ahren B. Intraoperative fall in plasma levels of intact parathyroid hormone after removal of one enlarged gland in hyperparathyroid patients. Eur J Surg 1991;147:109. 29. Bergenfelz A, Isaksson A, Ahren B. Intraoperative monitoring of the intact PTH during surgery for primary hyperparathyroidism. Langenbecks Arch Chir 1994;379:50. 30. Ryan MF, Jones SR, Barnes AD. Modification to a commercial immunoradiometric assay permitting intraoperative monitoring of parathyroid hormone levels. Ann Clin Biochem 1990;27:65. 31. Irvin GL, Dembrow VD, Prudhomme DL. Operative monitoring of parathyroid gland hyperfunction. Am J Surg 1991;162:299. 32. Carneiro DM, Irvin GL III. New point-of-care intraoperative parathyroid hormone assay for intraoperative guidance in parathyroidectomy. World J Surg 2002;26:1074. 33. Miura D, Wada N, Arici C, et aI. Does intraoperative quick parathyroid hormone assay improve the results of parathyroidectomy? World J Surg 2002;26:926. 34. Agarwal G, Barakate MS, Robinson B, et aI. Intraoperative quick parathyroid hormone versus same-day parathyroid hormone testing for minimally invasive parathyroidectomy-A cost-effectiveness study. Surgery 200 I; 130:963. 35. Palmer M, Bergstrom R, Akerstrom G, et aI. Survival and renal function in untreated hypercalcemia. Lancet 1987;1:59. 36. Palmer M, Adami HO, Bergstrom R, et aI. Mortality after surgery for primary hyperparathyroidism: A follow-up of 441 patients operated on from 1956-1979. Surgery 1987;102:1. 37. Ronni-Svivula H. Causes of death in patients previously operated on for primary hyperparathyroidism. Ann Chir GynaecoI1985;74:13. 38. Hedback G, Tisell LE, Bengtsson BA, et al. Premature death in patients operated on for primary hyperparathyroidism. World J Surg 1990; 14:829. 39. Pyrtek LJ, Belkin M, Bartus S, Schweizer R. Parathyroid gland exploration with local anesthesia in elderly and high-risk patients. Arch Surg 1988;123:614. 40. Bergenfelz A, Algotsson L, Ahren B. Surgery for primary hyperparathyroidism performed under local anaesthesia. Br J Surg 1992;79:931. 41. Chapuis Y, Icard PH, Fulla Y, et aI. Parathyroid adenomectomy under local anaesthesia with intraoperative monitoring of UcAMP and/or 1-84 PTH. World J Surg 1992;16:570. 42. Lafferty FW, Hubay CA. Primary hyperparathyroidism: A review of the long-term surgical and nonsurgical morbidities as a basis for rational approach to treatment. Arch Intern Med 1989;149:789. 43. Jansson S, Tisell LE, Linstedt G, Lundberg PA. Disodium pamidronate in the preoperative treatment of hypercalcemia in patients with primary hyperparathyroidism. Surgery 1991;110:480. 44. Karstrup S, Transbol I, Holm HH, et aI. Ultrasound-guided chemical parathyroidectomy in patients with primary hyperparathyroidism: A prospective study. Br J RadioI1989;62:1037. 45. Chapuis Y, Fulla Y, Bonnichon P, et aI. Values of ultrasonography sestamibi scintigraphy and intraoperative measurement of 1-84 PTH for unilateral neck exploration of primary hyperparathyroidism. World J Surg 1996;20:835. 46. Inabnet WB, Fulla Y, Richard B, et aI. Unilateral neck exploration under local anesthesia: The procedure of choice for asymptomatic primary hyperparathyroidism. Surgery 1999;126:1004.

47. Chen H, Sokoll LJ, Udelsman R Outpatient minimally invasive parathyroidectomy: A combination of sestamibi-SPECT localization, cervical block anesthesia, and intraoperative parathyroid hormone assay. Surgery 1999;126:1016. 48. Ditkoff BA, Chabot J, Feind C, et aI. Parathyroid surgery using monitored anesthesia care as an alternative to general anesthesia. Am J Surg 1996; 172:698. 49. Harness JK, Ramsberg SR, Nishiama RH, et aI. Multiple adenomas of the parathyroids: Do they exist? Arch Surg 1979;114:468. 50. Henry JF. Defechereux T, Gramatic L, et aI. Minimally invasive videoscopic parathyroidectomy by lateral approach. Langenbecks Arch Surg 1999;384:298. 51. Gauger PG, Reeve TS, Delbridge LW. Endoscopically assisted minimally invasive parathyroidectomy. Br J Surg 1999;86:1563. 52. Miccoli P, Berti P, Conte M, et aI. Minimally invasive video-assisted parathyroidectomy: Lesson learned from 137 cases. JAm Coll Surg 2000;191:613. 53. Dralle H, Lorenz K, Nguyen-Thanh P. Minimally invasive videoassisted parathyroidectomy-selective approach to localized single gland adenoma. Langenbecks Arch Surg 1999;384:556. 54. Miccoli P, Bendinelli C, Berti P, et aI. Video-assisted versus conventional parathyroidectomy in primary hyperparathyroidism: A prospective randomized study. Surgery 2000;128:121. 55. Henry JF, Raffaelli M, Iacobone M, Volot F. Video-assisted parathyroidectomy via the lateral approach vs conventional surgery in the treatment of sporadic primary hyperparathyroidism: Results of a casecontrol study. Surg Endosc 2001;15: 1116. 56. Henry JF, Iacobone M, Mirallie E, et aI. Indications and results of video-assisted parathyroidectomy by a lateral approach in patients with primary hyperparathyroidism. Surgery 2001;130:999. 57. Agarwal G, Barraclough BH, Robinson BG, et al. Minimally invasive parathyroidectomy using the "focused" lateral approach: 1. Results of the first 100 consecutive cases. Aust N Z J Surg 2002;72: 100. 58. Worsey MJ, Carty SE, Watson CG. Success of unilateral neck exploration for sporadic primary hyperparathyroidism. Surgery 1993;114:1024. 59. Westerdal J, Lindbom P, Valdemarsson S, et aI. Risk factors for postoperative hypocalcemia after surgery for primary hyperparathyroidism. Arch Surg 2000;135:142. 60. Irvin GL III, Sfakianakis G, Yeung L, et aI. Ambulatory parathyroidectomy for primary hyperparathyroidism. Arch Surg 1996; 131:1074. 61. Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg 2002;235:665. 62. Udelsman R, Donovan PI, Sokoll LJ. One hundred consecutive minimally invasive parathyroid explorations. Ann Surg 2000;232:331. 63. Udelsman R. Is unilateral neck exploration for parathyroid adenoma appropriate? Adv Surg 2000;34:319. 64. Reeve TS, Babidge WJ, Parkyn RF, et aI. Minimally invasive surgery for primary hyperparathyroidism: Systematic review. Arch Surg 2000; 135:481. 65. Sackett WR, Barraclough B, Reeve TS, Delbridge LW. World-wide trends in the surgical treatment of primary hyperparathyroidism in the era of minimally invasive parathyroidectomy. Arch Surg 2002; 137:1055. 66. Westerdahl J, Lindblom P, Bergenfelz A. Measurement of intraoperative parathyroid hormone predicts long-term operative success. Arch Surg 2002;137:186.

Minimally Invasive Parathyroid Surgery Paolo Miccoli, MD • Piero Berti, MD

Minimally invasive procedures proposed for the treatment of primary hyperparathyroidism (PHPT) have become widespread after the first operation performed by Michel Gagner in 1996.1 This term, however, can be misleading if one assumes that the simple shortening of the surgical scar is enough to define a surgical procedure as minimally invasive. In fact, if one uses the guidelines of the 1990 National Institutes of Health Consensus Conference as the starting point, all operations other than bilateral exploration with possible biopsy of suspected enlarged parathyroid glands constitute less invasive surgery; however, less invasive does not mean minimally invasive. The concept of invasiveness cannot be limited only to the length of the skin incision but must be extended to other structures, and above all this reduction in invasiveness must not decrease the operative field of vision. For this reason, an endoscope is usually (although not always) used in minimally invasive procedures. This chapter examines mainly endoscopic procedures. These can be performed either with gas flow insufflation and trocars or with external retraction instead of gas insufflation.

Techniques Although several approaches have been proposed as endoscopic parathyroidectomy, the most commonly used are the (1) endoscopic parathyroidectomy (Gagner, 1997),2 (2) video-assisted parathyroidectomy with external retraction (Miccoli, 1997),3·4 and (3) videoscopic parathyroidectomy by a lateral approach (Henry, 1998).5

Endoscopic Parathyroidectomy Endoscopic parathyroidectomy was the first technique described for endoscopic parathyroidectomy. It uses steady gas flow, not exceeding 8 mm Hg pressure." A 5-mm endoscope (0 degrees when starting and 30 degrees once the subplatysmal plane is reached) is inserted through a central neck trocar and two or three additional trocars are used for the instruments (Fig. 50-1). Needlescopic instruments are used.

462

The subplatysmal plane is dissected to obtain a good working space. The space anterior to the sternocleidomastoid muscle is then opened and the strap muscles are retracted medially to expose the thyroid lobes. The parathyroid glands are explored after the thyroid is dissected from the investing fascia. Once the parathyroid adenoma is completely mobilized, the vascular pedicle is dissected and divided between two 5-mm clips. The gland is then extracted in a small sac made from a fingertip from a surgical glove. A quick parathyroid hormone assay (qPTHa) is performed 10 and 20 minutes after resection. A bilateral exploration is possible with this technique.

Video-Assisted Parathyroidectomy Video-assisted parathyroidectomy is a technique that requires no trocars or gas insufflation. The patient's neck is not hyperextended so as to allow a sufficient operative space under the strap muscles. A 15-mm transverse incision is made 2 em above the sternal notch; even minimum bleeding should be avoided since gasless procedures cannot take advantage of the hemostatic effect of gas pressure. The strap muscles are then separated in the midline longitudinally for not more than 3 em. One retractor laterally retracts the strap muscles on the side of the suspected adenoma gently to include the carotid artery while the other one retracts medially to include the thyroid lobe. The thyrotracheal groove is then exposed after cutting the middle thyroid vein between the clips. The lobe is mobilized from the strap muscles using only small spatulas under direct vision. A 30-degree endoscope, 5 mm in diameter, is then introduced through the incision, and from this point on the entire procedure is performed endoscopically using small reusable surgical instruments (spatulas, forceps, scissors, and vascular clips) (Fig. 50-2). Three surgeons are generally involved in this video-assisted procedure: (1) the operator, (2) the first assistant (holding the endoscope and a spatula-aspirator), and (3) a second assistant holding the retractors, one more than during the endoscopic procedures. Usually, only one side of the neck is explored, but the opposite side can be explored through the same incision if necessary. Once the

Minimally Invasive Parathyroid Surgery - - 463

FIGURE 50-1. Endoscopic approach (Gagner procedure).

adenoma is located it is dissected without disrupting the which ~s capsule using spatuias. The pedicle. of t~e gl~d, well visualized under optical magnification (FIg. 50-3), IS then clipped. The adenoma is then retrieved.throug~ the skin incision. The incision is generally closed WIth a skin sealant while the surgeon is waiting for the result of the qPTHa.

Lateral Approach Parathyroidectomy The lateral approach parathyroidectomy, as described by Henry and associates,' uses a 12-mm. skin incision on ~e medial border of the sternocleidomastoid muscle on the SIde of the lesion. A lO-mm trocar is inserted, through which a a-degree lO-mm endoscope is inserted with low-~ressure (8 mm Hg) insufflation. Two small trocars (3 mm) are Inserted below and above the first trocar along the medial margin of the sternocleidomastoid muscle for instruments (Fig. 50-4). The adenoma is gently dissected by the surgeon, who needs only one assistant to hold the camera. Once completely

FIGURE 50-2. Video-assisted parathyroidectomy procedure).

FIGURE 50-3. Video-assisted parathyroidectomy-intraoperative view. PA = parathyroid adenoma.

isolated, the gland is partly extracted and its pedicle is ligated externally using a conventional forceps; qPTHa is also used. A bilateral exploration is not possible with this technique, which is a lateral approach.

Other Approaches In addition to endoscopic operations, other "minimally invasive" approaches to parathyroid surgery have been proposed, some based on the use of intraoperative nuclear mapping first described by Norman and Chheda,' and all characterized by small skin incisions (3 to 4 ern) directly over the supposed adenoma.f A clearly positive preoperative scintigraphic localization study is mandatory for these focused procedures. Some single, well-defined parathyroid adenomas can be visthey repr~ible by ultrasonography but not by scintigrap~y; sent 10% of patients undergoing an endoscopic procedure In our experience. They are excellent candidates for any of the endoscopic or video-assisted parathyroidectomies but not for a radio-guided parathyroidectomy.

(Miccoli FIGURE 50-4. Lateral approach (Henry procedure).

464 - - Parathyroid Gland

Indications Generally, the ideal patient for minimally invasive parathyroidectomy is one with sporadic PHPT and a single, welllocalized adenoma in a virgin neck. There is debate about the percentage of patients who are eligible for minimally invasive parathyroidectomy-this depends on the selection criteria used by the surgeon. In our experience, these criteria were modified by the experience acquired during the development of our technique and the continuing improvement of surgical instrumentation. Contraindications may be absolute or relative. Absolute contraindications include the following: • Large goiters • Recurrent disease • Extensive previous neck surgery • Multiple endocrine neoplasia and familial PHPT • Parathyroid carcinoma Relative contraindications include the following: • Adenomas larger than 3 em (depending on their shape, even larger adenomas can be removed) • Lack of preoperative localization (a bilateral exploration can be performed through a central incision) • Neck surgery on the opposite side of the suspected adenoma (a lateral access can be used) • Previous neck irradiation or small thyroid nodules (concurrent thyroidectomy is possible) Careful selection of the patient is most important to achieve an excellent outcome and to keep the conversion rate low. Although these criteria are presumably shared by most surgeons performing minimally invasive parathyroidectomy, the percentage of patients eligible for this surgery has varied greatly, from as little as 25%9 to as much as 66%.10

Conversion: When, Why? As in many other fields of endoscopic surgery, converting to open surgery is sometimes necessary. In minimally invasive parathyroid surgery, it is due to both technical difficulty of the procedure and drawbacks that are peculiar to parathyroid surgery. Thyroid abnormalities can cause bleeding or difficult dissection. Suspicion of malignancy, intrathyroidal parathyroid adenoma, and prolonged exploration time are also reasons for conversion. Although most minimally invasive procedures are targeted parathyroidectomies (identifying only the adenoma) that have been validated by qPTHa2,4 or postoperative scintigraphy,"!' we prefer a unilateral exploration (identifying both an adenoma and a normal gland), which is almost always possible when using the endoscope. Before elective conversion, at least one side of the neck should have been explored thoroughly. Then, if a lateral approach was used, one should convert to open operation; however, if a central approach was used, contralateral exploration is still possible by the endoscopic technique. We explore the contralateral side endoscopically only if the procedure has not taken too long (l to 1.5 hours) and if preoperative localization studies were not definitive. In our experience, an open operation does not guarantee that the adenoma will be easily found. In three cases out of nine conversions in our series, the

adenoma was still not found even after an extensive open exploration (see "Results").

Complications To define a new procedure as safe and effective, we need to demonstrate that both its complication rate and its success rate are comparable or better than those obtained by traditional surgery. This is particularly difficult when comparing endoscopic parathyroidectomy to traditional parathyroidectomy, which has a success rate of 95%12 with a negligible complication rate. These complications include recurrent nerve palsy and hypoparathyroidism. Hypoparathyroidism is particularly rare, probably due to minimal manipulation required by endoscopic surgery and improved visualization. This is in contrast to the traditional approach of extensive bilateral neck exploration and sometimes frequent biopsy. Thus, the incidence of postoperative hypocalcemia, either transient or permanent, is significantly less after minimally invasive parathyroidectomy.P This rate is similar to that of open unilateral exploration. The use of qPTHa also avoids the unnecessary removal of enlarged glands with normal function and minimizes postoperative hypoparathyroidism. 14 Recurrent nerve palsy is rare in all the series with rate of I % or lower both in traditional operations15 and in endoscopic approaches. !1.I6 There is no evidence of an increased rate of persistent disease after the adoption of minimally invasive parathyroidectomies. Our persistence rate is lower than 2% in almost 300 cases; other published rates of persistent disease also do not exceed 4% to 5%,5.10.11.16-18 which is similar to the results obtained by traditional surgery. 12.15 Nevertheless, it should be noted that patients undergoing minimally invasive parathyroidectomies are a selected group and this could bias the results.

Advantages and Disadvantages It is difficult to assess the advantages offered by minimally invasive parathyroid surgery because of the many different techniques considered minimally invasive. Similarly, "conventional parathyroidectomy" includes both bilateral and unilateral explorations. Furthermore, early sporadic reports of minimally invasive parathyroidectomy included only few cases that had inadequate follow-up and were not prospective studies. Possible advantages include cosmetic outcome and postoperative distress. There are two prospective papers comparing a minimally invasive to a conventional approach, both based on less than 50 patients, concluding that patients have less discomfort postoperatively after minimally invasive operations using a radio-guided'? or video-assisted approach.'? The advantage of the cosmetic outcome is generally considered obvious because a scar of I to 2 em tends to be better accepted than a 4- to 6-cm scar in the same region. Patients' satisfaction evaluated in a prospective study by means of a visual analog scale score proved to be significantly better in a minimally invasive video-assisted parathyroidectomy versus a conventional procedure. 19

Minimally Invasive Parathyroid Surgery - - 465 The duration of hospitalization cannot constitute a further advantage because parathyroid surgery is now frequently performed on an outpatient basis, even under locoregional anesthesia, whether the patient is undergoing a minimally invasive" or a conventional parathyroidectorny.P Endoscopic procedures are generally more expensive and thus a disadvantage. The expenses are due to surgical instrumentation and the technical support needed to set up a new procedure, as well as the longer duration of the procedure. The additional costs of preoperative imaging studies are also widely accepted by surgeons using the conventional approaches? I so this is not an issue. Furthermore, for minimally invasive surgery using a central approach, bilateral exploration is possible. thus making preoperative localization theoretically superfluous. 1I Similarly, qPl'Ha is used in both conventional and endoscopic operations, and its cost has sharply decreased lately, matching that of frozen section. Many surgeons consider it technically demanding, but the surgical equipment required does not differ much from that needed for other laparoscopic procedures.P Finally, the higher cost due to longer procedure duration occurs at the beginning of the surgeon's experience. The learning curve (Fig. 50-5), however, clearly shows that a reasonable operating time can be reached after the first 30 operations and it rivals that of conventional surgery. A significant disadvantage for the endoscopic procedures is the need for general anesthesia, whereas in conventional surgery locoregional anesthesia might be used." This issue is less relevant in Europe, where the problem of surgery on an outpatient basis is not considered of paramount importance. In our center, patients undergoing video-assisted parathyroidectomy are discharged within 24 hours (overnight stay).

Results Our experience consists of 282 patients who underwent minimally invasive video-assisted parathyroidectomy (MIVAP) from February 1997 to April 2002. They represented 76% of a total of 370 referred to our department in the same period for PHPl'. Correct preoperative localization

70

65.4

60

lil Q) 50 "5 c

I

Q)

~

40 30

ci. 20 0

27.5

24.4

25

10 0 1997 1998 1999 2000 2001 2002 FIGURE So-S. Learning curve associated with minimally invasive video-assisted parathyroidectomy. Op. = operating.

of the lesion was considered mandatory before performing MIVAP.This consisted of either an ultrasound examination or a double-phase Tc 99m sestamibi scan. In many cases, both imaging studies had already been performed before referral. The mean age of the patients was 56 ± 13 years (range, 20 to 87 years); there were 224 women (79.5%) and 58 men (20.5%). The mean operative time of the procedure was 39 ± 22 minutes (range, 10 to 180 minutes). Fifteen patients had a concurrent video-assisted thyroid resection for associated diseases (microfollicular nodule, small papillary cancer), including 11 thyroid lobectomies (8 ipsilateral and 3 contralateral) and 4 total thyroidectomies. Conversion to traditional cervicotomy was required in 20 patients (7%) (Table 50-1). The reasons for conversion were multiglandular disease in 4 (double adenoma); intrathyroid adenoma in 3; difficult dissection in 2; negative exploration in 9 (in 3 cases the adenoma was not found even after conversion); intraoperative suspicion of parathyroid carcinoma in 1 (confirmed by frozen section and thus treated with synchronous thyroid lobectomy); and inadequate intraoperative PTH assay in 1. The conversions for double adenoma and intrathyroid lesions occurred at the beginning of our experience, when we were concerned about the prolonging the operation. More recently, when a further adenoma (even contralateral) or intrathyroid adenoma was suspected, we always continued with the video-assisted technique to perform a bilateral exploration or even a thyroid lobectomy (if necessary). The mean size of the removed adenoma was 1.8 em in its largest diameter. The lesion was superior right in 20.5% of cases, superior left in 23.1 %, inferior right in 23.8%. and inferior left in 32.6%. Patients are usually discharged after careful evaluation overnight for clinical symptoms of hypocalcemia and for serum calcium measurement. There were two permanent laryngeal nerve palsies (0.7%) (6 months after surgery). There was one case of postoperative bleeding (0.3%) from a displaced clip on a middle thyroid vein, which required a reoperation 2 hours after surgery. Transient hypocalcemia occurred in 10 patients (3.5%) (Table 50-2). Five (1.7%) patients had persistent hyperparathyroidism. In three patients, the adenoma was not found at exploration even after conversion. These patients are being re-evaluated. In two patients, the persistence was due to a false-positive qPTHa. A second exploration revealed a second adenoma missed at the time of the first operation. Both missed second

466 - - Parathyroid Gland

adenomas were at the opposite side of the first operation, and they were successfully treated again by the MIVAP approach. In this series, six patients had previously undergone thyroid surgery and two patients had undergone a prior exploration for PHPT. We successfully used a lateral approach in these patients so as to avoid adhesions in the midline.

Conclusions Fewer patients now undergo classic open bilateral neck exploration for PHPT because of the desire for smaller scars, shorter postoperative stay, and less postoperative distress. Better preoperative localization studies now allow for patient selection for targeted parathyroidectomies with low rates of persistent disease.P Endoscopic parathyroidectomy offers thorough exploration of the neck, unilaterally-' or even bilaterally.l'P' The use of qPTHa reduces the possibility of missing a second adenoma or a hyperplasia. In our experience, qPTHa has helped avoid conversion to open surgery in 2% of our patients. Endoscopic parathyroidectomy is an excellent option. In contrast, radio-guided parathyroidectomy is logistically demanding, requiring nuclear mappings and coordination among the nuclear medicine physician, the operating room staff, and the surgical team." Endoscopic parathyroidectomy allows for neck exploration of two glands and, with a central incision, even bilateral exploration of four glands. This is not possible by the lateral approach.

REFERENCES I. Gagner M. Endoscopic parathyroidectomy [Letter]. Br J Surg 1996;83:875. 2. Gagner M. Endoscopic parathyroidectomy and thyroidectomy. Semin Laparosc Surg 1997;4:235. 3. Miccoli P, Cecchini G, Conte M, et al. Minimally invasive videoassisted parathyroid surgery for primary hyperparathyroidism. J Endocrinol Invest 1997;20:429.

4. Miccoli P. Minimally invasive surgery for thyroid and parathyroid diseases. Surg Endosc 2002;16:3. 5. Henry JF, Defechereux T, Gramatica L, de Boissezon C. Minimally invasive videoscopic parathyroidectomy by lateral approach. Langenbecks Arch Surg 1999;384:298. 6. Rubino F, Pamoukian VN, Zhu JF, et al. Endoscopic endocrine neck surgery with carbon dioxide insufflation: The intracranial pressure in a large animal model. Surgery 2000;128:1035. 7. Norman J, Chheda H. Minimally invasive parathyroidectomy facilitated by intraoperative nuclear mapping. Surgery 1997;122:998. 8. Chen H, Sokoll LJ, Udelsman R. Outpatient minimally invasive parathyroidectomy: A combination of sestamibi-SPECT localization, cervical block anesthesia, and intraoperative parathyroid hormone assay. Surgery 1999;126:1016. 9. Gauger PG, Reeve TS, Delbridge LW Endoscopically assisted, minimally invasive parathyroidectomy. Br J Surg 1999;86:1563. 10. Miccoli P, Berti P, Conte M, et al. Minimally invasive video-assisted parathyroidectomy: Lesson learned from 137 cases. J Am Coli Surg 2000;191:613. II. Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg 2002;235:665. 12. Duh QY, Uden P, Clark OH: Unilateral neck exploration for primary hyperparathyroidism: Analysis of a controversy using a mathematical model World J Surg 1992;16:654. 13. Lorenz K, Nguyen-Thanh P, Dralle H. Unilateral open and minimally invasive procedures for primary hyperparathyroidism: A review of selective approaches. Langenbecks Arch Surg 2000;385:106. 14. Irvin GL III, Sfakianakis G, Yeung L, et al. Ambulatory parathyroidectomy for primary hyperparathyroidism. Arch Surg 1996;131:1074. 15. Kaplan EL. Endocrine surgery. J Am Coli Surg 1999;188:118. 16. Lorenz K, Miccoli P, Monchick lM, et al. Minimally invasive videoassisted parathyroidectomy: Multi-institutional study. World J Surg 2001;25:704. 17. Goldstein RE, Blewins L, Delbeke D, Martin WH. Effect of minimally invasive radioguided parathyroidectomy on efficacy, length of stay, and costs in the management of primary hyperparathyroidism. Ann Surg 2000;231 :732. 18. Monchick JM, Barellini L, Langer P, Kahya A. Minimally invasive parathyroid surgery in 103 patients with local/regional anesthesia, without exclusion criteria. Surgery 2002; 131:502. 19. Miccoli P, Bendinelli C, Berti P, et al. Video-assisted versus conventional parathyroidectomy in primary hyperparathyroidism: A prospective randomized study. Surgery 1999;126:1117. 20. Lo Gerfo P. Bilateral neck exploration for parathyroidectomy using local anesthesia: A viable technique in patients with co-existing thyroid disease with or without sestamibi scanning. Surgery 1999;126:1011. 21. Sosa JA, Powe NR, Levine MA, et al. Cost implications of different surgical management strategies for primary hyperparathyroidism. Surgery 1998;124:1028. 22. Miccoli P, Monchick 1M. Minimally invasive parathyroid surgery: A review. Surg Endosc 2000;14:987. 23. Inabnet WB III, Dakin GF, Haber RS, et al. Targeted parathyroidectomy in the era of intraoperative parathormone monitoring. World J Surg 2002;26:921. 24. Gagner M, Rubino F. Endoscopic parathyroidectomy. In: Gagner M, Inabnet WB (eds), Minimally Invasive Endocrine Surgery. Philadelphia, Lippincott Williams & Wilkins, 2002, p 110. 25. Moley JF. Effect of minimally invasive radioguided parathyroidectomy on efficacy, length of stay, and costs in the management of primary hyperparathyroidism [Comment]. Ann Surg 2000;231 :741.

Endoscopic Parathyroidectomy Jean Francois Henry, MD • Frederic Sebag, MD

Since the first successful parathyroidectomy performed in 1925 by Felix Mandl of Vienna, I bilateral exploration and four-gland exploration has been considered the traditional approach in patients with primary hyperparathyroidism (pHPT). Performed by an experienced surgeon, this procedure is certainly one of the most gratifying of all operations. The success rate is reported to be of more than 96% with a concomitantly negligible operative mortality and morbidity rate? Nevertheless, today the surgical management of PHPT is in transition. The development and improvement of pre- and intraoperative localization methods, the introduction of intraoperative quick parathormone (QPTH) assessment, and the minimally invasive surgery revolution are the main reasons that have pushed surgeons at least to investigate the feasibility of other parathyroid procedures. Several new minimally invasive techniques for parathyroidectomy have been developed: the unilateral approach.r" radioguided surgery.'t? mini-open invasive techniques (miniincision with or without local anesthesiaj.v!" and video-assisted or fully endoscopic techniques. I 1-21 These techniques have two common threads: they all have a limited incision compared with the classic open transverse cervical incision, and the surgery is targeted to one specific parathyroid gland. In most cases, the exploration of other glands is not performed or is limited. Minimally invasive techniques are particularly suitable for parathyroid surgery for several reasons: they are only ablative procedures that do not require any elaborate surgical reconstruction, most parathyroid tumors are small and benign, and reduction in the length of the scar to about 10 to 15 mm is appealing to many patients. It has been demonstrated that endoscopic parathyroidectomy is a feasible surgical procedure. Curiously, the first endoscopic removal of enlarged parathyroid glands was not from the neck but from a major ectopic location in the mediastinum." The first case of an endoscopic parathyroidectomy in the neck was reported by Gagner in 1996. 11 Since then, the application of endoscopic techniques for parathyroid surgery has become more and more widely reported.

endoscopic when endoscopic equipment is used during the procedure. Techniques such as video-assisted parathyroidectomies that require the endoscope during one step but not necessarily during the whole operation should also be considered endoscopic procedures. The three endoscopic neck procedures in most widespread use are described in the following. Other techniques that have been proposed but are less commonly used are the axillary approach-" and the anterior chest approach.'?

Surgical Technique

Minimally Invasive Video-Assisted Parathyroidectomy

The term endoscopic parathyroidectomy must be clearly defined: a parathyroidectomy can be considered to be

Minimally invasive video-assisted parathyroidectomy (MIVAP) was described by Miccoli and colleagues."

Pure Endoscopic Parathyroidectomy This technique, first described by Gagner, II is carried out entirely under a steady gas flow. The patient is placed supine with the neck less hyperextended than for open operation to allow room for insufflation. Under general anesthesia, the neck area is prepared and draped in the fashion typical for conventional surgery. A 5-mm skin incision is made just above the sternal notch in the lower midline of the neck and a 5-mm trocar is inserted. Then, a 5-mm scope is introduced and a larger subplatysmal space is created by blunt dissection with the tip of the scope. Carbon dioxide insufflation is started at 12 to 15 mm Hg but can be decreased to 8 to 10 mm Hg. When enough space has been created, the midline is opened and the strap muscles retracted in order to expose the thyroid lobes. Two or three additional trocars are used: one 2-mm trocar is placed laterally above the clavicle on the side of exploration; another 2-mm trocar is placed at the midline just below the thyroid cartilage. An optional second 5-mm trocar is placed at the anterior border of the sternocleidomastoid muscle (SCM) below the angle of the mandible. Needlescopic instruments are used. A bilateral parathyroid exploration is possible with this technique. When the tumor is discovered and freed, it is placed in a bag, made from the tip of the finger of a rubber glove, and removed through the 5-mm port site. Subcuticular sutures and Steri-Strips or glue are used to close the skin incisions.

467

468 - - Parathyroid Gland The patient is placed in the supine position with the neck in slight extension. A 15-mm skin incision is made at the suprasternal notch. The cervical midline is opened, and complete dissection of the thyroid lobe is achieved by blunt dissection with small instruments under endoscopic vision using a 30-degree 5-mrn endoscope. Small conventional retractors maintain the operative space. Small instruments, 2 mrn in diameter, are used for the dissection. The harmonic scalpel is very useful, particularly during the dissection of the superior thyroid pedicle. The procedure is carried out only through the initial midline incision. There is no need for an additional trocar or for gas insufflation. This technique also permits bilateral exploration. The surgeon must be aided by two assistants.

Endoscopic Parathyroidectomy by Lateral Approach24 In both techniques described previously,access to the parathyroid is achieved through the midline. The midline approach is suitable for superficially located parathyroids, which in most cases means the inferior glands located at the lower pole of the thyroid lobe or in the thyrothymic tracts. However, for superior adenomas that tend to migrate posteriorly,the midline approach requires complete exposure and medial retraction of the thyroid lobe. This is sometimes difficult, particularly in patients with a short wide neck or with large thyroid glands. Conversely, the lateral approach or back door approach, already described by Feind in open surgery for parathyroid re-exploration," allows direct access to the lateral and posterior aspects of the thyroid lobe and therefore to the posteriorly located parathyroids. The patient is placed in the supine position but without extension of the neck. Under general anesthesia, a l2-mrn transverse skin incision is made on the anterior border of the SCM, 3 to 4 em above the sternal notch. Through this incision, the fascia connecting the posterior portion of the strap muscles to the carotid sheath is gently divided with scissors, far enough to visualize the prevertebral fascia. When enough space has been created, two 2- to 3-mrn trocars are inserted on the line of the anterior border of the SCM, 3 to 4 em above and below the first skin incision. A lO-mrn trocar is inserted through the l2-mrn skin incision (Fig. 51-1). The working space is easily created with minimal dissection and maintained with low CO2 pressure at 8 mrn Hg. At this low pressure, there is no risk of subcutaneous emphysema or pneumomediastinum. Unilateral video-assisted parathyroid exploration is then carried out using a lO-mrn O-degree endoscopic camera. The dissection is performed using 2- or 3-mrn instruments: graspers, scissors, and cautery hook. The anatomic structures, posterior aspect of the thyroid lobe, esophagus, trunk and branches of the inferior thyroid artery, inferior laryngeal nerve, and thyrothymic tract, can be explored. During the exploration, one can identify both the adenoma and the ipsilateral parathyroid gland but contralateral exploration is not possible. When the adenoma has been completely dissected, the vascular branches of its pedicle are coagulated with the cautery hook. Then, small adenomas are grasped and directly extracted through the 10-mm trocar; large adenomas that cannot be introduced into the 10-mrntrocar are extracted directly through the trocar site,

FIGURE 51-1. Endoscopic parathyroidectomy by a lateral approach: trocar positions.

with the thyroid lobe being retracted medially and anteriorly with a small conventional retractor. There is no need to place the gland into a sterile plastic bag. Draining is not necessary. The lateral approach is a rapid, direct, and bloodless approach. In our opinion, it is the procedure of choice in most cases because it provides the best access to the posterior aspect of the thyroid lobe. It is therefore applicable in all cases in which the parathyroid lesions are located posteriorly, meaning superior parathyroid glands, because their enlargement pushes them to migrate posteriorly and slide along the prevertebral plane next to the lateral esophageal border. The lateral approach is also ideal for inferior parathyroid glands located posterior to the inferior poles of the thyroid lobe. It is in these cases that they become intimate with the recurrent laryngeal nerve. The lateral view permits easy identification of the nerve abutting the adenoma and therefore allows a secure dissection. However, the lateral approach is not suitable for superficially located parathyroids, which means the inferior glands located at the lower pole of the thyroid lobe or in the thyrothymic tracts. These glands can easily be reached through a l5-mrn skin incision at the suprasternal notch. The procedure is carried out between the strap muscles with the assistance of a 5-mrn endoscope (0 or 30 degrees). All maneuvers are therefore performed openly without gas insufflation. All instruments are introduced through the midline incision. There is no need for an additional trocar. Because of their anterior locations, the dissection of these glands remains anterior to the trachea and does not require the previous identification of the recurrent laryngeal nerve, which runs more posteriorly. Parathyroid glands deeply located in the thymus can also be removed endoscopically using this midline access.

Contraindications Not all patients presenting with PHPT are candidates for this surgery. Contraindications are mainly due to a larger goiter,

Endoscopic Parathyroidectomy - -

previous surgery in the parathyroid vicuuty, suspicious multiglandular disease, and equivocal preoperative localization studies. Depending upon the operator's experience and according to the specific technique utilized, these contraindications can become relative. The central approach appears to be the best one for cases in which a bilateral exploration is anticipated or localization is uncertain. Occasionally, endoscopic parathyroidectomy by the lateral approach can be performed in patients who have previously undergone contralateral neck operation or tracheotomy. According to certain authors, more than 60% of patients with PTHP are candidates for video-assisted parathyroidectomy." The endoscopic dissection of large adenomas (>3 ern) can be difficult because the working area remains limited. With limited experience, some surgeons can encounter major difficulties that may lead to capsular rupture and local seeding of parathyroid adenomatous cells. When this happens, a conversion is recommended. Nevertheless, some large but elongated adenomas, especially if situated in the posterosuperior mediastinum, can be removed endoscopically. The pedicle can be easily dissected at the level of the inferior thyroid artery, and their shape is amenable to expeditious extraction. Patients with suggested multiglandular disease are not eligible for these procedures. Endoscopic parathyroid procedures should be reserved for patients with sporadic PHPT. All endoscopic parathyroid surgeons consider that the adenoma should be clearly localized before the operation. Therefore, the surgeon is highly dependent upon the quality of preoperative imaging to make a judicious choice for an endoscopic approach. Once contraindications have been eliminated, all patients with sporadic primary PHPT are considered candidates for this procedure. The choice between approaches is dependent on the quality and adequate interpretation of preoperative imaging studies. If the cervical ultrasonography and the nuclear scan do not correlate with a unique lesion at the same site, a traditional open cervical transverse incision is preferable. However, if the lesion is unique and confirmed by both studies, an endoscopic approach can be proposed. Depending on a posterior or anterior location, one can choose a central or lateral approach (Fig. 51-2). Absolute contraindications remain the presence of a carcinomatous parathyroid gland, voluminous goiter, or both, no matter the experience of the surgeon or type of endoscopic technique employed. Finally, endoscopic thyroidectomy and parathyroidectomy can be performed at the same time through the midline, but these procedures are indicated for small suspicious thyroid nodules less than 2.5 em in diameter associated with PHPT.

Results In cases of removal of mediastinal parathyroid adenomas by thoracoscopy, the advantages to the patient are irrefutable. However, taking into account the excellent results of the traditional bilateral cervical exploration, the same advantages are more difficult to demonstrate for all cervical approaches. Two studies comparing conventional parathyroid surgery with endoscopic techniques have clearly shown a diminution of postoperative pain and better cosmetic results with

.:

469

Sestamibi scan + Ultrasonography

<.

Single focus

-:

No single focus

<,

Anterior location

Posterior location

Endoscopic midline approach

Endoscopic lateral approach

1

Open conventional approach

FIGURE 51-2. Algorithm for the surgical management of patients eligible for an endoscopic parathyroidectomy.

endoscopic tecbniques.Pr" MIVAP is also associated with a shorter operative time." Those results await confirmation by further randomized studies. In our opinion, compared with other minimally invasive procedures performed without the endoscope, endoscopic techniques are safer. The endoscope provides a greater and better surgical image, with magnification of all anatomic structures. By direct vision through mini-incisions, it is probably more difficult to get an adequate view of structures, and it is our belief that optimal conditions for exploration are not met even if surgeons use frontal lamps and surgical loops. According to the type of access, conversion to conventional parathyroidectomy is necessary in 8% to 15% of cases,26.29,30 Main causes for conversion include difficulties of dissection, false-positive results of imaging studies, and multiglandular disease not detected by preoperative imaging but correctly predicted by QPTH assay results. Therefore, as with other minimally invasive techniques, the availability of the QPTH assay is of utmost importance. The overall accuracy of intraoperative QPTH monitoring is reported to be 97%.31 This test may be especially useful when localization studies are less certain. The risk of multiglandularity is nearly zero when both studies are positive for the same lesion site. This has been found to be 3.6% when only one localization study is positive versus 31.6% when both are negative"; the less certain the localization studies, the more certain the need for QPTH assay. In experienced hands, endoscopic parathyroid techniques are as safe as the standard open procedure. There is no mortality. The incidence of recurrent nerve palsy is very low, less than 1%. Once again, we think that the use of the endoscope allows the surgeon to perform a dissection as safely as in open surgery. The rate of transient hypocalcemia is reduced, between 2.5% and 3.2%.17,27 Similar findings have been reported with other minimally invasive techniques.P This may be the result of a less extensive dissection and the targeted removal of the adenoma. Carbon dioxide insufflation may cause hypercarbia, respiratory acidosis, and subcutaneous emphysema.

470 - - Parathyroid Gland Nevertheless, insufflation is harmless as long as the procedure is performed under low pressure. Endoscopic procedures can be performed in less than I hour and the operating time improves dramatically after the first procedures. The operating time may be even shorter than that of conventional cervicotomy, but it must be kept in mind that it is a focused operation and not a bilateral exploration. Endoscopic procedures are better performed under general anesthesia. Trocars are badly tolerated by patients under local anesthesia. In addition, swallowing and spontaneous breathing present impediments when dissecting in such a small operative space. Therefore, as for the conventional operation, in most cases one night of hospitalization is necessary. Whether endoscopic techniques are actually less costly than conventional parathyroidectomy is questionable." After surgery, 95% to 100% of patients are normocalcemic. However, it should be kept in mind that these excellent results have been obtained in a group of carefully selected patients; these patients are considered to present a sporadic PHPT with a solitary adenoma clearly localized by imaging studies. In addition, the risk of persistent PHPT is minimized by the use of intraoperative QPTH assessment. The learning curve must be considered. First of all, one must emphasize the need for expertise in performing conventional open parathyroidectomy. Mentoring by a surgeon who has experience with endoscopic neck techniques is recommended. These new operations are technically more challenging than standard cervical exploration. They should be confined to tertiary care centers.

Experience with Endoscopic Parathyroidectomy by the Lateral Approach We developed the technique for endoscopic parathyroidectomy by the use of a lateral approach on the line of the anterior border of the SCM in 1998.13 Since then, over the course of 5 years (1998 to 2002), we operated on 528 patients with PHPT.34 An endoscopic approach was proposed for patients with sporadic PHPT, without associated goiter and without previous neck surgery, in whom a single adenoma was localized by means of sonography and sestamibi scanning. The procedure was performed by a lateral approach with insufflation for patients with adenoma located deep in the neck and by a gasless midline approach for patients with adenoma located anteriorly. QPTH assay was used during the surgical procedures. Blood was drawn at the time of intubation, first skin incision, adenoma extraction, and 5 and 15 minutes after extirpation. The highest preexcision level of QPTH falling more than 50% was considered significant. Calcemia, phosphoremia, and PTH were systematically evaluated in patients on days 1 and 8, 1 month, and I year after surgery. All patients underwent preoperative and postoperative investigations of vocal cord movements. Of the 528 surgical patients, 228 (43%) had a conventional open approach and 300 (57%) an endoscopic technique. Patients who underwent an open approach had some contraindications to an endoscopic approach: a large multinodular

goiter that needed an associated thyroidectomy in 99 cases, previous cervical surgery in 42 cases, suspicion of multiglandular disease in 25 cases, inconclusive localizing studies in 48 cases, and other reasons in 14 cases (Table 51-I). Endoscopic parathyroidectomy was performed in 300 patients with sporadic PHPT, by a lateral approach in 282 cases and by a central approach in 17 cases. One patient underwent thoracoscopy for an adenoma located very low in the anterior mediastinum. Of the 17 patients who had a central approach, 2 had an associated lobar thyroidectomy. The median operative time recorded was 50 minutes, which was lowered to 41 minutes in the last 100 cases. Recurrent laryngeal nerves were identified in 94.6% of cases, as was the ipsilateral parathyroid gland in 63.8% of cases when a lateral approach was used. We were obliged to perform 42 conversions (14%) to open conventional surgery (Table 51-2). Causes for conversion included nothing found after a 2-hour search (11 cases), difficulties of dissection or a large adenoma taking most of the working space (7 cases), false-positive imaging studies (11 cases), and inadequate fall of rapid PTH assay (13 cases). Interestingly, 10 of the 13 patients had a multiglandular disease during open conversion and 3 had a falsenegative QPTH assay. Thus, multiglandular disease was not detected by preoperative imaging in 10 cases but, in all 10 cases, was correctly predicted by QPTH assay. Postoperative morbidity included permanent recurrent laryngeal nerve damage in one patient, two hematomas in the SCM muscle, and five capsular tears. The capsular disruptions occurred during the dissection of large and fragile adenomas weighing on average 4200 mg. There was no mortality, and most patients were discharged without morbidity from the hospital the next day. Two patients were left with hypercalcemia; persistent PHPT is suspected in the first patient, and another cause of hypercalcemia is likely in the second patient. With a median follow-up of 20.5 months, I of 150 patients had recurrent hypercalcemia after removal of an adenoma, whereas for 15 months the patient had normal serum calcium levels.

Conclusion In contrast to the surgeon performing open surgery, in which surgery alone can be successful in more than 95% of cases, the endoscopic parathyroid surgeon must depend on multiple

Endoscopic Parathyroidectomy - - 471

techniques such as preoperative specialized imaging, intraoperative QPTH assessment, and use of special surgical instruments. The possible advantages of endoscopic parathyroidectomy are a better cosmetic result and more comfort for the patient. Endoscopic parathyroidectomy should not be opposed to conventional parathyroidectomy. Theses operations will probably tum out to be complementary in the future. Endoscopic parathyroidectomy should be reserved for patients with sporadic PHPT, with a single adenoma clearly localized preoperatively. Among many minimally invasive techniques applied to parathyroidectomy, the endoscopic technique has the main advantage of offering a magnified view that permits a precise and careful dissection with minimal risks. The lateral approach is particularly suitable for patients with adenoma located posteriorly in the neck. The central access is reserved for inferior adenomas located anteriorly. As with other minimally invasive techniques, a longer follow-up is needed before one can evaluate the real risk of recurrent PHPT following endoscopic techniques.

REFERENCES 1. Mandl E Therapeutischer versuch ber ostitis fibrosa generalisata mittels extirpation eine epithelkorpercher-tumors. Wien K1in Wochenschr 1925; 38:1343. 2. Van Heerden lA, Grant CS. Surgical management of primary hyperparathyroidism: An institutional perspective. World 1 Surg 1991;15:688. 3. Tibblin SA, Bondeson AG, Ljunberg O. Unilateral parathyroidectomy in hyperparathyroidism due to single adenoma. Ann Surg 1982;195:245. 4. Russel CF, Laird 10, Fergusson WR. Scan-directed unilateral cervical exploration for parathyroid adenoma: A legitimate approach? World 1 Surg 1990;14:406. 5. Chapuis Y, Richard B, Fulla Y, et al. Chirurgie de I'hyperparathyroi'die primaire par abord unilateral sous anesthesie locale et dosage per operatoire de la PTH 1-84. Chirurgie 1993-1994;1\9:12l. 6. Norman 1, Chheda H. Minimally invasive parathyroidectomy facilitated by intraoperative nuclear mapping. Surgery 1997;122:998. 7. Burkey SH, Van Heerden lA, Farley DR, et al. Will directed parathyroidectomy utilizing the gamma probe or intraoperative parathyroid hormone assay replace bilateral cervical exploration as the preferred operation for primary hyperparathyroidism? World 1 Surg 2002; 26:914.

8. Udelsman R, Donovan PI, Sokoll U. One hundred consecutive minimally invasive parathyroid explorations. Ann Surg 2000;232:331. 9. Inabnet WB, Biertho L. Chirurgie parathyroi'dienne dirigee: Une serie de 100 patients consecutifs. Ann Chir 2002;127:751. 10. Ikeda Y,Takarni H, Tajima G, et al. Direct mini-incision parathyroidectomy. Biomed Pharmacother 2002;56(Suppll):14S. 11. Gagner M. Endoscopic parathyroidectomy. Br 1 Surg 1996;83:875. 12. Miccoli P, Bendinelli C, Vignali E, et aI. Endoscopic parathyroidectomy: Report of an initial experience. Surgery 1998;124:1077. 13. Henry JF, Defechereux T, Grarnatica L, et aI. Parathyroi'dectomie videoassistee par abord latero-cervical. Ann Chir 1999;53:302. 14. Cougard P, Goudet P, Osmak L, et al. La video-cervicoscopie dans la chirurgie de I'hyperparathyroi'die primitive. Etude preliminaire portant sur 19 patients. Ann Chir 1998;52:885. 15. Gauger PG, Reeve TS, Delbridge LW. Endoscopically assisted minimally invasive parathyroidectomy. Br 1 Surg 1999;86:1563. 16. Duh QY. Videoscopic parathyroidectomy: Rationales, techniques, indications and contraindications. Acta Chir Aust 1999;31:214. 17. Lorenz K, Nguyen-Thanh P, Dralle H. First experience with minimally invasive video-assisted parathyroidectomy. Acta Chir Aust 1999; 30:218. 18. Yeung GHC. Endoscopic surgery of the neck. A new frontier. Surg Laparosc Endosc 1998;8:227. 19. Okido M, Shimizu S, Kuroki S, et al. Video-assisted parathyroidectomy for primary hyperparathyroidism: An approach involving a skin-lifting method. Surg Endosc 2001;15:1120. 20. Ikeda Y, Takarni H, Tajima G, et al. Total endoscopic parathyroidectomy. Biomed Pharmacother 2002;56(Suppl 1):22s. 21. Suzuki S, Fukushima T, Ami H, et al. Video-assisted parathyroidectomy. Biomed Pharmacother 2002;56(Suppl I): 18s. 22. Prinz RA, Longhyna V, Carnaille B, et al. Thoracoscopic excision of enlarged mediastinal parathyroid glands. Surgery 1994;116:999. 23. Miccoli P, Bendinelli C, Conte M. Endoscopic parathyroidectomy by a gasless approach. 1 Laparoendosc Adv Surg Tech A 1998;8:189. 24. Henry IE Endoscopic exploration. In: Van Heerden lA, Farley DR (eds), Udelsman R (guest ed), Operative Technique in General Surgery. Surgical Exploration for Hyperparathyroidism. Philadelphia, WB Saunders, 1999, p 49. 25. Feind CR. Re-exploration for parathyroid adenoma. Am 1 Surg 1964; 108:543. 26. Miccoli P, Berti P, Conte M, et al. Minimally invasive video-assisted parathyroidectomy: Lesson learned from 137 cases. 1 Am Coli Surg 2000;191:613. 27. Miccoli P, Bendinelli C, Berti P, et al. Video-assisted versus conventional parathyroidectomy in primary hyperparathyroidism: A prospective randomized study. Surgery 1999;126:11\7. 28. Henry IF, Raffaelli M, Iacobone M, et al. Video-assisted parathyroidectomy via lateral approach versus conventional surgery in the treatment of sporadic primary hyperparathyroidism. Results of a casecontrol study. Surg Endosc 2001; 15:1116. 29. Cougard P, Goudet P, Bilosi M, et al. Exerese videoendoscopique des adenomes parathyroidiens: Resultats 11 propos d'une serie prospective de 100 patients. Ann Chir 2001;126:314. 30. Henry IF, Iacobone M, Mirallie E, et aI. Indications and results of video-assisted parathyroidectomy by a lateral approach in patients with primary hyperparathyroidism. Surgery 2001; 130:999. 31. Irvin GL, Carneiro OM. Rapid parathyroid hormone assay guided exploration. In: Van Heerden lA, Farley DR (eds), Operative Technique in General Surgery. Surgical Exploration for Hyperparathyroidism. Philadelphia, WB Saunders, 1999, p 18. 32. Sebag F, Hubbard IGH, Maweja S. Negative preoperative localization studies are highly predictive of multiglandular disease in sporadic primary hyperparathyroidism. Surgery 2003;134:1038. 33. Lorenz K, Nguyen-Thanh P, Dralle H. Unilateral open and minimally invasive procedures for primary hyperparathyroidism: A review of selective approaches. Langenbecks Arch Surg 2000;385:106. 34. Henry IF, Sebag F, Maweja S, et al. Video-assisted parathyroidectomy in the management of patients with primary hyperparathyroidism. Ann Chir 2003;128:379.

Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism George L. Irvin III, MD • Denise M. Carneiro, MD

Many techniques have been tried during parathyroidectomy to differentiate between normal and abnormal parathyroid glands and to predict operative success. At present, none is superior to the intraoperative measurement of parathyroid hormone (PTH) by a quick assay (QPTH) in predicting operative outcome during parathyroidectomy. This surgical adjunct allows the surgeon to quantitatively determine intraoperatively when all hyperfunctioning parathyroid tissue has been excised. Furthermore, in the case of multiglandular disease (MGD), QPTH accurately identifies the presence of additional hypersecreting glandes), guiding the surgeon to further exploration. Since first suggested in 1988by Nussbaum and coworkers, the intraoperative monitoring of intact parathyroid hormone (PTH) levels has been adopted as a quantitative predictor of postoperative serum calcium levels in the treatment of sporadic primary hyperparathyroidism (SPHPT) in many institutions.l" This surgical adjunct became a real intraoperative tool in 1991 with an immunoradiometric assay and was later changed to a more stable, practical, sensitive, and nonradionuclear two-site antibody immunochemiluminescent assay (leMA) in 1993.15. 16 This rapid PTH assay became commercially available as a point of care system in 1996 and is the most widely used intraoperative method for hormone measurement in the United States. The operative results, using this surgical adjunct to guide the resection during parathyroidectomy, are reported with success rates ranging from 94% to lOO%.1.2.5-9.1l-13.17-25 However, the accuracy of QPTH in guiding the surgeon intraoperatively to a successful outcome is directly related to the protocol and criteria used to interpret the measured hormone levels. The intraoperative hormone assay only provides PTH levels at specific times during the operation; therefore, the surgeon's knowledge of the timing of sample collection and interpretation of changes in the hormone

472

values are necessary to ensure a high rate of success. At the University of Miami, this assay is used to (1) determine the complete excision of all hyperfunctioning parathyroid tissue before the operative procedure is finished; (2) guide the surgeon to further cervical exploration when the PTH levels do not drop sufficiently; (3) differentiate parathyroid from nonparathyroid tissues biopsied using measurement of PTH levels in fine-needle aspiration (FNA) samples; (4) localize the side of the neck harboring the hypersecreting parathyroid(s) through differential jugular venous sampling when the preoperative localization study is equivocal; and (5) safely allow limited parathyroidectomy with resection of only hypersecreting glandes) along with preservation of the normally functioning parathyroids in patients with SPHPT. The traditional parathyroidectomy, associated with a bilateral neck exploration, is intended to excise all abnormal glands while preserving all macroscopically normal parathyroids. A "limited parathyroidectomy" is guided by QPTH and helped by preoperative localization studies in an attempt to achieve operative success with rapid, minimal dissection. This quantitative operative approach allows the excision of only the hypersecreting parathyroids with preservation of the remaining normally secreting glands, despite their macroscopic appearance, without disturbing or visualizing them. When a secure diagnosis of SPHPT is obtained (hypercalcemia, elevated PTH levels, normal or high 24-hour urinary calcium levels, and normal renal function) and the patient has defined indications for parathyroidectomy, a preoperative localization study is performed in an attempt to guide the surgeon to the side of the neck harboring the hypersecreting parathyroid gland. The localization study should not be used to diagnose, indicate, or contraindicate parathyroidectomy. It is used only for guidance of a targeted neck or mediastinal exploration when positive. Even when localization studies are negative,

Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism - -

patients with definitive surgical indications are entitled to limited parathyroidectomy guided by QPTH. 26 This chapter describes in detail the authors' 9-year experience in developing, improving, and testing the most ac~urate intraoperative QPTH criterion for predicting operative outcome in patients with SPHPT.

473

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The QPTH criterion to predict operative success (no~al or low calcium levels for at least 6 months after parathyroidectomy) used in our institution is a drop i~ the PT.H ~e~el of 50% or more from the highest level, either premcision or pre-excision, 10 minutes after complete resection of all hyperfunctioning tissue. This criterion was studied and selected before 1993 when the assay was used with previously standard bilateral neck explorations and has proven to be effective through prospective use in patients with SPHPT since. 2,3,18,20-22,27 If there is not a sufficient drop in the hormone level at the lO-minute interval following the excision of a suspected gland, further cervical exploration is mandatory in an attempt to find and resect the remaining hyperfunctioning parathyroid tissue. Figure 52-1 graphically pictures ~e intraoperative PTH results obtained in a patient with eXCIsion of a single hyperfunctioning parathyroid gland. The 92% drop in the PTH level 10 minutes after excision of a single tumor confirms that no other hypersecreting parathyroid glands are present and predicts postoperative eucalcemia, Further neck exploration in an attempt to visualize and/or biopsy the remaining normally secreting parathyroid glands is not necessary. Figure 52-2 shows the PTH levels measured by QPTH in a patient with two hyperfunctioning parathyroid glands. After excision of an enlarged parathyroid gland in the right superior position, the hormone level did not decrease 50% from the pre-excision level, signifying that further exploration was necessary. This led to the 461

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Timed operative blood samples FIGURE 52-1. Timed measurements of intraoperative hormone levels before and following excision of a single hypersecreting parathyroid gland. Intact parathyroid hormone (PTH) levels are expressed in picograms per milliliter. The lO-minute postexcision sample represents a 92% drop in hormone level from the highest pre-excision value. At 10 minutes following the excision of all hypersecreting glands, a drop in the hormone level greater than 50% from the highest peak before tumor excision meets the criterion for predicting postoperative normal or low serum calcium levels.

43

Enlarged rightsuperior parathyroidgland excision

58% 43

PrePre- 5 min 10 min Pre- 5 min 10 min incision excision excision 2 Timed operative blood samples FIGURE 52-2. Hormone levels obtained during parathyroidectomy in a patient with multiglandular disease. A drop of 30% after excision of the right superior parathyroid resection did not predict a return to eucalcemia. Further exploration resulted in excision of a hypersecreting gland in the right inferior parathyroid gland with a decrease of 58% in the hormone level predicting operative success. PTH = intact parathyroid hormone.

discovery and excision of the second hyperfunctioning parathyroid gland, in the right inferior position, resulting in a drop in the PTH level of 58% 10 minutes after gland resection, predicting a return to eucalcemia. It is important to define the QPTH data used to predict operative outcome. As shown in Table 52-1, a true-positive QPTH result is defined as a sufficient drop in the hormone level 10 minutes after the resection of all hyperfunctioning tissue in a patient that returned to normal or low serum calcium levels lasting at least 6 months after parathyroidectomy. A true-negative result is present when the hormone level fails to fall below 50% at the 10-minute interval and the patient remains or returns to hypercalcemia within 6 months following parathyroidectomy. A true-negative QPTH result is also defined as a PTH level that does not drop below 50% after resection of a parathyroid gland or a mistaken nonparathyroid tissue, thus avoiding operative failure by pointing out the presence of MGD or missed overactive glandes). A false-positive result is determined if the hormone level drops 50% or more but the patient has persistent hypercalcemia within 6 months after resection. The visualization of an enlarged, but normally functioning, parathyroid gland after the excision of a single tumor followed by a sufficient hormone level drop is not considered a false-positive result. A false-negative result is defined if the PTH level does not drop in 10 minutes and the patient has a successful return to low or normal calcium levels lasting at least 6 months. Hormone levels that drop in 20 minutes or later after gland excision in a postoperative eucalcemia patient are also considered false-negative QPTH results. Occasionally, these delayed drops influenced the surgeon to discontinue the cervical exploration but are considered false negative when analyzing results. Table 52-1 shows how the QPTH results, with the described criteria to predict postoperative calcium levels, are defined. The criterion published from this institution has matured over the years, becoming more accurate in predicting operative outcome. The present criterion no longer requires a

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Parathyroid Gland

drop in the hormone level at 10 minutes after tumor resection below the preoperative (preincision) level as stated in the past.2 If a drop below the preincision level is required to minutes after gland resection, a decrease in test sensitivity with an increase of the number of false-negative results is encountered. The use of such a requirement would mislead the surgeon to perform further exploration in many patients already successfully treated. The pre-excision sample should be taken specifically just before clamping the gland blood supply and not when the parathyroid is identified or during surgical manipulation.W? Some authors require a return to a normal range of PTH levels after resection to predict operative success.t-" Our experience in 401 patients using the assay to guide parathyroidectomy has shown that hormone dynamics calculated as a percentage change between the levels during the operation is more accurate in predicting operative outcome than a return of the PTH levels to normal range. Furthermore, the quick assay is not reliable for absolute values of PTH in the lower range of the assay standard curve. Variation of the "quick assay" values expressed in picograms per milliliter is often present when compared with the standard 2-hour assay, even though the coefficient correlation is excellent.

Intraoperative Protocol: Blood Sample Collection Time and Processing In the operating room, a 14- or l6-gauge cannula is placed into an antecubital or other available peripheral vein. If not available, an arterial line can be used. This vascular access is maintained without heparin using a saline drip with extension tubing and a three-way stopcock at the head ofthe table. This allows blood sampling at the required intervals. Such access can also be used by the anesthesiologist as long as administered drugs are not collected with the blood samples used for PTH measurement. The blood volume required for the measurement depends on the surgeon's protocol and assay methodology. Usually, no more than 2 mL of whole blood is necessary, but it is wise to save a few milliliters of whole blood for control and future correlation if unexpected results are found postoperatively. For instance, if a patient has a sufficient PTH drop intraoperatively but has persistent hypercalcemia and elevated PTH (false positive), the saved

intraoperative frozen plasma samples should be measured again and the intraoperative results reviewed for technical errors. Blood sample dilution, an incorrect standard assay curve, or high coefficient variation may lead to incorrect interpretation of hormone levels. In an attempt to avoid this problem, 4 to 5 mL of whole blood is drawn into a syringe after the intravenous tubing has been cleared of residual saline solution by a previous extraction with a separate syringe until undiluted blood is available. Once the syringe with whole blood is handed off the table, it is transferred into an ethylenediaminetetraacetic acid (EDTA) glass tube. The tube is inverted several times to ensure proper anticoagulation. Sampling can be done by anesthesia personnel at any time requested by the surgeon. The part of these blood samples that is not used for intraoperative measurement should be later separated by centrifugation and the plasma frozen for future control use. Routinely, there are four samples drawn at specific intervals: before the skin incision (1); just before clamping the blood supply of a completely dissected suspicious parathyroid gland (2); and at the 5-minute (3) and to-minute (4) intervals after the interruption of the blood supply and excision of this gland. The first sample is taken before the incision is made and serves as a baseline, or preincision, PTH level. A PTH level measured for diagnosis before the operation cannot be used as the preincision value or for hormone dynamic calculation. All samples must be measured with the same conditions and by the same assay standard curve at the time of the operation. The second sample, called pre-excision, is taken after complete dissection of the suspected tissue and just before clamping its blood supply. This sample is important since some patients have a substantial increase in the circulating hormone during manipulation, making this pre-excision sample necessary to meet the criterion of a 50% drop in to minutes, as shown in Figure 52-3. In some patients, the pre-excision level will be decreased if the blood supply to the hypersecreting gland is interrupted early during dissection. When this occurs, the higher preincision sample should be used to calculate the drop in PTH level at 10 minutes. If the pre-excision sample is taken too early (e.g., before or during gland manipulation), the peak of the hormone level might be missed, leading to a false delay in the hormone decay at the to-minute interval.Such a false delay is probably due to an unmeasured, very high, pre-excision PTH level. This phenomenon has been observed by others as well." A 5-minute sample taken after gland resection is

Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism - - 475 595

PTH pg/mL

76% from pre-excision

o +----........------r----~---., Pre-incision Pre-excision

40% from pre-incision 5min

10 min

Timed operative blood samples

FIGURE 52-3. Representation of intraoperative hormone monitoring in a patient with a single gland involved. During resection of the parathyroid gland, the intact parathyroid hormone (PTH) level increased significantly, leading to a 76% drop in 10 minutes after gland resection and predicting operative success. This graph shows the importance of the pre-excision sample sample in some patients. If only the preincision sample had been measured, the criterion would not have been met in 10 minutes with a drop of only 40%. This false-negative result can and was prevented by a correct registration of the peak of the hormone caused by gland manipulation.

optional and is measured in an attempt to predict a rapid fall in the PTH level before the 1Q·minutc interval, allowing the surgeon to close the cervical incision earlier. Manipulation of normal parathyroid glands can elevate PTH; therefore, before the 5-minute sample is taken, cervical manipulation, except for fascia and skin closure, should not be performed. Since only 81% of successfully treated patients have a 50% or greater drop in hormone level at 5 minutes, a sample taken 10 minutes after gland resection is always indicated. This last measurement will determine operative success or not. If a significant hormone level drop is not found in 10 minutes, the surgeon should continue further neck exploration for an additional hyperfunctioning gland(s). The same protocol is used for each gland or suspected tissue resected with pre-excision, and 5 and 10-minute levels measured.

The Intraoperative PTH Assay The samples are measured in a short time, as they are drawn, by any available rapid assay for PTH. Most assays available for intraoperative use at the present time are two-site antibody ICMAs that are performed in the operating room or at a nearby central laboratory. The technique differs between assays, with results provided to the surgeon ranging from 8 to 30 minutes from the time of blood collection, depending on the assay and/or location of the laboratory.I.3,5,9,17,19,2I.24,28-30 For obvious reasons, we prefer and work with point of care assays, which provide results in 8 minutes, with a technician present in the operating room to use the hormone information in a timely fashion to guide the operative decision process. Since there are several commercially available assays to measure PTH in a rapid manner, we do not intend to describe the assay's technique itself. 1,3,5,9, 17,19,21,24,28-30 Each assay has advantages and disadvantages. One fact is common in all quick assays: the published normal ranges are inaccurate at times. These assays demonstrate, with good efficacy, the percentage change in the hormone levels during

surgery, but absolute PTH values, especially at the low concentrations, are not always accurate. In our experience, the normal range can differ from the published directional insert, especially when different batches of antibodies are used. If the normal range is used as a part of the criterion, the laboratories should evaluate their own normal range for its population, which should be rechecked over a period of time and with each new batch of antibodies. A change of normal range does not affect intraoperative use as long as the standard assay curve is acceptable before the procedure and all samples are measured against the same curve.

Advantages of QPTH and Criterion The QPTH as used with the described criterion not only can determine when complete resection of all hypersecreting tissue is accomplished but the assay can also guide the surgeon in localizing the offending gland(s).

Biochemical Fine-Needle Aspiration This useful technique, as first described by Perrier and coworkers, consists of determining PTH levels in tissue samples obtained from FNA. The PTH levels in these samples differentiate parathyroid from other tissues, such as thyroid nodules or lymph nodes, with a specificity of 100%,31 A 25-gauge needle attached to a syringe is used to collect the tissue sample. The aspirated content in the needle is diluted with 1 mL of saline solution, centrifuged for 10 seconds, and the supernatant is used for PTH measurement by the rapid assay. This technique provides timely tissue identification without frozen section, and it can be helpful when gland identification is difficult-for example, in the case of an intrathyroidal parathyroid or an indeterminate thyroid nodule. Such quick tissue identification may decrease the operative time by preventing the further dissection of suspicious but nonparathyroid tissue.

Differential Internal Jugular Venous Sampling This technique, which is positive in 70% of cases, can guide the surgeon to the side of the neck harboring the hypersecreting parathyroid gland when other preoperative localization studies are equivocal. These results were also found by other authors. 32,33 Internal jugular vein punctures, as caudal as possible, are performed before skin incision. Samples from each jugular and a peripheral vein are measured for PTH simultaneously. Figure 52-4 demonstrates a positive differential jugular venous test in a patient with a left-sided hypersecreting parathyroid gland. This single overactive gland was not identified on preoperative localization studies, but a clear differential in hormone levels allowed a successful unilateral neck exploration that was confirmed by QPTH. In our experience, few patients had a negative preoperative imaging study and a differential jugular venous sampling that did not localize the overactive parathyroid to the appropriate side of the neck.

476 -

Parathyroid Gland

213 pg/mL Peripheral vein

FIGURE 52-4. Representation of the differential jugular venous sampling and measurement ofPTH levels with rapid assay performed in the operating room just before skin incision. In this patient with a negative sestamibi scan, the differential jugular venous sampling pointed out the presence of a hyperfunctioning parathyroid in the left side of the neck, allowing a successful unilateral neck exploration confirmed by QPTH. (From Irvin GL ill, Carneiro DM: Rapid parathyroid hormone assay-guided exploration. In: van Heerden JA, Farley DR reds], Operative Techniques in General Surgery. Philadelphia, WB Saunders, 1999, p 18.)

Limited Parathyroidectomy, Shorter Operative Time, and Cost Savings After the excision of the hypersecreting glandes) has been ensured by meeting the QPTH criterion, the surgeon may discontinue any further neck exploration without examination and/or biopsy of the remaining parathyroid glands. This decreases the operative time, in that a continued search for the often hard to find, normally functioning glands is unnecessary. This is usually accomplished with a limited unilateral neck exploration. Most patients are sent home after parathyroidectomy without an overnight hospital stay. With biochemical confirmation predicting a return to eucalcemia, frozen section histopathology is not necessary, thereby decreasing the operative time, allowing outpatient procedures, and decreasing the charges to the patient for parathyroidectomy.v'
Improved Success Rate QPTH and the described criterion have improved the success rate of initial and reoperative parathyroidectomy in patients with SPHPT.20.24.25

Limitations of the Established Criterion It is important to understand that QPTH only measures PTH levels at any given time during parathyroidectomy. Most published limitations of the intraoperative assay are related to the protocol and criteria used to interpret the intraoperative hormone values and not to the assay itself. The use of different protocols and criteria in interpreting the hormone levels has led to reports that differ in degrees of accuracy.17.19,23,27,29,35-43

1. QPTH and criterion do not predict the size of the remaining normally secreting parathyroid glands. Some surgeons using QPTH during bilateral neck explorations have published the finding of a second enlarged, but not hypersecreting, gland after successful resection of a single adenoma confirmed by the drop in hormone levels, Because these enlarged, normally functioning glands are interpreted as "second adenomas" and are excised, the QPTH results were reported as false positive because eucalcemia is achieved,36.37,39,41,43 The criterion used in our series does not predict the size of the remaining normally functioning glands. These glands were not hypersecreting either at the time of the surgery or found to be responsible for hypercalcemia during the postoperative period, which averaged 3 years." This emphasizes that abnormal secretion is not necessarily associated with parathyroid gland size.44,45 This can also be supported by the fact that when parathyroid resection is guided by hormone secretion, 6% fewer glands are excised with a 98% success rate, when compared with gland resection guided by the surgeon's judgment of gland size. Therefore, we can conclude that those enlarged glands left in situ were not hyperfunctioning." 2. QPTH and criterion do not predict PTH levels in postoperative eucalcemic patients. Some authors have pointed out that the use of QPTH in parathyroidectomy, with this described criterion, fails to predict high PTH levels in postoperative eucalcemic patients. It is known that despite the operative approach used, PTH levels are found to be elevated in 8% to 17% of eucalcemic patients following successful parathyroidectomy. Many of these patients return to normal PTH levels months later.46-49 Carty," Bergenfelz," and their associates have suggested that these high PTH levels are compensatory, with parathyroid glands responding to a deficit in total body calcium. We observed no difference in intraoperative hormone dynamics found in eucalcemic patients presenting with normal or high postoperative PTH levels, 3. QPTH and criterion do not predict late recurrence. No difference was found in the operative hormone dynamics between long-term postoperative eucalcemic patients and those who developed recurrent hypercalcemia. 4. QPTH and criterion do not identify the secretion of the first glands resected in a MOD case. If, after resection of an enlarged parathyroid gland, the hormone level does not drop sufficiently and a second gland is found and resected with a sufficient hormone drop, it is not possible to evaluate the parathyroid hormone secretion of the first resected gland. QPTH does not differentiate this gland from an enlarged normally functioning parathyroid, because the hormone level remained high after its removal. 5. The described criterion does not accurately predict the postoperative outcome in patients with secondary hyperparathyroidism (HPT) and multiple endocrine neoplasia (MEN). The outcome of patients with secondary HPT and MEN may be predicted by a different criterion, but a drop of

Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism - -

50% in the hormone level from the highest preincision or pre-excision level, as measured by the current PTH assays, does not accurately predict outcome in patients with these diseases. 28,30,43,50,51 One must not combine QPTH results in secondary, tertiary HPT, and MEN patients in an attempt to evaluate the usefulness of QPTH and the described criterion in the treatment of SPHPT, since the outcome and etiologies are differenr."

Disadvantages of QPTH and Criterion The disadvantages of QPTH and the criterion are as follows: 1. QPTH cannot guarantee operative success. QPTH predicts, but does not prevent, operative failure in patients whose offending gland(s) could not be found by localization studies, differential jugular venous sampling, and careful bilateral neck exploration performed by an experienced surgeon. In addition, it cannot prevent operative failure due to misdiagnosis. 2. QPTH accuracy is criterion and protocol dependent. If the surgeon is not aware of the possible mistakes and the need for a strict protocol of blood collection and interpretation of the changing hormone values during the procedure, the accuracy of QPTH will decrease considerably. There are several different protocols and criteria to evaluate intraoperative PTH levels. Some studies used criteria that require a drop in the PTH level of 60% or 70%, 10 or 15 minutes after gland resection, to predict operative success.v" Others required a drop in the PTH level and its return to the published normal range, or a value below the preincision level, to predict cure. 4, J7, 19.29.35 The different criteria used for evaluating hormone dynamics have different sensitivities and specificities in predicting operative outcome. For instance, in an attempt to not overlook any patients with MOD (QPTH false positive), some require a greater percentage drop in the PTH level at 10 minutes to predict a postoperative return to eucalcemia. Such a change in the criterion leads to an increased number of patients that will not have a sufficient hormone drop in 10 minutes even though they had complete resections of all hypersecreting glands (QPTH false negative). This alteration increases the specificity of this surgical adjunct but decreases its sensitivity, making the use of intraoperative assay less beneficial. 27 3, The assay is technician dependent. This surgical adjunct is dependent on the expertise of the technician in performing the test, handling the blood, and running the assay itself as a functioning system. Plasma pipetting and blood dilutions with a high coefficient variation of the samples, inability to solve system problems (antibodies, washer system and luminometer breakdowns), and delay in sample drawing are all factors that are dependent on good technical skills. The usefulness of QPTH will improve as the assay becomes more automated. 4. The cost of QPTH is high. This surgical adjunct is expensive. The benefits of QPTH, however, compensate for its cost by allowing a

477

shorter operative time, decreasing the need for frozen section histopathology and eliminating an overnight hospital stay. In an attempt to make QPTH more affordable, some hospitals locate this surgical adjunct at the central laboratory where the system can be used for other purposes without dislocating a technician to the operative room. This limits the use of intraoperative hormone dynamics since the assay turnaround time is prolonged. If the number of samples obtained during parathyroidectomy is reduced to decrease costs (e.g., if the pre-excision sample is omitted from the protocol), the accuracy of the assay will decrease.

Results of "Limited" Parathyroidectomy Guided by QPTH Since 1993, in our institution, exploration and parathyroid resection have been guided exclusively by hormone dynamics using a rapid leMA point of care assay. Bilateral neck exploration is no longer performed as a standard procedure and is done only when indicated by QPTH or when a preoperative localization study has initially guided the surgeon to the incorrect side of the neck. From September 1993 until July 2002, 403 consecutive patients with SPHPT were operated on. Of these, 401 patients had the intraoperative hormone assay used during their parathyroidectomy. Two patients were excluded because technical problems made the assay unavailable. All patients had total serum calcium levels measured within 1 or 2 days postoperatively, and then a designed follow-up was sought, with measurement of total serum calcium and PTH levels at 2 months, 6 months, and yearly intervals, Definitions used with this data analysis are as follows: Operative success is considered when a patient has normal or low calcium levels for at least 6 months after parathyroidectomy. Operative failure is defined as persistent hypercalcemia and elevated PTH levels occurring within 6 months of parathyroidectomy. Recurrent disease is defined as hypercalcemia and high PTH levels occurring later than 6 months following a successful parathyroidectomy. MGD is considered the presence of two or more hyperfunctioning glands at the time of parathyroidectomy. Recurrent HPT after single gland resection is not considered MOD. Out of 401 consecutive patients with SPHPT undergoing parathyroidectomy (359 initial and 42 reoperations), 391 had normal or low calcium levels in the first days after surgery, with 10 patients (5 initial and 5 reoperations) continuing with persistent hypercalcemia. Since all the resections were guided by hormone dynamics instead of the surgeon's judgment of gland size, 97% patients were successfully treated with only one gland excised. Twelve patients with MOD had the QPTH and criterion pointing out the presence of additional hyperfunctioning gland(s) at the time of the surgery, whereas in two patients the QPTH failed to identify MOD. To evaluate operative success and the accuracy of the intraoperative hormone assay using our criterion, results are

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Parathyroid Gland

reported in all patients followed for 6 months or longer, including all known operative failures in the immediate postoperative period.

Initial Parathyroidectomy From 294 consecutive patients with more than 6 months of follow-up (an average of 34 months [range, 6 to 98 months]), including all known operative failures, 262 had initial parathyroidectomies. Two-hundred-fifty-seven patients (98%) had successful procedures and five were operative failures. During the operative procedure, QPTH correctly predicted postoperative outcome in 254 (97%) of 262 patients, including 4 of 5 operative failures. Using the protocol and the criterion described in this chapter, QPTH wrongly predicted the postoperative outcome in eight patients, with one falsepositive result and seven false-negative results. The falsenegative results did not lead to unnecessary neck exploration in these patients since a 20-minute postexcision sample was drawn that showed a sufficient hormone drop to lead the surgeon to suspend further exploration. The delayed hormone drop was probably due to a premature timing of the preexcision sampling or unavailability of this important sample because of venous access problems. A false delayed drop is the result of a missed peak of the hormone level and not due to a delayed metabolism. There was one false-positive result leading to an operative failure within this 9-year period. This patient had a parathyroid cyst ruptured during dissection with an increase in the peripheral PTH level to 1100 pg/mL. With a drop of 62% in 10 minutes and 80% in 20 minutes, further neck exploration was not performed. Even though this is only a hypothesis, we believe that this fluid, with a high content of PTH spilled in the operative field, altered the hormone dynamic, thus generating a false-positive result. On the other hand, QPTH predicted the presence of MGD in 8 of 9 patients. The incidence of MG in this group presenting with a success rate of 98% is 3.4%. In addition, QPTH pointed out, with a specificity of 100%, the continued presence of a hyperfunctioning gland in patients in whom nonparathyroid tissue was mistakenly resected as a gland (26 of 35 patients with true-negative results not caused by MGD). Using this operative approach with QPTH guiding an initial limited parathyroidectomy, 238 (91%) of 262 patients had a successful unilateral neck exploration. In terms of length of stay, 183 (70%) of 262 patients were discharged on the day of surgery or stayed at the hospital overnight for social reasons (living alone or out of town). The average operative time for these 262 initial patients was 60 minutes (range, 15 to 300 minutes).

Reoperative Parathyroidectomy From the 294 consecutive patients with more than 6 months of follow-up, including all known operative failures, 32 were reoperative cases from which 27 (84%) were successfully treated with a limited parathyroidectomy and unilateral neck exploration. QPTH correctly predicted the postoperative outcome in 31 of 32 patients (27 true positive and 4 true negative). There was one false-positive result due to a

technician's error. The falsely elevated pre-excision PTH level in this patient was later found to be wrong by measurement of control serum. There were no false-negative results in this group. In two patients with MGD, QPTH predicted failure intraoperatively despite the resection of one or more parathyroid glands. In addition, QPTH identified the resection of nonparathyroid tissue misinterpreted as parathyroid glands in 8 patients, with a total of 13 true-negative results. The reoperative patients had an average operative time of 108 minutes (range, 35 to 325 minutes), with 6 of these patients eligible for same-day discharge.

QPTH Results: "Biochemical" FNA, Differential Jugular Venous Sampling, and Sestamibi Scans A "biochemical" FNA of tissue for hormone content was performed multiple times in 32 patients. This technique had a sensitivity and specificity of 100% in differentiating parathyroid from nonparathyroid tissue. Differential jugular venous sampling was performed in 89 patients with positive results (high levels on the side of the tumor) in 70%. In our series, the sestarnibi scan results, based on the radiologist's interpretation, correctly localized the offending parathyroid gland(s) (true positive) in 317 (79%) of 401 patients. In 26 patients, the scan incorrectly localized the overactive parathyroid gland (false positive/false negative). A second overactive gland was overlooked by the sestamibi scan in 12 of 401 patients (true positive/false negative), and another 11 had a second spot(s) falsely identified as positive (true positive/false positive). Of 22 patients with completely negative scans, 13 had differential jugular venous sampling. Eight of these patients had a positive differential allowing a successful unilateral neck exploration. The sestamibi scans were incorrect in 20% of cases. The QPTH was useful in identifying and correcting these mistaken localization studies in all 80 patients (20%) with the use of differential venous sampling and the intraoperative PTH monitoring interpreted with the described criterion.

QPTH and Criterion Accuracy In predicting postoperative serum calcium levels, the intraoperative PTH hormone assay, using the described criterion, has a sensitivity of 98%, specificity of 97%, positive predictive value of 99%, negative predictive value of 90%, and overall accuracy of 97% in the 401 patients with SPHPT. Analyzing only those patients with more than 6 months of follow-up, including all known operative failures, the sensitivity, specificity, and accuracy remained unchanged.

Conclusion The intraoperative measurement of parathyroid hormone is an established surgical adjunct that can be of help during

Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism - - 479

parathyroidectomy in patients with SPHPT. This rapid assay has been shown to be effective in ensuring operative success with a limited operative approach that allows minimal dissection and selected gland excision. A specific protocol for defining hormone dynamics and a strict criterion for predicting operative success are necessary. With the method described in this chapter, the surgeon can excise only the hyperfunctioning parathyroid gland(s) without visualizing or disturbing the remaining normally functioning parathyroids. This surgical adjunct also redefines MGD. Instead of the traditional method of identifying abnormal glands based on size, weight, and/or histopathology, QPTH allows a precise recognition of gland hyperfunction based on hormone secretion during parathyroidectomy. The QPTH-guided parathyroidectomy is as successful as a bilateral neck exploration. Guided by hormone levels, parathyroidectomy has evolved into a highly successful and rapid operation, usually requiring minimal dissection, performed in an ambulatory setting.

REFERENCES I. Bergenfelz A, Isaksson A, Lindblom P, et al: Measurement of parathyroid hormone in patients with primary hyperparathyroidism undergoing first and reoperative surgery. Br J Surg 1998;85:1129. 2. Boggs JE, Irvin GL III, Carneiro DM, et al: The evolution of parathyroidectomy failures. Surgery 1999;126:998. 3. Carneiro DM, Irvin GL III: New point-of-care intraoperative parathyroid hormone assay for intraoperative guidance in parathyroidectomy. World J Surg 2002;26: 1074. 4. Carty SE, Roberts MM, Virji MA, et al: Elevated serum parathormone level after "concise parathyroidectomy" for primary sporadic hyperparathyroidism. Surgery 2002; 132:1086. 5. Chen H, Sokoll LJ, Ude1sman R: Outpatient minimally invasive parathyroidectomy: A combination of sestamibi-SPECT localization, cervical block anesthesia, and intraoperative parathyroid hormone assay. Surgery 1999;126:1016. 6. Garner SC, Leight GS Jr: Initial experience with intraoperative PTH determinations in the surgical management of 130 consecutive cases of primary hyperparathyroidism. Surgery 1999;126:1132. 7. Inabnet WB, Dakin GF, Haber RS, et al: Targeted parathyroidectomy in the era of intraoperative parathormone monitoring. World J Surg 2002;26:921. 8. Jaskowiak NT, Sugg SL, Helke J, et al: Pitfalls of intraoperativequick parathyroid hormone monitoring and gamma probe localization in surgery for primary hyperparathyroidism. Arch Surg 2002;137:659. 9. Johnson LR, Doherty G, Lairmore T, et al: Evaluation of the performance and clinical impact of a rapid intraoperative parathyroid hormone assay in conjunction with preoperative imaging and concise parathyroidectomy. Clin Chem 2001;47:919. 10. Mandell DL, Genden EM, Mechanick Jl, et al: The influence of intraoperative parathyroid hormone monitoring on the surgical management of hyperparathyroidism. Arch Otolaryngol Head Neck Surg 2001;127:821. II. Miccoli P, Berti P, Conte M, et al: Minimally invasive video-assisted parathyroidectomy: Lesson learned from 137 cases. J Am CoIl Surg 2000;191:613. 12. Patel PC, Pellitteri PK, Patel NM, et al: Use of a rapid intraoperative parathyroid hormone assay in the surgical management of parathyroid disease. Arch Oto1aryngol Head Neck Surg 1998;124:559. 13. Vignali E, Picone A, Materazzi G, et al: A quick intraoperative parathyroid hormone assay in the surgical management ·of patients with primary hyperparathyroidism: A study of 206 consecutive cases. Eur J EndocrinoI2002;146:783. 14. Yang GP, Levine S, Weigel RJ: A spike in parathyroid hormone during neck exploration may cause a false-negative intraoperative assay result. Arch Surg 2001;136:945. 15. Irvin GL III, Dembrow VD, Prudhomme DL: Operative monitoring of parathyroid gland hyperfunction. Am J Surg 1991;162:299. 16. Irvin GL III, Deriso GT III: A new, practical intraoperative parathyroid hormone assay. Am J Surg 1994;168:466.

17. Burkey SH, Van Heerden JA, Farley DR, et al: Will directed parathyroidectomy utilizing the gamma probe or intraoperative parathyroid hormone assay replace bilateral cervical exploration as the preferred operation for primary hyperparathyroidism? World J Surg 2002;26:914. 18. Carneiro DM, Irvin GL III: Late parathyroid function following successful parathyroidectomy guided by intraoperative hormone assay (QPTH) compared with the standard bilateral neck exploration. Surgery 2000;128:923. 19. Carty SE, Worsey J, Virji MA, et al: Concise parathyroidectomy: The impact of preoperative SPECT 99mTc sestamibi scanning and intraoperative quick parathormone assay. Surgery 1997;122:1107. 20. Irvin GL III, Molinari AS, Carneiro, DM, et al: Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Ann Surg 1999;229:874. 21. Irvin GL III, Carneiro DM: Rapid parathyroid hormone assay-guided exploration. In: van Heerden JA, Farley DR (eds), Operative Techniques in General Surgery. Philadelphia, WB Saunders, 1999, p 18. 22. Molinari AS, Irvin GL III, Deriso GT, et al: Incidence of multiglandular disease in primary hyperparathyroidism determined by parathyroid hormone secretion. Surgery 1996; 120:934. 23. Starr FL, DeCresce R, Prinz RA: Use of intraoperative parathyroid hormone measurement does not improve success of bilateral neck exploration for hyperparathyroidism. Arch Surg 2001;136:536. 24. Thompson GB, Grant CS, Perrier ND, et al: Reoperative parathyroid surgery in the era of sestamibi scanning and intraoperative parathyroid hormone monitoring. Arch Surg 1999;134:699. 25. Irvin GL, Carneiro DM, Solorzano CC: Progress in the operative management of sporadic primary hyperparathyroidism over 34 years. Ann Surg 2004;239:704. 26. Irvin GL III, Carneiro DM: Management changes in primary hyperparathyroidism. JAMA 2000;284:934. 27. Carneiro DM, Solorzano CC, Nader MC, et al: Comparison of intraoperative iPTH assay (QPTH) criteria in guiding parathyroidectomy: Which one is the most accurate? Surgery 2003;134:973. 28. Chou FF, Lee CH, Chen JB, et al: Intraoperative parathyroid hormone measurement in patients with secondary hyperparathyroidism. Arch Surg 2002;137:341. 29. Inabnet WB, Fulla Y, Richard B, et al: Unilateral neck exploration under local anesthesia: The approach of choice for asymptomatic primary hyperparathyroidism. Surgery 1999;126:1004. 30. Seehofer D, Rayes N, Ulrich F, et al: Intraoperative measurement of intact parathyroid hormone in renal hyperparathyroidism by an inexpensive routine assay. Langenbecks Arch Surg 2001;386:440. 31. Perrier ND, Ituarte P, Kikuchi S, et al: Intraoperative parathyroid aspiration and parathyroid hormone assay as an alternative to frozen section for tissue identification. World J. Surg 2000;24: 1319. 32. Taylor J, Fraser W, Banaszkiewicz P, et al: Lateralization of parathyroid adenomas by intraoperative parathormone estimation. J R CoIl Surg Edinb 1996;41:174. 33. Udelsman R, Osterman F, Sokoll LJ, et al: Rapid parathyroid hormone measurement during venous localization. Clin Chim Acta 2000; 295:193. 34. Irvin GL III, Sfakianakis G, Yeung L, et al: Ambulatory parathyroidectomy for primary hyperparathyroidism. Arch Surg 1996;131:1074. 35. Agarwal G, Barakate MS, Robinson B, et al: Intraoperative quick parathyroid hormone versus same-day parathyroid hormone testing for minimally invasive parathyroidectomy: A cost-effectiveness study. Surgery 2001;130:963. 36. Gauger PG, Agarwal G, England BG, et al: Intraoperative parathyroid hormone monitoring fails to detect double parathyroid adenomas: A two-institution experience. Surgery 2001;130:1005. 37. Gordon LL, Snyder WH, Wians F Jr, et al: The validity of quick intraoperative hormone assay: An evaluation in seventy-two patients based on gross morphology criteria. Surgery 1999;126:1030. 38. Libutti SK, Alexander HR, Bartlett DL, et al: Kinetic analysis of the rapid intraoperative parathyroid hormone assay in patients during operation for hyperparathyroidism. Surgery 1999; 126:1145. 39. Miura D, Wada N, Arici C, et al: Does intraoperative quick parathyroid hormone assay improve the results of parathyroidectomy? World J Surg 2002;26:926. 40. Nussbaum SR, Thompson AR, Hutcheson KA, et al: Intraoperative measurement of parathyroid hormone in the surgical management of hyperparathyroidism. Surgery 1988;104:1121. 41. Perrier ND, Ituarte PH, Morita E, et a1: Parathyroid surgery: Separating promise from reality. J Clin Endocrinol Metab 2002;87:1024.

480 -

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42. Starr FL, DeCresce R, Prinz RA: Normalization of intraoperative parathyroid hormone does not predict normal postoperative parathyroid hormone levels. Surgery 2000;128:930. 43. Weber CJ, Ritchie JC: Retrospective analysis of sequential changes in serum intact parathyroid hormone levels during conventional parathyroid exploration. Surgery 1999;126:1139. 44. Berger AC, Libutti SK, Bartlett DL, et al: Heterogeneous gland size in sporadic multiple-gland parathyroid hyperplasia. J Am Coil Surg 1999;188:382. 45. Liechty RD, Teter A, Suba EJ: The tiny parathyroid adenoma. Surgery 1986;100:1048. 46. Bergenfelz A, Valdemarsson S, Tibblin S: Persistent elevated serum level of intact parathyroid hormone after operation for sporadic parathyroid adenoma: Evidence of detrimental effects of severe parathyroid disease. Surgery 1995;119:624.

47. Lundgren E, Rastad J, Ridefelt P, et al: Long-term effects of parathyroid operation on serum calcium and parathyroid hormone values in sporadic primary hyperparathyroidism. Surgery 1992;112:1123. 48. Tisell L-E, Jasson S, Nilsson B, et al: Transient rise in intact parathyroid hormone concentration after surgery for primary hyperparathyroidism. Br J Surg 1996;83:665. 49. Westerdahl J, Lindblom P, Bergenfelz A: Measurement of intraoperative parathyroid hormone predicts long-term operative success. Arch Surg 2002;137:186. 50. Clary BM, Garner SC, Leight GS Jr: Intraoperative parathyroid hormone monitoring during parathyroidectomy for secondary hyperparathyroidism. Surgery 1997;122:1034. 51. Tonelli F, Spini S, Tommasi M, et al: Intraoperative parathormone measurement in patients with multiple endocrine neoplasia type 1 syndrome and hyperparathyroidism. World J Surg 2000;24:556.

Parathyroid Hyperplasia: Parathyroidectomy Saif AI-Sobhi, MD • Orlo H. Clark, MD

More than one abnormal parathyroid gland is present in about 20% of patients with primary hyperparathyroidism (HPT) and in virtually all patients with secondary HPT. When all parathyroid glands are enlarged and hyperplastic, these patients have diffuse hyperplasia. In some patients with primary or secondary hyperplasia, the size of the parathyroid glands varies considerably. More than one abnormal parathyroid gland may occur in patients with other histologically proven normal parathyroid glands; these patients have double or triple adenomas.' Problems exist that contribute to the controversy as to how patients with primary and secondary HPT and multiple abnormal parathyroid glands should be managed. For example, patients with familial parathyroid disease are more likely to have multiple abnormal parathyroid glands (",80%) and experience recurrent disease than are patients with sporadic disease.P There is also no consensus as to the precise size of the parathyroid remnant to leave at subtotal parathyroidectomy, the precise amount of parathyroid tissue to autotransplant, and the site to autotransplant into during total parathyroidectomy with autotransplantation. We recommend parathyroid cryopreservation for all patients having subtotal or total parathyroidectomy with autotransplantation in case the parathyroid remnant or autotransplanted tissue does not function adequately. Long-term follow-up studies are also necessary to determine the incidence of hypoparathyroidism and recurrent or persistent HPT after subtotal or total parathyroidectomy with autotransplantation. Better histologic and molecular biologic criteria must be developed to determine precisely whether an abnormal parathyroid gland is an adenoma or a hyperplastic gland.

Embryology and Anatomy of Parathyroid Gland Normal parathyroid glands originate from the third and fourth pharyngeal pouches and are of endodermal origin." The inferior parathyroid glands and the thymus are derived from the third pharyngeal pouch, whereas the superior

parathyroid glands arise from the fourth pharyngeal pouch.' Because third pharyngeal pouch derivatives (i.e., the inferior parathyroid glands and thymus) migrate farther, these parathyroid glands are more likely to be in ectopic or aberrant positions than are the superior parathyroid glands. Despite this observation, about 80% of the inferior parathyroid glands are situated anterior to the recurrent laryngeal nerve on the lower (dorsal position) aspect of the thyroid gland, within 1 em of where the inferior thyroid artery crosses the recurrent laryngeal nerve (Fig. 53-1). About 15% of lower parathyroid glands are found in the thymus or perithymic fat." Occasionally, parathyroid glands fail to descend. This results in an "undescended parathymus,"? The superior parathyroid glands are usually situated at the level of the cricoid cartilage. They are more dorsal in position than the inferior parathyroid glands. When not found at this site, they often descend caudally along the esophagus and sometimes (especially when abnormal) into the posterior mediastinum (Fig. 53-2). Superior parathyroid glands may be situated intrathyroidally, within the carotid sheath, or may also fail to descend and be situated in the pharyngeal musculature.f Supernumerary parathyroid glands occur in about 20% of patients and can be situated in normal or ectopic sites. Supernumerary parathyroid glands situated at ectopic sites in patients with multiple adenomas are a common cause of persistent HPT. When four normal parathyroid glands are identified in a patient with primary HPT, the fifth supernumerary parathyroid gland is almost always situated in the mediastinum, usually within the thymus or peri thymic fat.

Parathyroid Morphology Most people (80%) have four parathyroid glands. Normal parathyroid glands measure up to 7 mm in maximal diameter and usually weigh between 15 and 65 mg; all parathyroid glands weigh less than 300 mg.? About 20% of persons have more than four parathyroid glands, and about 5% have fewer than four (Fig. 53-3). Parathyroid glands assume

481

482 - - Parathyroid Gland adults because there is little intraparathyroidal fat. At puberty, the normal parathyroid glands assume a light beigebrown color, and 70% to 80% of the chief cells have intracellular lipid droplets.t-'! Normal parathyroid glands are a darker brown than the adjacent fat, which is yellow. They also differ from lymph nodes, which are more pinkish and "glassy" in color, and the thymus, which is whiter. Hypercellular parathyroid glands are darker brown than normal parathyroid glands because they have little intracellular fat, and parathyroid adenomas often have a compressed rim of more normal beige-colored parathyroid tissue. In general, parathyroid adenomas are firmer than hyperplastic parathyroid glands found in patients with primary parathyroid hyperplasia. Hyperplastic parathyroid glands are more likely to be lobular than are parathyroid adenomas (Fig. 53-5). Hyperplastic parathyroid glands in patients with secondary HPT tend to be darker, firmer, and better encapsulated than those in patients with primary hyperplasia. Parathyroid carcinomas are rare and occasionally occur in patients with parathyroid hyperplasia and in those with familial HPT.12-14 Parathyroid carcinomas are usually harder and more fibrotic than adenomas, have a whitish color, are irregular, and often invade the adjacent tissues." FIGURE 53-1. The recurrent laryngeal nerve and its relationship to the parathyroid glands. (From Clark OR [ed], Endocrine Surgery of the Thyroid and Parathyroid Glands. St. Louis, CV Mosby, 1985.)

Etiology of Hyperplasia

different shapes. About 83% are bean shaped, oval, or spherical, whereas about II % are elongated, 5% are bilobated, and 1% are multilobated (Fig. 53_4).10.11 The color of the parathyroid glands depends on the ratio of parathyroid cells to intracellular parathyroid fat. In newborns and infants up to 3 months old, the normal parathyroid glands are gray, glistening, and semitransparent. Children have relatively darker or browner parathyroid glands than

The development of hyperplastic parathyroid glands in patients with renal failure is primarily due to hypocalcemia, although other factors, including low calcitriol or 1,25-hydroxyvitamin D 3, high phosphate levels, and local growth factors, are involved. The decrease in serum calcium levels results from a decrease in the enzyme Ia-hydroxylase in the kidney that converts 25-dihydroxy vitamin D3 to 1,25-dihydroxyvitamin D. Hyperphosphatemia in patients with renal failure decreases the activity of la-hydroxylase. The consequent decrease in 1,25-dihydroxyvitamin D results in decreased

Large parathyroid

adenoma

FIGURE 53-2. CT scan of the mediastinum shows a large parathyroid adenoma in the right superior mediastinum. The patient is a 72-year-old man with persistent primary hyperparathyroidism after subtotal resection of three hypercellular parathyroid glands.

Parathyroid Hyperplasia: Parathyroidectomy - - 483

FIGURE 53-3. Common bean-shaped adenomatous hyperplasia

and enlarged right upper and right and left lower hyperplastic parathyroid glands.

53-5. Multilobed parathyroid gland (hyperplastic gland) a 62-year-old woman with multiple endocrine neoplasia I and multiple abnormal parathyroid glands.

~IGURE III

calcium absorption from the gastrointestinal tract and lower serum calcium levels. The parathyroid glands, therefore, compensate by increased secretion of parathyroid hormone (PTH). In general, the size of the hyperplastic glands in patients with secondary hyperplasia as documented by ultrasonography or surgery correlates with the degree of elevation of serum PTH levels. 16 The cause of primary parathyroid hyperplasia or multiple abnormal parathyroid glands is less clearly understood. Certainly, patients with both multiple endocrine neoplasia (MEN) types I and 2 as well as those with familial non-MEN primary HPT have multiple abnormal parathyroid glands. 1719 Patients with MEN I have had a chromosomal abnormality documented on chromosome 11,20 and patients with MEN 2A and MEN 2B have point mutations on RET protooncogene." Patients exposed to low-dose therapeutic radiation also are more likely to acquire parathyroid as well as thyroid neoplasms.t-" Whether parathyroid hyperplasia occurs more often than in sporadic disease is unknown. Children given

Bilobated

the diuretic furosemide (Lasix) experience parathyroid hyperplasia as the parathyroids enlarge to compensate for increased urinary calcium loss." Neonatal HPT has been documented to be caused by specific point mutations on chromosome 3.25,26 These patients have homozygous mutations, whereas patients with benign farnili.al hypocalciuric hypercalcemia have heterozygous mutations at the same sites. 25,26 Patients with neonatal HPT require total parathyroidectomy with autotransplantation and cryopreservation, whereas those with benign familial hypocalciuric hypercalcemia should be treated nonoperatively because they do not appear to be adversely affected by the hypercalcemia, and virtually all patients experience recurrent hypercalcemia after parathyroidectomy." Studies have been performed to determine whether hyperplastic glands and parathyroid adenomas are monoTheoretically, the parathyroid clonal or ~0~yclonaI.28-30 adenoma ongmates from one cell because it is a neoplasm r~ther than a hyperplastic growth of normal parathyroid tissue. One study, however, showed that only 75% of adenomas are monoclonal.P Hyperplasia theoretically originates from more than one cell. However, studies showed that in patients with MEN I large glands are monoclonal, whereas small glands are often polyclonal.v-? Further studies are required to better clarify the mechanisms of parathyroid overgrowth.

Multilobated

Indications for Parathyroidectomy

FIGURE 53-4. Hypercellular parathyroid glands are usually oval or kidney shaped but occasionally are elongated, bilobated, or mUl~lobated. (From Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95: 14.)

The indications for parathyroidectomy in patients with parathyroid hyperplasia resulting from secondary HPT are (1) a calcium-to-phosphorus product greater than 70; (2) a serum calcium greater than 11.5 mg/dL; (3) symptoms of

Oval, bean-shaped, or spherical

Elongated

484 - - Parathyroid Gland bone pain and pruritus; (4) osteitis fibrosa cystica; (6) tumoral calcinosis; and (7) calciphylaxis.W" With primary HPT, it is difficult to know preoperatively whether a patient will have a solitary adenoma or multiple abnormal parathyroid glands. The diagnosis of primary HPT is usually relatively easy to establish on the basis of hypercalcemia and an increased intact or two-site PTH level in a patient without hypocalciuria. Most patients with hypercalcemia lasting longer than 6 months have primary HPT. Some patients with primary HPT can be suspected of having multiple abnormal parathyroid glands on the basis of preoperative localization studies, although localization studi~s are unreliable in patients with multiple abnormal parathyroid glands'"; that is, they often identify only one abnormal gland when more are present. Because virtually all patients with primary HPT benefit symptomatically and metabolically and have improved survival after successful parathyroidectomy, we recommend parathyroid exploration and parathyroidectomy for most patients when a surgeon experienced in this field is available." When parathyroidectomy is performed by an experienced surgeon, the complication rate is less than 1%, blood transfusions are not required, and the duration of hospitalization is usually 1 day, unless the patient has severe osteitis fibrosa . or ot her seri . me diica 1 pro bl ems. 36'37 cystica er senous preoperative Patients with osteitis fibrosa cystica can be identified preoperatively because they have elevated serum alkaline phosphatase levels." Radiographs of the hands in such patients are useful for documenting subperiosteal resorption (Fig. 53-6).

Operative Treatment Although successful parathyroid operations have been done since the first successful operation in Vienna in 1925 by Felix Mandl, there has been controversy regarding the surgical management of the parathyroid glands in patients with primary and secondary hyperplasia." Cope'? identified patients with primary hyperplasia and recommended subtotal parathyroidectomy. Stanbury," in 1960, recommended a similar operation for patients with secondary HPT resulting from renal failure. Ogg, in 1967, recommended total parathyroidectomy without autotrans. . patients . . h second ary (rena1) HPT42-45 P1antation In WIt . Although this operation may be acceptable for patients who are not candidates for kidney transplantation, aparathyroid patients are extremely difficult to manage metabolically after successful renal transplantation, and we do not believe these patients should undergo total parathyroidectomy. Aparathyroid patients with chronic renal failure can also acquire low-turnover bone disease with increased bone pain. Alveryd and associates, in 1968,70 first recommended total parathyroidectomy with parathyroid autotransplantation into the muscle in the neck. Wells and colleagues.tv" in 1973, recommended autotransplantation into the forearm muscle so that one could document whether the autotransplanted hyperplastic parathyroid tissue was functioning by sampling the blood for PTH in a vein just proximal to the transplant site." Wells,46,47 Wagner/" and Brennan" and their colleagues subsequently documented the effectiveness of cryopreserving parathyroid tissue for patients who may or may not have any remaining parathyroid after parathyroidectomy. Unfortunately, cryopreserved parathyroid tissue functions adequately only in about 60% of patients, whereas primarily autotransplanted parathyroid tissue functions adequately in about 90% to 95% of patients. 51-55 We recommend subtotal rather than total parathyroidectomy with autotransplantation for virtually all patients with primary or secondary HPT and parathyroid hyperplasia." We base this recommendation on our own experience as well as on a review of the literature. We realize that other endocrine surgeons recommend total parathyroidectomy with primary autotransplantation, especially for patients with familial disease or secondary HPT because of the higher recurrence rate in these patients.56-58 We also recommend total parathyroidectomy and autotransplantation for patients with neonatal HPT, because the recurrence rate is very high,4l,59 and in noncompliant patients with secondary HPT. We cryopreserve parathyroid tissue in virtually all our patients treated with either subtotal or total parathyroidectomy and for all patients requiring reoperation.

Operative Technique

FIGURE 53-6. Radiograph of hands in patient with hyperparathyroidism; osteitis fibrosa cystica is also shown. Subperiosteal resorption is best seen on the radial aspect of the middle digit of the second and third phalanges.

A Kocher incision is used. All the parathyroid glands are identified. If all the glands are abnormal, the parathyroid gland closest in size to normal and the farthest from the recurrent nerve should undergo biopsy or subtotal resection first before the other hyperplastic glands are removed. The parathyroid remnant should be about 50 mg, which is the size of a normal parathyroid gland.

Parathyroid Hyperplasia: Parathyroidectomy - - 485

The selected parathyroid gland undergoes biopsy or subtotal resection initially to ensure that the remaining parathyroid remnant from which a biopsy has been taken has an adequate blood supply. When the remnant tissue is of questionable viability, it should be removed and another parathyroid gland should undergo biopsy or subtotal resection. In all patients with parathyroid hyperplasia, we recommend thymectomy because a fifth parathyroid gland is found in the thymus in 13.7% to 25% of patients.P'" When a biopsy specimen is taken from the parathyroid remnant, the site is marked with a silver clip or stitch. As previously mentioned, using this technique, we have had no patients with persistent hypoparathyroidism. Patients treated with subtotal parathyroidectomy have few complications, and permanent hypoparathyroidism and

recurrent HPT vary considerably (Tables 53-1 to 53-4). Some of the reported differences perhaps are due to "bone hunger" resulting from osteitis fibrosa cystica. These patients may experience profound postoperative hypocalcemia, but PTH levels are increased or normal. Most of these patients eventually become normocalcemic. As mentioned, we recommend cryopreserving parathyroid tissue in all patients undergoing subtotal or total parathyroidectomy with autotransplantation as insurance against possible permanent hypoparathyroidism. Some centers report a high incidence of permanent hypoparathyroidism (see Table 53_1),61.62 which we believe is unacceptable after initial operations for patients with primary or secondary HPT. The incidence of permanent hypoparathyroidism should be less than 1%. For the small number of patients in whom recurrent HPT

486 - - Parathyroid Gland

develops after subtotal parathyroidectomy (see Table 53-2), the remnant parathyroid tissue can usually be relatively easily and safely removed because its position was marked at the initial operation and its relationship to the recurrent laryngeal nerve was also clearly described in the operative note. Numerous studies 63-67 suggest that subtotal parathyroidectomy is the procedure of choice for most patients with parathyroid hyperplasia.

Total Parathyroidectomy and Autotransplantation During this operative procedure, all parathyroid glands are identified and removed. We also recommend removing the thymus via the cervical incision in these patients because the thymus is a frequent site for supernumerary parathyroid glands. All tissue is confirmed histologically by frozen section examination, and tissue from the more normal-appearing hyperplastic parathyroid gland is placed in iced physiologic saline for autotransplantation and cryopreservation. About 12 to 15 l-mm pieces of this parathyroid tissue are then autotransplanted into separate pockets in the forearm muscle.46,47 One-millimeter pieces of parathyroid tissue

ensure better tissue perfusion, and separate pockets are used in case a hematoma develops, which might compromise the viability of the autotransplant. Numerous studies have documented that PTH can be measured in the transplanted arm and that a gradient can be determined by measuring the PTH after 2 weeks in both arms. When the PTH level is twofold or greater on the side of the transplanted tissue, the autotransplanted tissue is working. To determine if the patient's systemic PTH value is normal, serum PTH and calcium levels should be measured in the opposite arm. An advantage of autotransplantation over subtotal parathyroidectomy is that the hyperplastic parathyroid graft can be excised, under local anesthesia, if it overfunctions. To remain viable, the autotransplanted parathyroid tissue must invade into muscle. Removal of all autotransplanted parathyroid tissue from the forearm can, thus, sometimes be difficult. Late failure of the transplanted tissue also sometimes occurs perhaps because of fibrosis. 52,68 Both early and late permanent hypoparathyroidism are more common after total parathyroidectomy with autotransplantation than after subtotal parathyroidectomy (see Table 53-1). We believe, as mentioned, that parathyroid tissue should be cryopreserved in patients having subtotal or total parathyroidectomy as well as in patients having reoperations as

Parathyroid Hyperplasia: Parathyroidectomy - - 487

insurance against permanent hypoparathyroidism. We advocate total rather than subtotal parathyroidectomy in the following circumstances: I. For patients with secondary HPT who are noncompliant and will not take their medication to suppress parathyroid stimulation 2. For agonal patients who will not tolerate general anesthesia 3. For technical reasons when it is difficult to preserve viable parathyroid tissue on a vascular pedicle 4. For patients with neonatal HPT27,41

Cryopreservation of Parathyroid Tissue Parathyroid tissue to be cryopreserved is confirmed to be parathyroid tissue by frozen section examination, and a portion is immediately placed on ice in physiologic saline. The tissue is subsequently placed into a Petri dish in RPMI1640 tissue culture medium. The cold parathyroid tissue is sectioned into 1- to 2-mm pieces with a scalpel blade. Using sterile technique, about five to eight pieces are placed into a cryovial, and several vials are usually prepared. We then add 0.5 mLof20% dimethyl sulfoxide in RPMI-I640 and 0.5 mL of RPMI-I640 containing 20% of serum from the patient per vial. The tissue is transferred first to the -80 0 C freezer to freeze slowly (temperature decreases about 10 C per minute); then it is transferred to be stored in liquid nitrogen. Complete patient information and location are documented in case the tissue is subsequently needed to treat hypoparathyroidism.

Long-Term Results of Different Techniques About 95% of patients with primary hyperplasia improve," and most patients with secondary HPT also experience dramatic clinical improvement (see Table 53-3). Lundgren and coworkers?' reported a 73% incidence of permanent hypocalcemia after total parathyroidectomy with autotransplantation. Rothmund and others52.56.70 reported no difference in the incidence of hypocalcemia after total or subtotal parathyroidectomy, but the number of patients was small and follow-up time was short.53 Mozes and coworkers in 1980 reported that 25% of their patients experienced late failure of the parathyroid graft.68 These data, we believe, support subtotal parathyroidectomy for most patients. None of our patients have experienced permanent hypoparathyroidism, although recurrent HPT has OCCUlTed. The relative incidences of complications after total and subtotal parathyroidectomy are documented in Tables 53-1 and 53-2.

Summary Parathyroidectomy should be performed by surgeons with experience in this field. Patients with secondary HPT and hyperplasia are somewhat more difficult to manage than those with primary HPT because recurrent and persistent disease is more common. We believe that most patients with

either primary or secondary hyperplasia are best managed with subtotal rather than total parathyroidectomy. Total parathyroidectomy with parathyroid autotransplantation, however, is useful in selected patients. Cryopreservation of parathyroid tissue should be done in all patients treated with either total or subtotal parathyroidectomy and in patients requiring reoperation to decrease the risk of possible permanent hypoparathyroidism.

REFERENCES I. Tezelman S, Shen W, Shaver JK, et al. Double parathyroid adenomas: Clinical and biochemical characteristics before and after parathyroidectomy. Ann Surg 1993;218:300. 2. Levin KE, Clark OH. The reasons for failure in parathyroid operations. Arch Surg 1989;124:911. 3. Kraimps J, Duh QY, Demeure M, Clark OH. Hyperparathyroidism in multiple endocrine neoplasia syndrome. Surgery 1992;112:1080. 4. Mansberger AR, Wei JP. Surgical embryology and anatomy of the thyroid and parathyroid glands. Surg Clin North Am 1993;73:727. 5. Gilmour JR. The gross anatomy of the parathyroid glands. J Pathol 1938;46:133. 6. Clark OH. Mediastinal parathyroid tumors. Arch Surg 1988;123:1096. 7. Edis AI, Purnell DC, van Heerden JA. The undescended "parathymus": An occasional cause of failed neck exploration for hyperparathyroidism. Ann Surg 1979;190:64. 8. Simeone DM, Sandelin K, Thompson NW. Undescended superior parathyroid gland: A potential cause of failed cervical exploration for hyperparathyroidism. Surgery 1995;118:949. 9. Smith M, Edward P. Anatomy of the parathyroid glands. In: Nyhus L, Baker R (eds), Mastery of Surgery, 2nd ed. Boston, Little, Brown, 1992, p 219. 10. Akerstrom G, Malmaens J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95:14. II. Wang C-A. Anatomy of parathyroid glands. In: Najarian JS, Delaney JP (eds), Advances in Breast and Endocrine Surgery. Chicago, Year Book, 1986, p 375. 12. de Papp AE, Kinder B, Livolsi V, et al. Parathyroid carcinoma arising from parathyroid hyperplasia: Autoinfarction following intravenous treatment with parnidronate. Am J Med 1994;97:399. 13. Yamaguchi K, Kishikawa H, Shichiri M. Familial hyperparathyroidism. Nippon Rinsho 1995;53:895. 14. Iwamoto N, Yamazaki S, Fukuda T, et al. Two cases of parathyroid carcinoma in patients on long-term hemodialysis. Nephron 1990;55:429. 15. Levin KE, Galante M, Clark OH. Parathyroid carcinoma versus parathyroid adenoma in patients with profound hypercalcemia. Surgery 1987;101:649. 16. Clark OH, Stark DA, Duh QY, et al. Value of high-resolution real-time ultrasonography in secondary hyperparathyroidism. Am J Surg 1985;150:9. 17. Tisell L-E, Hedman I, Hansson G. Clinical characteristics and surgical results in hyperparathyroidism caused by water-clear cell hyperplasia. World J Surg 1981;5:565. 18. Rothmund M, Wagner PK. Total parathyroidectomy and autotransplantation of parathyroid tissue for renal hyperparathyroidism. Ann Surg 1983;197:7. 19. O'Riordain DS, O'Brien T, Grant CS, et al. Surgical management of primary hyperparathyroidism in multiple endocrine neoplasia type I and 2. Surgery 1993;114:1033. 20. Nakamura Y, Larsson C, Julier C, et al. Localization of the genetic defect in multiple endocrine neoplasia type I within a small region of chromosome II. Am J Hum Genet 1989;44:751. 21. Chi DD, Toshima K, Donis-Keller H, Wells SA Jr. Predictive testing for multiple endocrine neoplasia type 2A (MEN 2A) based on the detection of mutations in the RET protooncogene. Surgery 1994;116:124. 22. Hedman I, Fjalling M, Lindberg S, et al. An assessment of the risk of developing hyperparathyroidism and thyroid disorders subsequent to neck irradiation in middle-aged women. J Surg OncoI1985;29:78. 23. De Jong SA, Demeter JG, Jarosz H, et al. Thyroid carcinoma and hyperparathyroidism after radiation therapy for adolescent acne vulgaris. Surgery 1991;110:691.

488 - - Parathyroid Gland 24. Venkataraman PS, Han BK, Tsang RC, Daugherty CC. Secondary hyperparathyroidism and bone disease in infants receiving long-term furosemide therapy. Am J Dis Child 1983;137:1157. 25. Pollak MR, Brown EM, Chou YH, et al. Mutations in the human Ca 2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism [see comments]. Cell 1993;75: 1297. 26. Pollak MR, Brown EM, Estep HL, et al. Autosomal dominant hypocalcemia caused by a Ca 2+-sensing receptor gene mutation. Nature Genet 1994;8:303. 27. Blair JW, Carachi R. Neonatal primary hyperparathyroidism: A case report and review of the literature. Eur J Pediatr Surg 1991;1:110. 28. Bondeson AG, Bondeson L, Busch C, et al. ABO blood group antigens in parathyroid adenoma and hyperplasia. Surgery 1989;105:734. 29. Arnold A, Staunton CE, Kim HG, et al. Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. N Engl J Med 1988;318:658. 30. Noguchi S, Motomura K, Inaji H, et al. Clonal analysis of parathyroid adenomas by means of the polymerase chain reaction. Cancer Lett 1994;78:93. 31. Thakker RV, Bouloux P, Wooding C, et al. Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. N Engl J Med 1989;321:218. 32. Friedman E, Sakaguchi K, Bale AE, et al. Clonality of parathyroid tumors in familial multiple endocrine neoplasia type I. N Engl J Med 1989;321:213; Erratum. N Engl J Med 1989;321:1057. 33. Tezelman S, Siperstein AE, Duh QY, Clark OH. Tumoral calcinosis: Controversies in the etiology and alternatives in the treatment. Arch Surg 1993;128:737. 34. Duh QY, Lim RC, Clark OH. Calciphylaxis in secondary hyperparathyroidism: Diagnosis and parathyroidectomy. Arch Surg 1991;126:1213. 35. Rodriquez JM, Tezelman S, Siperstein AB, et al. Localization procedures in patients with persistent or recurrent. hyperparathyroidism. Arch Surg 1994;129:870. 36. Clark OH, Duh QY. Primary hyperparathyroidism: A surgical perspective. Endocrinol Metab Clin North Am 1989; 18:701. 37. Ransom K, Hardin CA, Lukent B. Surgical treattnent of primary hyperparathyroidism. Am J Surg 1977;134:763. 38. Felts JH, Whitley JE, Anderson DD, et al. Medical and surgical treatment of azotemic osteodystrophy. Ann Intern Med 1965;62:1272. 39. Kaplan EL, Yashiro T, Salti G. Primary hyperparathyroidism in the 1990s. Ann Surg 1992;215:300. 40. Cope O. Primary chief cell hyperplasia of the parathyroid gland. Ann Surg 1958;148:375. 41. Stanbury SW. Elective subtotal parathyroidectomy for renal hyperparathyroidism. Lancet 1960;1:793. 42. Ogg CS. Total parathyroidectomy in treatment of secondary (renal) hyperparathyroidism. BMJ 1967;4:331. 43. Kaye M, D'Amour P, Henderson J. Elective total parathyroidectomy without autotransplantation in end-stage renal disease. Kidney Int 1989;35: 1390. 44. Llach E Parathyroidectomy in chronic renal failure: Indications, surgical approach, and use of calcitriol. Kidney Int Suppl 1990;29:S62. 45. Farrington K, Varghese Z, Chan MK, et al. How complete is a total parathyroidectomy in uraemia? BMJ 1987;294:743. 46. Wells SA Jr, Ellis OJ, Gunnells JC, et al. Parathyroid autotransplantation in primary parathyroid hyperplasia. N Engl J Med 1976;295:57. 47. Wells SA, Frandon JR, Dale JK, et al. Long-term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy heterotopic autotransplantation. Ann Surg 1980; 192:451. 48. Casanove D, Sarafati E, De Francisco A, et al. Secondary hyperparathyroidism: Diagnosis of site ofrecurrence. World J Surg 1991;15:546. 49. Wagner PK, Seesko HG, Rothmund M. Replantation of cryopreserved human parathyroid tissue. World J Surg 1991;15:751. 50. Brennan MF, Brown EM, Spiegel AM, et al. Autotransplantation of cryopreserved parathyroid tissue in man. Ann Surg 1979;189:139. 51. Ogg CS: Parathyroidectomy in treatment of secondary renal hyperparathyroidism. Kidney Int 1973;4:168. 52. Rothmund M, Wagner PK. Assessment of parathyroid graft function after autotransplantation of cryopreserved tissue. World J Surg 1984;8:527. 53. Rothmund M, Wagner PK, Schar KC. Subtotal parathyroidectomy versus total parathyroidectomy and autotransplantation in secondary hyperparathyroidism: A randomized trial. World J Surg 1991;15:745.

54. Niederle B, Roka R, Brennan ME The transplantation of parathyroid tissue in man: Development, indication, technique, and results. Endocr Rev 1982;3:245. 55. Niederle B, Stamm L, Langle F, et al. Primary hyperparathyroidism in Austria: Results of an 8-year prospective study. World J Surg 1992; 16:777. 56. Clark OH, Way LW, Hunt TK. Recurrent hyperparathyroidism. Ann Surg 1976;184:391. 57. Demeure MJ, McGee DC, Wilkes W, et al. Results of surgical treatment for hyperparathyroidism associated with renal disease. Am J Surg 1990;160:337. 58. De Francisco AM, Ellis HA, Owen JP, et al. Parathyroidectomy in chronic renal failure. Q J Med 1985;55:289. 59. Fujimoto Y, Hazama H, Oku K. Severe primary hyperparathyroidism in a neonate having a parent with hypercalcemia. Surgery 1990; 108:933. 60. Meakins JL, Milne CA, Hollomby OJ, Goltzman D. Total parathyroidectomy: Parathyroid hormone levels and supernumerary glands in hemodialysis patients. Clin Invest Med 1984;7:21. 61. Lundgren G, Asaba M, Magnusson G, et al. The role of parathyroidectomy in the treatment of secondary hyperparathyroidism before and after renal transplantation. Scand J Urol Nephrol Suppl 1977;42: 149. 62. Prinz RA, Gamrros 01, Sellu D, Lynn JA. Subtotal parathyroidectomy for chief cell hyperplasia of the multiple endocrine neoplasia type I syndrome. Ann Surg 1981;193:26. 63. Castleman B, Schantz A, Roth S. Parathyroid hyperplasia in primary hyperparathyroidism. Cancer 1976;38:1668. 64. Rudberg C, Akerstrom G, Palmer M, et al. Late results of operation for primary hyperparathyroidism in 441 patients. Surgery 1986;99:643. 65. Scholz DA, Purnell DC, Edis AJ, et al. Primary hyperparathyroidism with multiple parathyroid gland enlargement. Mayo Clin Proc 1978; 53:792. 66. Uden P, Chan A, Duh QY, et al. Primary hyperparathyroidism in young and older symptoms and outcome of surgery. World J Surg 1992; 16:719. 67. Zodon MJ, Lliopoulos JL, Thomas JH, et al. Subtotal parathyroidectomy for secondary hyperparathyroidism. Surgery 1984;96:1103. 68. Mozes MF, Soper WO, Jonasson 0, Lang GR. Total parathyroidectomy and autotransplantation in secondary hyperparathyroidism. Arch Surg 1980;115:378. 69. Niederle B, Roka R, Woloszczuk W, et al. Successful parathyroidectomy in primary hyperparathyroidism: A clinical follow-up. Surgery 1987;102:903. 70. Alveryd A, El-Zawahry MD, Herlitz P, et al. Primary hyperplasia of the parathyroid. Acta Chir Scand 1975;141 :24. 71. Cordell LJ, Maxwell JG, Warden GD. Parathyroidectomy in chronic renal failure. Am J Surg 1979; 138:951. 72. Dubost CT, Drueke T, Jeaneau PL, et al. Hyperparathyroidie secondaire: Parathyroidectomie subtotale ou totale avec autotransplantation parathyroidienne. Nouv Presse Med 1980;9:2709. 73. Malmaeus J, Grimelius L, Johansson H, et al. Parathyroid surgery in chronic renal insufficiency. Acta Chir Scand 1982;148:229. 74. Albertson DA, Poole GV, Myers RT. Subtotal parathyroidectomy versus total parathyroidectomy with autotransplantation for secondary hyperparathyroidism. Am Surg 1985;51:16. 75. Delmonico FL, Wang CA, Rubin NT, et al. Parathyroid surgery in patient with renal failure. Ann Surg 1984;200:644. 76. Sitges-Serra A, Caralps-Riera A. Hyperparathyroidism associated with renal disease. Surg Clin North Am 1987;67:539. 77. Welk RA, Alix DR. A community hospital experience with total parathyroidectomy and autotransplantation for renal hyperparathyroidism. Am Surg 1987;53:622. 78. Hellman PG, Akerstrom G, Ljunghall S, Rastad 1. Surgical findings and results of subtotal and total parathyroidectomy in hypercalcemic patients with uremic hyperparathyroidism. Acta Chir Scand 1989; 155:573. 79. Takagi H, Tominaga Y, Uchida K, et al. Total parathyroidectomy with forearm autograft for secondary hyperparathyroidism in chronic renal failure. Ann Surg 1988;208:639. 80. Sicard GA, Anderson CB, Hruska KA, et al. Parathormone levels after subtotal and total (autotransplantation) parathyroidectomy for secondary hyperparathyroidism. J Surg Res 1980;29:541. 81. Fujimoto Y, Obara T, Ito Y, et al. Surgical treatment of secondary hyperparathyroidism in patients with chronic renal failure. Endocrinol Jpn 1985;32:863.

Familial Hyperparathyroidism in Multiple Endocrine Neoplasia Syndromes Mauricio Sierra, MD • Helene Gibelin, MD • Jean-Louis Kraimps, MD

Multiple Endocrine Neoplasia 1 When talking of multiple endocrine neoplasia type I (MEN 1), a proper definition is difficult to establish because the syndrome can result from up to 20 different combinations of endocrine and nonendocrine tumors.P No definition could cover all registered cases or families. Thus, a patient with MEN 1, or Wenner's syndrome, is one who presents with alterations of hypersecretion or hyperplasia, or both, from two of the three main MEN I-related endocrine tumors-that is, parathyroid adenomas, enteropancreatic endocrine tumors, and pituitary tumors. These alterations mayor may not occur simultaneously. Familial MEN 1 is defined as a case of MEN 1 plus at least one first-degree relative with one of the three aforementioned tumors. The MEN 1 gene location was first described in 1997.3-6 It is located at chromosome llq13 and consists of 10 exons with an 1830-bp coding region that encodes a novel 610-amino acid nuclear protein named menin.? Genetic linkage and germline mutation studies have established that familial MEN 1 always arises from the same locus at chromosome llq13 and always from the same gene.3,4,8- IO MEN 1 mutations are diverse and have been predicted to change the amino acid chain in menin. These mutations render menin absent or truncated, the so-called first hit. This condition is inherited as an autosomal dominant trait and predisposes the individual to neoplasias of certain tissues. A combination of the first hit with a somatic or postnatal loss of the other copy of MEN 1 in one cell (the second hit) initiates neoplastic clonal expansion. The final result is inactivation of the tumor suppressor MEN 1 gene and tumor growth, hyperplasia, or hypersecretion of the referred glands. I 1-14 The fact that an inherited alteration is the origin of the MEN syndromes explains the aggressive nature of hyperparathyroidism (HPT) in these patients, A different approach in the diagnosis and special considerations before, during, and after surgery are warranted.

Clinical Aspects Although the occurrence of MEN syndromes in the population is rare (l in 5000 to 50,000 births)," primary hyperparathyroidism (PHPT) is by far the most common endocrinopathy in MEN 1, reaching almost 100% penetrance by age 50 years. 15-17 Patients present with HPT as the primary form of expression of MEN 1. However, symptoms arise at age 20 to 25,30 years earlier than their sporadic counterparts. Patients usually complain of weakness, fatigue, constipation, or bone pain. Hypercalcemia per se increases secretion of gastrin from gastrinomas, and it is not unusual for patients to present with signs and symptoms of HPT associated with those of acid hypersecretion from Zollinger-Ellison syndrome." Less frequently, patients can present with urolithiasis, psychiatric alterations, renal insufficiency, or cardiovascular disease. Mild symptoms of HPT may be masked by those of other endocrine disorders such as gastrinoma, insulinoma, or acromegaly. 16

Diagnosis In evaluating patients with PHPT, MEN syndromes should always be considered. An adequate account of the signs and symptoms and family history of endocrine disease should be noted. Upon interview, symptoms of parathyroid disease may be present in 90% to 100% of patients, of endocrine pancreas 80%, pituitary 65%, adrenal cortex 36%, and thyroid 24%. Manifestations of the MEN syndromes may develop at different times, and not all patients present initially with the complete syndrome.P:'? Thus, PHPT is diagnosed pretty much in a straightforward manner as in other cases of HPT. Serum calcium elevation with marked hypersecretion of parathyroid hormone (PTH) is the rule. Mild hypercalciuria and an elevated chloride-to-phosphate ratio can also occur. Four-gland disease is generally present in these patients. This is the reason why preoperative imaging studies play

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490 - - Parathyroid Gland little part in the diagnostic algorithm for patients with PHPT and MEN 1.Although ultrasonography, 99mTc sestamibi scanning, and magnetic resonance imaging have proven sensitivity, they provide limited information and are not really cost -effecti ve. The usefulness of the "quick" PTH assay has been demonstrated in surgery for sporadic cases of PHPT. The sensitivity and specificity of the study are high and, although expensive, the study has been proved cost-effective. Most studies have been done in patients with adenomas; however, one report has addressed the use of the assay in patients with MEN 1 undergoing total parathyroidectomy. PTH levels decreased in a stepwise fashion but had good predictive value related to the extent of surgical treatment and postoperative normocalcemia." High-frequency ultrasonography and nuclear mapping can help identify ectopic or supernumerary tissue in patients with hyperplasia. To our knowledge, these studies remain to be used in patients with MEN 1.21

Treatment PHTP in MEN 1 patients poses a clear challenge because of the nature of the disease and high rate of recurrence. This should be explained to the patient and the family before the intervention. Notes of the procedure must describe the technique in detail, and remaining tissue must be marked in case reoperation should become necessary. Treatment should be directed not to a tumor but to all the abnormal or potentially abnormal glands. Therefore, efforts should be directed to identify all four glands. Supernumerary glands are not uncommon, occurring in approximately 15% of the population. One should look for ectopic tissue, especially in the thymus and perithymic fat. As with other forms of HPT, there is no method that best describes how to differentiate an adenoma from hyperplasia. Hyperplasic glands can vary in size, and this asymmetry may cause the surgeon to mistake an enlarged gland for an adenoma. As a consensus, two enlarged glands are considered as hyperplasia." Failure to identify all parathyroid tissue results in persistent or recurrent hypercalcemia. Parathyroidectomy was usually recommended before treating gastrinoma because of the effects of hypercalcemia on acid secretion.P However, proton pump inhibitors have demonstrated efficacy equal to that of parathyroidectomy, and this has ceased to be considered an indication for surgery." Because complete exploration and identification of the four glands are required during surgery, minimally invasive surgery has no role in the treatment of these patients. Complete neck exploration is not feasible using this technique. Controversy exists about the extension of parathyroidectomy. An aggressive treatment has been proposed as an option because of the high rate of recurrence or persistent hypercalcemia in these patients.P The fact that cure rates after re-exploration in patients with persistent or recurrent hypercalcemia were lower than those of patients undergoing primary operation is another argument in favor of total resection. Morbidity associated with a second cervical exploration with scarred tissue in case of postoperative hypercalcemia is avoided by removing grafted tissue from the forearm.

After total parathyroidectomy and autotransplantation, 5.6% of patients develop permanent hypoparathyroidism and 30% develop hypercalcemia postoperatively." We consider this rate of hypoparathyroidism too high. Autotransplantation does not prevent postoperative hypoparathyroidism, and the most frequent cause of recurrence or persistence of HPT is not overgrowth of hyperplasic grafts but failure to identify and resect one or more supernumerary glands in the neck or mediastinum. Because of this, we advocate subtotal parathyroidectomy with bilateral thymectomy and cryopreservation. In case hypoparathyroidism develops, transplantation can be accomplished in the forearm with local anesthesia as an outpatient procedure.P'" Occasionally, a single parathyroid tumor may be encountered during surgery.16.30,31 If this is the case, all glands must be identified and marked and biopsy specimens sent for frozen section evaluation. We recommend removal of the affected and the normal-appearing ipsilateral gland. Inspection of ectopic or supernumerary glands along with thymectomy without damaging the circulation of the normal contralateral glands is recommended. With this procedure, recurrent hypercalcemia and postoperative hypoparathyroidism are avoided in most cases. It is estimated that 20% to 100% of patients with PHPT and MEN I have recurrences 8 to 12 years after operation. 28,32-35 Patients operated at an early age are the group with the highest risk of recurrence. This is why the term "cure" is not appropriate in these patients. The first step is to reconfirm the diagnosis. If recurrence is indeed the case, imaging studies are in order. A combination of ultrasonography, 99mTc sestarnibi scanning, and/or magnetic resonance imaging is indicated. A diagnostic accuracy of up to 87% is achieved with this combination.v-v-'? Selective venous sampling can be added if the former studies are negative or nonconfirmatory. The latter study improves accuracy by 95%.35,38 This algorithm helps the surgeon to plan the procedure and reduces the complication rate associated with a reintervention. Previous operative notes and pathology reports should be reviewed. Resecting the tissue identified by localization studies is the primary objective. For lesions located in the anterior mediastinum, a cervical approach may be indicated. Thoracoscopy may help avoid a sternotomy in selected cases. Autotransplantation should be performed in the same operation if subtotal parathyroidectomy was the initial procedure, and cryopreservation of fresh tissue is recommended. In the past, medical treatment had no part in the treatment of patients with PHPT and MEN 1.39 Calcimimetics, which decrease PTH release directly acting on the calcium-sensing receptor, may also decrease parathyroid growth. Trials are under way to evaluate their role as primary treatment or alternative therapy for recurrent cases of PHPT.

Follow-up and Screening Long-term follow-up in these patients is warranted to detect recurrences early as well as the development of other endocrine tumors. Annual measurements of calcium and PTH levels should be scheduled, with determinations of the appropriate hormones or markers to detect other pathologies. II Most laboratories use direct DNA sequencing strategies for screening kindreds of patients with MEN syndromes.

Familial Hyperparathyroidism in Multiple Endocrine Neoplasia Syndromes - -

Indications and methods have been described and are beyond the scope of this chapter." The process is complicated because family members are tested for a disease for which they are asymptomatic. Psychological syndromes that arise from being identified as carriers or noncarriers during the screening process have also been described.v-v A multispecialty approach is recommended. Whether a positive screening test for MEN I could eventually indicate a prophylactic procedure remains to be discussed."

Multiple Endocrine Neoplasia 2 MEN 2 syndrome is an autosomal dominant inherited disease, affecting approximately 500 to 1000 kindreds.P Medullary thyroid cancer (MTC), pheochromocytomas, and parathyroid hyperplasia are the typical association for patients with MEN 2A. MEN 2B patients present with tumors from the adrenal medulla, intestinal and mucosal ganglioneuromatosis, and a characteristic marfanoid habitus. Other less frequent variants include familial medullary thyroid carcinoma (FMTC), MEN 2A with cutaneous lichen amyloidosis, and MEN 2A or FMTC with Hirschsprung's disease. All variants of MEN 2 show high penetrance for MTC. More than 90% of all MEN 2 carriers show evidence of MTC as a solitary thyroid nodule or as an abnormal elevation of serum thyrocalcitonin in their life span.P The gene responsible for MEN 2 has been mapped to chromosome 10.23,44,45 The RET gene is located near the centromere and encodes a plasma membrane-bound tyrosine kinase enzyme termed ret. Through an inherited mutation that changes an amino acid, RET is activated, causing oncogenic or transforming changes. Primary HPT occurs in 20% to 30% of MEN 2A patients. 23,29,46,47 The relationship between specific mutations and syndromic features has been established. The highest frequency of pheochromocytoma and HPT occurs in those who are found to have a mutation on codon 634, more specifically, C634R.48 The prevalence of HPT is high, however, irrespective of the mutation detected (i.e., C634Y, C634S, C634F, C634G, C634W). It has been suggested that HPT is an earlier component of the syndrome. Patients are 30 years or older at diagnosis. They occasionally have classic symptoms of HPT, hypercalciuria, or even renal calculi. However, asymptomatic hypercalcemia is usually found during the work-up for a patient with a solitary thyroid nodule or MTC. One or more enlarged glands can be found incidentally during thyroid surgery. The evolution of HPT is milder than that of its MEN I counterparts, and it is rare for patients to develop HPT after the thyroid gland has been removed. A theory of a parathyroid growth-stimulating factor from C cells has been proposed but not proved.

Diagnosis The diagnostic algorithm for patients with HPT and MEN 2 is the same as that for patients with other forms of HPT. Hypercalcemia and PTH elevation confirm the diagnosis, along with an elevated chloride-to-phosphate ratio and mild hypercalciuria.

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Ruling out excessive catecholamine production is mandatory in these patients because of the morbidity and mortality associated with operating on patients with coexistent pheochromocytoma. If the diagnosis is made, pheochromocytoma is dealt with and HPT operated on later. The treatment of patients with MEN 2A deals primary with the MTC. A total thyroidectomy with central node dissection is performed. Total parathyroidectomy with forearm autotransplantation is recommended by some authors for this reason." Disease is milder in these patients, however,and we consider a total resection too aggressive. To date, the rate of postoperative hypoparathyroidism remains high. This may also be the case with the association of parathyroidectomy and thyroidectomy with lymph node excision. If hyperplasia is encountered during surgery, we recommend identification of the four parathyroid glands and resection of only macroscopically enlarged tissue. 16,46,47 A search for ectopic parathyroid tissue and a cervical thymectomy should be added to the procedure. Cryopreservation is done routinely if there is concern about the development of postoperative hypoparathyroidism. This technique is associated with a low rate of persistent or recurrent HPT.

Follow-up and Screening Because of the other two components of the MEN 2A syndrome, life-long follow-up is mandatory. Serum thyrocalcitonin and calcium levels are measured periodically. Screening for the syndrome in kindreds of patients with MEN 2A involves demonstration of the RET mutation in chromosome 10.49. 5 1 A provocative screening test for thyrocalcitonin has lost its role in the detection of kindreds with MEN 2. Pentagastrin is not always available, and the study is uncomfortable for individuals. Prophylactic surgery is indicated for patients with a positive RET mutation test, even at a young age. Genetic testing in this instance has demonstrated an impact on the clinical course of these patients.

Summary PHPT occurs in MEN I and less frequently in patients with MEN 2A. The gene responsible for MEN I is located in chromosome 11q13. An inherited mutation "inactivates" menin, a nuclear protein, predisposing these patients to tumor growth and hypersecretion. The gene responsible for MEN 2A has been mapped to chromosome 10. The RET protooncogene is activated, causing oncogenic growth or transformation. HPT occurs more frequently in patients with a codon C634R mutation. Hyperplasia of the four glands is the rule. Patients may present with symptoms of hypercalcemia, although a thorough clinical history and laboratory work-up are advised to rule out other endocrinopathies. HPT in MEN I is more aggressive, and there is a high rate of persistent or recurrent HPT. Patients with MEN 2 may develop hypoparathyroidism associated with thyroidectomy for MTC. We recommend subtotal parathyroidectomy with thymectomy and cryopreservation for patients with MEN I. A more conservative approach can be used for patients with MEN 2A because the disease is not as aggressive and PHPT is not always present at the time of diagnosis.

492 - - Parathyroid Gland

REFERENCES 1. Carty SE, Helm AK, Amico lA, et al. The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type I. Surgery 1998;124:1106. 2. Marx Sl. Multiple endocrine neoplasia type I. In: Scriver CR Beaudet AL, Sly WS, VaIleD (eds), The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York, McGraw-Hill, 2001, p 943. 3. Chandrasekharappa SC, Guru SC, Manickam P, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997;276:404. 4. Lemmens I, Van de Ven W1M, Kas K, et al. Identification of the multiple endocrine neoplasia type 1 gene. The European Consortium on MEN 1. Hum Mol Genet 1997;6:1177. 5. Larsson C, Skogseid B, Oberg K, et al. Multiple endocrine neoplasia type I gene maps to chromosome II and is lost in insulinoma. Nature 1988;332:85. 6. Lemmens I, Wim 1M, de Ven V, et al. Identification of the multiple endocrine neoplasia type 1 (MEN 1) gene. Hum Mol Genet 1997;6:1177. 7. Guru SC, Goldsmith PK, Burns AL, et al. Menin, the product of the MEN 1 gene, is a nuclear protein. Proc Nat!Acad Sci USA 1998;95:1630. 8. Agarwal SK, Guru SC, Heppner C, et al. Menin interacts with the API transcription factor lunD and represses lunD-activated transcription. Cell 1999;96:143. 9. Agarwal SK, Kester MB, Debe1enko LV, et al. Germline mutations of the MEN 1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 1997;6:1169. 10. Mayr B, Braband G, von Zur Miihlen A. Menin mutations in MEN 1 patients. 1 Clin Endocrino1 Metab 1998;83:3004. 11. Bassett lHD, Forbes SA, Panett AAJ, et al. Characterization of mutations in patients with multiple endocrine neoplasia type I. Am 1 Hum Genet 1998;62:232. 12. Brown EM, Pollak M, Hebert SC. The extracellular calcium-sensing receptor: Its role in health and disease. Annu Rev Med 1998;49:15. 13. Heppner C, Kester MB, Agarwal SK, et al. Somatic mutation of the MEN I gene in parathyroid tumors. Nat Genet 1997;16:375. 14. Mutch MG, Dilley WG, Sanjurjo F, et al. Germ1ine mutations in the multiple endocrine neoplasia type 1 gene: Evidence for frequent splicing defects. Hum Mutat 1999;13:175. 15. Cougard P,Calender A, Proye C, et al. GENEM 1: L'hyperparathyroide, signal privilegie du depistage des neoplasies endocriniennes multiples type I (NEM1). Rev Fr Endocrinol Clin 1995;36:360. 16. Kraimps Jl., Duh QY, Demeure M, Clark OH. Hyperparathyroidism in multiple endocrine neoplasia syndrome. Surgery 1992;112:1080. 17. Teh BT, McArdle 1, Parmeswaran V, et al. Sporadic primary hyperparathyroidism in the setting of multiple endocrine neoplasia type 1. Arch Surg 1996;131:1230. 18. lensen RT. Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type I. 1 Intern Med 1998;243:477. 19. Boey lA, Cooke TJC, Gilbert 1M, et al. Occurrence of other endocrine tumors in primary hyperparathyroidism. Lancet 1975;2:781. 20. Tonelli F, Spini S, Tommasi M, et al. Intraoperative PTH measurement in patients with MEN 1 syndrome and hyperparathyroidism. World 1 Surg 2000;24:556. 21. Norman 1, Chheda H. Minimally invasive parathyroidism facilitated by intraoperative nuclear mapping. Surgery 1997;122:998. 22. Thompson NW. The surgical management of hyperparathyroidism and endocrine disease of the pancreas in the multiple endocrine neoplasia type 1 patient. 1 Intern Med 1995;269. 23. Ponder BAJ. Multiple endocrine neoplasia type 2. In: Scriver CR Beaudet AL, Sly WS, Valle D (eds), The Metabolic and Molecular Bases of Inherited Disease, 8th ed. NewYork,McGraw-Hill, 2001, p 931. 24. Wells SA, Famdon lR, Dale lK, et al. Long-term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surg 1980;192:451. 25. Dotzenrath C, Cupitsi K, Goretski PE, et al. Long term biochemical results after operative treatment of primary hyperparathyroidism associated with multiple endocrine neoplasia types 1 and 2a: Is a more or less extended operation essential? Eur 1 Surg 2001;167:173. 26. Feldman AL, Sharaf RN, Skarulis MC, et al. Results of heterotopic parathyroid autotransplantation: A 13-year experience. Surgery 1999;126:1042. 27. Goretski PE, Dotzwnrath C, Roeher HD. Management of primary hyperparathyroidism caused by multiple gland disease. World 1 Surg 1991;15:693.

28. Goudet P, Cougard P,Verges B, et al. Hyperparathyroidism in multiple endocrine neoplasia type 1: Surgical trends and results of a 256-patient series from Groupe d 'Etude des Neoplasies Endocriniennes Multiples Study Group. World 1 Surg 2001;25:886. 29. O'Riordain DS, O'Brien T, Grant CS, et al. Surgical management of primary hyperparathyroidism in multiple endocrine neoplasia types I and 2. Surgery 1993;114:1031. 30. Allo M, Thomson NW. Familial hyperparathyroidism caused by solitary adenomas. Surgery 1982;92:486. 31. van Heerden lA, Kent RB, Sizemore GW, et al. Primary hyperparathyroidism in patients with multiple endocrine neoplasia syndromes. Arch Surg 1983;118:533. 32. Burgess lR, David R, Venkateswaran P, et al. The outcome of subtotal parathyroidectomy for the treatment of hyperparathyroidism in multiple endocrine neoplasia type 1. Arch Surg 1998;133:126. 33. Clark OH, Okerlund MD, Moss AA, et al. Localization studies in patients with persistent or recurrent hyperparathyroidism. Surgery 1985;98:1083. 34. Hellman P, Skogseid B, Oberg K, et al. Primary and reoperative parathyroid operations in hyperparathyroidism in multiple endocrine neoplasia 1. Surgery 1998;124:993. 35. Kiv1en MH, Bartlett DL, Libutti SK, et al. Reoperation for hyperparathyroidism in multiple endocrine neoplasia type I. Surgery 2001; 130:991. 36. De Feo ML, Colagrande S, Biagini C, et al. Parathyroid glands: combination of (99m)Tc MillI scintigraphy and US for demonstration of parathyroid glands and nodules. Radiology 2000;214:393. 37. Shen W, Duren M, Morita E, et al. Reoperation for persistent or recurrent primary hyperparathyroidism. Arch Surg 1996;131:861. 38. laskowiak N, Norton lA, Alexander HR, et al. A prospective trial evaluating a standard approach to reoperation for missed parathyroid adenoma. Ann Surg 1996;224:308. 39. Silverberg Sl, Bone HG, Marriott TB, et al. Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism. N Engl 1 Med 1997;337:1506. 40. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. 1 Clin Endocrinol Metab 2001;86:5658. 41. Goretzki PE, HoppnerW, Dotzenrath C, et al. Genetic and biochemical screening for endocrine disease. World 1 Surg 1998;22:1202. 42. Kinder BK. Genetic and biochemical screening for endocrine disease. II. Ethical issues. World 1 Surg 1998;22: 1208. 43. Kopp I, Bartsch D, Wild A, et al. Predictive genetic screening and clinical findings in multiple endocrine neoplasia type 1 families. World 1 Surg 2001;25:6610. 44. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. lAMA 1996;276:1575. 45. Ponder BA1, Ponder MA, Coffey R, et al. Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet 1988;1:397. 46. Kraimps Jl., Denizot A, Camaille B, et al. Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: Retrospective French multicentric study. Groupe d'Etudes des Tumeurs a Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons. World 1 Surg 1996;20:808. 47. Raue F, Kraimps Jl., Dralle H, et al. Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. 1 Intern Med 1995;238:369. 48. Schuffeneker I, Virally-Monod M, Brohet R, Ie Groupe D'Etude des Tumeurs a Calcitonine. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. 1 Clin Endocrinol Metab 1998;83:487. 49. Easton DF, Ponder MA, Cummings T, et al. The clinical and screening age-at-onset distribution for the MEN-2 syndrome. Am 1 Hum Genet 1989;44:208. 50. Lips C1M. Clinical management of the multiple endocrine neoplasia syndromes: Results of a computerized opinion poll at the Sixth International Workshop on Multiple Endocrine Neoplasia and vonHippe1-Lindau disease. 1 Intern Med 1998;243:589. 51. Wells SA Jr, Chi DD, Toshima K, et al. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 1994;220:237.

Familial Hyperparathyroidism Shih-Ming Huang, MD

Although most cases of primary hyperparathyroidism (HPT) occur sporadically, familial clusters have been reported. Most of these familial cases occur in association with multiple endocrine neoplasia (MEN). Goldman and Smyth in 1936 were the first to report a patient with familial HPT who had no other manifestations of MEN.l Many more familial cases have subsequently been reported.l" Similarly to the classification of medullary thyroid cancer, HPT can be classified into four types: (1) sporadic HPT, (2) familial HPT with MEN 1 and 2, (3) non-MEN familial HPT (NMFH) or familial isolated HPT(FIH), and (4) non-MEN familial HPT associated with jaw tumor syndrome. Because NMFH is uncommon, these patients are frequently included in the series of patients with familial HPT with MEN, or they are confused with patients with benign familial hypocalciuric hypercalcemia (BFHH).7,34 From our experience at the University of California, San Francisco (UCSF) (Table 55-1) and from a review of the literature.t" we confirm that NMFH is a distinct entity.-? This chapter emphasizes the clinical characteristics and management of NMFH, In the literature, NMFH has been associated with an increased risk of parathyroid cancer, especially when associated with the jaw tumor syndrome.21,33,35-43 Familial HPT occurring in infants (familial neonatal HPT) is different from NMFH in adults. Neonatal HPT occurs in children of parents with BFHH, and most patients have high serum calcium levels.44-56 Patients with neonatal primary HPT have a specific chromosomal defect on chromosome 3 and always present before 10 years of age. Patients with NMFH almost always develop hypercalcemia after 10 years of age. Patients with NMFH are diagnosed by means of family history.A thorough personal family history must be taken concerning the clinical manifestations of MEN 1 and 2, Laboratory tests should include prolactin,gastrin, chromogranin, and pancreatic peptide to rule out MEN-associated parathyroid disease. Progressive genetic mapping has proved useful in excluding the possibility of MEN 1, MEN 2, or BFHH'

Non-MEN Familial Hyperparathyroidism Clinical Features The clinical information concerning the 16 patients with NMFH from 14 families treated at UCSF is summarized in Table 55-1. The most striking clinical feature of NMFH is the high incidence of profound hypercalcemia, which rarely occurs in patients with sporadic HPT or HPT associated with MEN 1 or 2. In the UCSF series, the patients with NMFH had hypercalcemia ranging from 10.5 to 20.3 mg/dL (mean, 13.9 mgldL); 44% of these patients had profound hypercalcemia (serum calcium> 15 mg/dL), and 31% presented in hypercalcemic crisis, requiring emergency hospitalization. As seen in Table 55-2, 45% of 51 patients in the literature presented with a serum calcium of 15 mg/dL or greater and 67% with a serum calcium of 13.5 mg/dL or greater. Thus, unlike the non-MEN familial medullary thyroid cancer that is less aggressive than sporadic medullary thyroid cancer or MEN 2B, NMFH appears to be more aggressive than other forms of the disease. One third to one half of the patients with NMFH experience nephrolithiasis. One fifth of the patients have severe osteoporosis, and osteitis fibrosa cystica with brown tumors is more common. Other nonspecific symptoms or signs that occur more frequently in the patients with primary HPT, including hypertension, fatigue, weakness, pancreatitis, or peptic ulcer, may also be common in patients with NMFH, but currently there is insufficient information to know with certainty. Four patients in the UCSF series were asymptomatic initially, but two of these initially asymptomatic patients experienced hypercalcemic crises when the disease persisted after the initial parathyroidectomy at another medical center. The mean age of the patients with NMFH at initial diagnosis was 43.5 years (range, 12 to 86 years) in the UCSF 493

494 - - Parathyroid Gland

series, which is older than that of patients in other reports (mean, 32.3 years; range, 12 to 68 years) but is similar in that of patients with MEN 157-68 and younger than that of patients with sporadic primary HPT.69 Both genders are affected, Some patients experience NMFH as children but rarely, if ever, before 10 years of age. The mechanism of inheritance of NMFH is unknown. In contrast to the autosomal dominant inheritance characteristic of MEN, Law and colleagues reported on an autosomal recessive inheritance of NMFH in three siblings.'? The inheritance of NMFH may therefore vary and be more complex. Restriction fragment length polymorphism linkage analysis showed the presence of HPT to be linked to a locus on chromosome llq13 (near or identical to the MEN 1 gene) in members of a family with NMFH, and genetic mapping found few families with NMFH that have incomplete expression or a subset of MEN 1.70-76 No distinctive genetic abnormalities, except NMFH with tumors of jawbones, have been found to date with NMFH.33,77

Associated Diseases Coexistent thyroid disease occurred in 62% of patients with NMFH in the UCSF patients, and 19% of the patients had coexistent papillary thyroid cancer. Because thyroid abnormalities are common in patients with other types of primary HPT,78-82 this apparent increase in frequency of benign and malignant thyroid neoplasms may not be statistically significant. Fibroosseous tumors of the mandible or maxilla (i.e. tumors of the lower and upper jawbones) or so-called NMFH-JT or FlH-JT, rather than brown tumors caused by osteitis fibrosa cystica, have been associated with patients with NMFH in 28 families in the literature, and genetic studies have revealed that this disorder is autosomal dominant and linked to chromosome lq25_q31.19,2J.23-33.38,77,83 In addition, 16 of these 28 families have family members with parathyroid cancer, Other associations such as colon cancer, diabetes mellitus, breast cancer, neurilemoma, and sarcoidosis are also occasionally described.

Familial Hyperparathyroidism - -

Initial Impression

Initial Operation

Final Pathology

~

Cure 4

~

~

9--remove one adenoma

~

4--remove two adenomas

495

Recurrent 3

-E

4

34 Y r ~

1

10 yr ~

1

8yr~1

Persistent 2

~

c u re 2

~2

Persistent 2 ~

2

1

~1 8§] 3 --subtotal--Cure 3 ------8§] 3 parathyroidectomy

Persistent or Recurrent Hyperparathyroidism Multiple abnormal parathyroid glands (two or more) were present in 75% of patients treated at UeSF and in 45% of patientsreported in the literature with NMFH (see Table 55-2). Persistent or recurrent (normocalcemia for at least 6 months after parathyroidectomy) HPT occurred in 44% of patients treated at UeSF and in 20% of patients reported in the literature (see Table 55-2).A shorter duration of follow-up probably accounts for the lower incidence of recurrence reported in the literature. As with MEN 1,84 supernumeraryglands were found in 19% of patients treated at UeSF with NMFH, which is similar to the rate reported in patients with MEN and contributed to the high incidence of persistent or recurrent disease. Because three of our patients experienced recurrent HPT after 8, 10, and 34 years of normocalcemia, respectively (Fig. 55-1), postoperative normocalcemia does not preclude subsequent recurrence of the disease. Long-term follow-up of these patients, as well as screening of family members, is essential.

Surgical Treatment The more aggressive biologic behavior of the parathyroid disease in patients with NMFH, as well as the high incidence of multiple abnormal glands and supernumerary glands and high recurrence rate, warrants a somewhat more aggressive surgical approach. Failure in these patients, as in others with primary HPT, was usually due to failure to identify and remove parathyroid glands in their usual location as well as failure to identify and remove supernumerary parathyroid glands. Because parathyroid rests or supernumerary glands are often present in the thymus or perithymic tissue, we advocate bilateral cervical thymectomy with removal of all perithymic fat.

FIGURE 55-1. UCSF patients' data on persistent or recurrent hyperparathyroidism and pathology. ITQ]N = one abnorm~and, no. of cases; ~N = two abnormal~nds, no. of cases; l1QjN = three abnorm~lands, no. of cases;~N =four abnormal glands, no. of cases; ~ N = five abnormal glands, no. of cases.

If all glands appear to be abnormally enlarged, we recommend subtotal parathyroidectomy, leaving about 50 mg of the most normal parathyroid glands with bilateral thymectomy. Although total parathyroidectomy with autotransplantation has been recommended for patients with hyperplasia and familial disease, we believe this results in an increased frequency of hypoparathyroidism and thus prefer subtotal resection. For patients with recurrent or persistent disease, we recommend total parathyroidectomy with autotransplantation to the forearm and cryopreservation. Although cryopreserved parathyroid tissue functions adequately in only about 60% of patients, it is still useful in these patients for preventing permanent hypoparathyroidism. Postoperatively, it is often difficult to know whether a patient has bone hunger or permanent hypoparathyroidism. The intact parathyroid hormone (PTH) assay helps to differentiate between these two conditions. When a solitary adenoma is found and the three other parathyroid glands appear normal, we recommend removal of the adenoma, ipsilateral thymectomy, and removal of the normal-appearing gland on the same side to confirm that it is not hyperplastic. If there is recurrence, this side of the neck usually does not have to be reexplored. When double adenomas are found, a similar surgical approach to patients with a solitary adenoma can be applied: the pathologic glands should be removed, and one of the normal-appearing parathyroid glands is excised or undergoes biopsy, preferably leaving parathyroid tissue on only one side of the neck.

Key Points for Differential Diagnosis Defined NMFH is diagnosed by excluding other cases of familial hypercalcemia with HPT. The three following

496 - - Parathyroid Gland disorders should be considered. First, BFHH is known as an autosomal dominant, symptomless, nonprogressive, lifelong hypercalcemic disorder with 100% penetration. Individuals with BFHH show abnormal parathyroid and renal responsiveness to changes in extracellular calcium levels.t' Linkage studies have demonstrated that the disease locus in most BFHH patients is located on chromosome 3q13.3q2l68,-69, and the defect has proven to be the calciumsensing receptor (CASR) gene. 86-91 Rare kindreds are linked to a defect on chromosome 19p13.3 or 19q13.86,92 Patients with BFHH are heterozygous for this mutation, whereas patients with neonatal HPT tend to be homozygous for the mutation,93,94 Patients with BFHH are hypercalcemic before age 10 years. The serum calcium level is usually moderate (the values were 10.9 ± 0.1 mg/dL in a study of 21 BFHH families?') and never greater than 14 mg/dL.85-88,95-102 The symptoms and signs are usually vague or mild, Although the incidence of gallstone, diabetes mellitus, relapsing pancreatitis, and myocardial infarction is slightly increased, the incidence of nephrolithiasis is normal. Occasionally, fatigue, mental problems, headaches, arthralgia, and polydipsia may be noted. 97,101 These patients do not appear to benefit from parathyroidectomy.P'v'P However, patients with neonatal HPT need to be treated by total parathyroidectomy with parathyroid autotransplantation and cryopreservation.w''" In 20% of BFHH patients, the serum PTH is usually normal'" or mildly elevated.f-"? The normal or mildly elevated PTH values in the presence of hypercalcemia imply or represent a set-point error of parathyroid function and parathyroid cells insensitive to serum calcium because of functional loss of the CASR. 89,98 The parathyroid glands are normal grossly and histologically demonstrate mild hyperplastic changes.l'" Hypocalciuria is another important feature because the capacity of renal tubular reabsorption of calcium increases in patients with BFHH. Because magnesium is handled similarly to calcium by the kidney in these patients, about half of the patients with BFHH have an elevated serum magnesium concentration.f The urinary calcium level of less than 0.01 for the urinary calcium-to-creatinine clearance ratio (Cca/Ccr) is the most reliable diagnostic criterion for BFHH to distinguish it from primary HPT.85 Genetic mapping is another powerful diagnostic tool for differentiating BFHH from primary HPT. Medical or surgical therapy is unnecessary and uniformly ineffective. 101. 102 Hypercalcemia usually persists after partial parathyroidectomy and permanent hypocalcemia after total parathyroidectomy. Second, MEN 1 is a genetic autosomal dominant disorder characterized by multiple neoplasms of the parathyroid, neuroendocrine tumors of the pancreas, and neoplasms of the anterior pituitary gland. Multiple lipomas and carcinoid tumors are also more common in patients with MEN 1, The predisposing genetic defect has been assigned to chromosome region llqll-q13 by linkage analysis. 57.58 Germline mutations have been identified in about 90% of MEN 1 families. The mutations included nonsense, missense, splice, frameshift, and in-frame deletions. 104 - 106 The clinical features of MEN 1 depend on the number and combinations of endocrine glands that are hyperfunctioning.

Although Majewski and coworkers suggested an "all or none" phenomenon in which the affected members invariably have pathologic changes if tissue from these three glands are examined.t" there is considerable variation of the endocrine glands of patients with MEN 1. Not only do the features of MEN 1 vary among members within the same family, but also some families with MEN 1 may have different degrees of penetration. In addition, the age at which the clinical manifestations of MEN 1 develop can differ considerably from one family member to another, which is also true for NMFH. Most often, the first sign of MEN 1 is HPT. HPT usually antedates other manifestations of MEN L60 Virtually all individuals who inherit the trait experience hypercalcemia by the age of 40 years. 61,62 Periodic testing should begin at about 12 years of age and be repeated yearly; a normocalcemic person older than 50 years is unlikely to have inherited the MEN 1 gene. The incidence of clinically detectable islet cell lesions increases as patients grow older. Because some islet cell tumors fail to elaborate functioning hormone, the absence of any clinical syndrome does not rule out the presence of a pancreatic islet cell tumor, A secretin provocative test for gastrin helps to make the diagnosis in patients with a "silent" gastrinoma, Pituitary tumors are common in MEN 1 patients. About one third of patients with MEN 1 experience pituitary tumors and clinical symptoms. Autopsy studies demonstrate that pituitary microadenomas occur even more often. 63 Although DNA genetic techniques are being developed to diagnose patients with MEN 1 and familial HPT,57 a detailed family history concerning the presence of ulcer disease, renal stones, or recognized parathyroid, pancreatic, or pituitary tumor is essential. Patients with MEN 1 also often have multiple lipomas and angiomas. The following three points are crucial for excluding the possibility of MEN 1 from patients with familial HPT: 1. Autopsy data of family members with isolated familial HPT showing that no pancreatic or pituitary tumors are present. 2. Repeated laboratory tests for gastrin, prolactin, insulin, glucagon, pancreatic peptide, corticotropin, and growth hormone for family members yielding normal results. 3. Genetic mapping of chromosome 11 to detect MEN 1 gene mutations or the possibility of incomplete phenotype expression of MEN 1. The hypercalcemia in most patients with MEN 1 is usually mild (serum calcium level less than 11 mg/dL), and most of these patients are relatively asymptomatic, The mean serum calcium level is usually less than 12 mg/dL and rarely greater than 14 mg/dL,60,64.65,67 although one patient has been reported with a calcium level of 16 mg/dL. 64 Patients with MEN 1 and HPT usually have multiple abnormal parathyroid glands with a high incidence of supernumerary glands." Subtotal parathyroidectomy or total parathyroidectomy with autotransplantation is recommended by most authorities in this field. Among our patients with primary HPT and MEN, we have identified two populations of patients: one population has solitary or double adenomas and recurrence is uncommon, whereas the other group has diffuse hyperplasia and persistent or recurrent disease

Familial Hyperparathyroidism - -

is common.v' We recommend a similar operative strategy for treating patients with HPT and MEN 1 and for patients with NMFH.64 Both groups are susceptible to recurrent HPT. Third, MEN 2 is known to be an autosomal dominant cancer syndrome characterized by medullary thyroid cancer, pheochromocytoma (usually bilateral), and HPT. The genes responsible for MEN 2 have been mapped to genetic intervals within lOql1.2 107,108 and a mutation in either exon 10 or 11. A point mutation of the ret protooncogene has been found in more than 95% of the patients with MEN 2A.109,11O MEN 2B is also an autosomal dominant disease, attributable to a site-specific point mutation on codon 918 of the ret protooncogene.l'" characterized by medullary thyroid cancer, pheochromocytoma, and the presence of mucosal neuromas, ganglioneuromatosis, or marfanoid habitus, producing a distinct clinical phenotype. HPT is a very rare component of MEN 2B. Medullary thyroid cancer or C-ce1l hyperplasia is the dominant feature and usually is first seen in all the affected members, III but the penetrance of pheochromocytoma or HPT is variable. The prevalence of HPT varies from 0% to 70% (median about 20%), and the prevalence of pheochromocytoma ranges from 5% to 95%.112-114 HPT is the least common feature of MEN 2 and tends to develop later than medullary thyroid cancer or C-ce1l hyperplasia, usually after the third decade of life. lIS A normal serum calcitonin level excludes the possibility of MEN 2 in patients without previous total thyroidectomy. The reason for the different penetrance of HPT in MEN 2 is unknown. The increased calcitonin levels in patients with medullary thyroid cancer do not account for the HPT because patients with sporadic medullary thyroid cancer or those with MEN 2B do not have parathyroid tumors. Of interest, primary HPT rarely develops in individuals who undergo total thyroidectomy at a young age.!" Removed parathyroid glands from patients with MEN 2A usually demonstrate chief cell hyperplasia.U':'!? Even in patients with normocalcemic MEN 2A, enlarged parathyroid glands or normal-appearing parathyroid glands are often microscopically hyperplastic when removed at total thyroidectomy.U? The parathyroid glands are often asymmetrically involved. I 18 We recommend a conservative selective approach to the parathyroid glands in these patients because postoperative hypocalcemia is more common than persistent or recurrent hypercalcemia. Only about 30% of patients with HPT and MEN 2A have symptoms, and most of these patients have only slightly elevated serum calcium levels.!" The most common clinical manifestations reveal colic and nephrolithiasis. Hypercalcemic crisis or significant bone disease rarely occurs. 67,l17 At the Mayo Clinic, for patients with MEN 2A and HPT, the serum calcium level ranged from 10.2 to 13.5 mg/dL (mean, 10.7 mg/dL). As mentioned, because an unacceptable consequence of subtotal parathyroidectomy or total parathyroidectomy with autotransplantation in patients with MEN 2 and HPT is hypoparathyroidism, we and others''? recommend excision of only grossly enlarged parathyroid glands, and at least one or two normal-sized glands should be left intact and marked with a metal clip or suture to facilitate their identification if reoperation becomes necessary. This recommendation is

497

based on the findings that selective parathyroid excision has cured most patients with MEN 2 and HPT and recurrent HPT is rare in these patients.

Non-MEN Familial Hyperparathyroidism and Parathyroid Cancer Both parathyroid cancer and NMFH are rare parathyroid disorders. The association of these rare conditions suggests a common cause. Until 2002, 29 patients with NMFH and parathyroid cancer in 22 families were reported. 16,21,23,27-33,35,43 Sixteen of these families have NMFH-JT or FIR-JT, and about one fourth of reported NMFH families have one or two affected members suffering from parathyroid cancer. Endocrinologists and surgeons should be aware of this association for proper management of these patients.

Clinical Features Reviews of 15 cases of NMFH and cancer were reported before 1993. The mean age of the patients with NMFH and parathyroid cancer at initial diagnosis was 30 years (range, 14 to 43 years), which is considerably younger than that of other patients with parathyroid cancer (50 years) (Table 55_3).41 Seven males and eight females were affected. The clinical manifestations among these patients were similar to those of other patients with parathyroid cancer. The mean serum calcium level was 16.1 mg/dL, and one third presented in hypercalcemic crisis. Sixty-one percent of these patients had severe osteitis fibrosa cystica and 30% had nephrolithiasis. Twenty-three percent presented with a palpable neck mass.

Pathogenesis In some patients with NMFH and parathyroid cancer, one or more of the other parathyroid glands were also abnorma1.21,35,43 This occurrence raises the possibility of the transformation of benign parathyroid neoplasms to parathyroid cancer similar to the transformation of C-ce1l hyperplasia to medullary thyroid carcinoma. In most studies, however, there is no evidence of transformation proceeding from hyperplastic glands to parathyroid cancer because 60% of these patients have only parathyroid cancer. 36.37,39-42

498 - - Parathyroid Gland NMFH-JT or FIH-JT is known to be linked to chromosome Iq25-q31 abnormalities. NMFH and parathyroid cancer arising without tumors of the upper and lower jawbones have never, to our knowledge, been identified with a specific genetic mutation.P although three somatic chromosome abnormalities (reciprocal translocation between chromosomes 3 and 4, trisomy 7, and a pericentric inversion in chromosome 9) were also noted in cultured parathyroid cells from one patient with NMFH and parathyroid cancer." At operation, when one encounters a parathyroid tumor that is hard, grayish white, lobulated, or invasive, parathyroid cancer must be suspected. An en bloc excision of the parathyroid neoplasm and ipsilateral thyroid lobe or other adherent tissues is recommended (especially for patients with profound hypercalcemia). For such patients with recurrent or metastatic disease, an aggressive surgical approach, even when palliative, is recommended to palliate symptoms of HP'f'I1 and to decrease the metabolic problems. Persistent or recurrent hypercalcemia occurred in about 40% of the patients with NMFH and parathyroid cancer, a rate similar to that reported for patients with sporadic parathyroid carcinoma.

Familial Neonatal Hyperparathyroidism Neonatal HPT is a rare disorder. It is usually associated with severe hypercalcemia, requiring urgent treatment. More than 50 cases of neonatal HPT have been reported in the literature. 44-56,89,119-126 They may be sporadic or familial. Hillman and colleagues first drew attention to the familial occurrence of neonatal HPT.119 About half of the patients with neonatal HPT have a documented familial inheritance.44-56,120,121 Two types of inheritance-autosomal dominant and autosomal recessive-have been reported in neonatal HPT. The documentation of seven cases from three families suggests an autosomal recessive transmission.'!"!" Other cases of neonatal HPT are associated with BFHH. Patients with BFHH appear to have a benign course with normal survival. In contrast, children with neonatal HPT often have a poor clinical course. Pollak and associates'? demonstrated that a single defective allele causes BFHH, whereas two defective alleles cause severe neonatal HPT, and the genetic defect maps to the CASR gene on chromosome 3q13.3-21. Genetic studies also showed that a de novo CASR gene mutation resulted in sporadic neonatal HPT,127,128 and infants with a homozygous CASR gene mutation or infants with a heterozygous mutation,89,93,94 delivered by a normal mother, develop neonatal HPT.89,127 At birth, newborns are usually normal in terms of size and weight. Both genders are affected. The clinical manifestations usually become evident during the first week of life but may not be recognized until 3 or 4 months of age or later. Severe hypotonia is almost always present in children with profound hypercalcemia. Failure to thrive is common and is usually combined with digestive disorders, including constipation, anorexia, difficult feeding, vomiting, and ileus. Some infants present with dehydration, and renal stones have been reported in three infants. Advanced demineralization is present in most children, and limb and thoracic cage deformities or pathologic fractures have been reported.

At neck exploration, the parathyroid glands are diffusely enlarged and chief cell hyperplasia is evident histologically.123 Medical management, including vigorous hydration, should be instituted in all patients and may be successful in milder cases,46,51,52 although urgent parathyroidectomy is recommended for most patients with severe urgent conditions. Because of the high recurrence rate after subtotal parathyroidectomy, total parathyroidectomy with immediate autotransplantation or with late autotransplantation of cryopreserved parathyroid tissue is recommended. After total parathyroidectomy and parathyroid autotransplantation, some infants have modest hypercalcemia, a normal serum PTH level, hypermagnesemia, and relative hypocalciuria, similar to patients with BFHH. 49 All newborns from families with BFHH must have a serum calcium determination.

Summary NMFH is a distinct clinical entity. The definite diagnosis can be made either by complete clinical work-up or by genetic study to exclude the possibility of MEN 1, MEN 2, or BFHH. These patients are younger and more susceptible to the development of profound hypercalcemia or hypercalcemic crisis than are patients with sporadic HPT or those with HPT and MEN. Patients with NMFH also appear to have a higher incidence of parathyroid cancer and perhaps thyroid neoplasms. Patients with NMFH-JT have unique genetic mutations that are often associated with an extraordinarily high incidence of parathyroid cancer. Patients with NMFH, like those with MEN 1, frequently have multiple abnormal parathyroid glands, either synchronously or metachronously, and, therefore, are at risk for persistent or recurrent disease. NMFH is a unique disease that warrants appropriate recognition, screening of family members, aggressive treatment, and long-term follow-up. Patients with neonatal HPT differ from those with NMFH, although both often present with profound hypercalcemia. Neonatal HPT is associated with BFHH. Determination of the serum calcium level at birth is most important in patients with BFHH to detect this condition early and treat it appropriately.

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500 - - Parathyroid Gland 65. Brandi ML, Marx SJ, Aurbach GD, et al. Familial multiple endocrine neoplasia type I: A new look at pathophysiology. Endocr Rev 1987;8:391. 66. Lamers C, Froeling P. Clinical significance of hyperparathyroidism in familial multiple endocrine adenomatosis type I (MEA I). Am J Med 1979;66:422. 67. O'Riordain DS, O'Brien T, Grant CS, et al. Surgical management of primary hyperparathyroidism in multiple endocrine neoplasia types 1 and 2. Surgery 1993;114:1031. 68. Malmaeus J, Benson L, Johansson H, et al. Parathyroid surgery in the multiple endocrine neoplasia type I syndrome: Choice of surgical procedure. World J Surg 1986;10:668. 69. Niederle B, Roka R, Woloszczuk W, et al. Successful parathyroidectomy in primary hyperthyroidism: A clinical follow-up study of 212 consecutive patients. Surgery 1987;102:903. 70. Kassem M, Zang X, Brask S, et al. Familial isolated primary hyperparathyroidism. J Bone Miner Res 1992;7(Suppl):S249. 71. Karges W, Jostamdt K, Maier S, et al. Multiple endocrine neoplasia type I (MEN 1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region. J Endocrinol2oo0;166:1. 72. Bergman L, Teh B, Cardinal J, et al. Identification of MEN 1 gene mutations in families with MEN 1 and related disorders. Br J Cancer 2000;83: 1009. 73. Kassem M, Kurse TA, Wong F, et al. Familial isolated hyperparathyroidism as a variant of multiple endocrine neoplasia type 1 in a large Danish pedigree. J Clin Endocrinol Metab 2000;85:165. 74. Honda M, Tsukada T, Tanaka H, et al. A novel mutation of the MENI gene in a Japanese kindred with familial isolated primary hyperparathyroidism. Eur J Endocrinol2oo0;142:138. 75. Miedlich S, Lohmann T, Schneyer U, et al. Familial isolated primary hyperparathyroidism-A multiple endocrine neoplasia type 1 variant? Eur J Endocrinol2oo1;145:155. 76. Takami H, Shirahama S, Ikeda Y, et al. Familial hyperparathyroidism. Biomed Pharmacother 20oo;54(Suppll):S21. 77. Jackson CE, Norum RA, Boyd SB, et al. Hereditary hyperparathyroidism and multiple ossifying jaw fibroma: A clinically and genetically distinct syndrome. Surgery 1990;108:1006. 78. Strichartz SD, Giuliano AB. The operative management of coexisting thyroid and parathyroid disease. Arch Surg 1990;125:1327. 79. Van der Schaar H, Mulder H. Lesions of the thyroid gland in patients with primary hyperparathyroidism. Surg Gynecol Obstet 1985; 160:407. 80. Prinz RA, Barbato AL, Braithwaite SS, et al. Simultaneous primary hyperparathyroidism and nodular thyroid disease. Surgery 1982;92:454. 81. Lever EG, Refetoff S, Straus FH, et al. Coexisting thyroid and parathyroid disease: Are they related? Surgery 1983;94:893. 82. Stark DD, Clark OH, Gooding GAW, et al. High-resolution ultrasonography and computed tomography of thyroid lesions in patients with hyperparathyroidism. Surgery 1983;94:863. 83. Kennett S, Pollick H. Jaw lesions in familial hyperparathyroidism. Oral Surg 1971;31:502. 84. Thompson NW. Surgical considerations in the MEN 1 syndrome. In: Thompson NW, Vinik AI (eds), Endocrine Surgery Update. New York, Grune & Stratton, 1983, p 144. 85. Kristiansen JH. Familial hypocalciuric hypercalcaemia. Dan Med Bull 1992;39:321. 86. Heath H III, Jackson CE, Otterud B, et al. Genetic linkage analysis in familial benign (hypocalciuric) hypercalcemia: Evidence for locus heterogeneity. Am J Hum Genet 1993;53: 193. 87. Heath H III. Familial benign hypercalcemia-From clinical description to molecular genetics. World J Med 1994;160:554. 88. Pollak MR, Beown EM, Chou YH, et al. Mutations in the human Ca 2+sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993;75:1297. 89. Hendy GN, D'Souza-Li L, Yang B, et al. Mutations of the calciumsensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 2000;16:281. 90. D'Souza-Li L, Cole DEC, Hanley DA, et al. Four novel calciumsensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia. Bone 1998;23S:W350. 91. Heath H III, Odelberg S, Jackson CE, et al. Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains. J Clin Endocrinol Metab 1996;81:1312.

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Metabolic Complications of Secondary Hyperparathyroidism Juan J. Sancho, MD • Antonio Sitges-Serra, MD

The term secondary hyperparathyroidism (SHPT) means that external factors stimulate the parathyroid glands to increase the production of parathyroid hormone (PTH) and eventually to develop hyperplastic or adenomatous overgrowth, or both. The most common condition causing the parathyroid glands to grow is chronic renal failure (CRF). The often used term renal hyperparathyroidism reflects this fact. SHPT may develop, however, in a variety of conditions such as idiopathic hypercalciuria,' hypennagnesuria, osteomalacia, rickets, malnutrition, or osteoporosis' with low serum levels of 1,25-dihydroxyvitamin D3 (1,25-[OHhD 3, calcitriol).' Hyperparathyroidism in psychiatric patients receiving longterm treatment with lithium is also associated with parathyroid hyperplasia.' In this chapter, the pathogenesis of SHPT related to CRF, its metabolic complications, and its relationship with the clinical manifestations of CRF are reviewed.

Pathogenesis of Secondary Hyperparathyroidism Stimulated by the description of enlarged parathyroid glands in uremic patients by Albright and colleagues,' the Viennese pathologists Pappenheimer and Wilens6 were the first to attribute parathyroid hyperplasia to CRE Since then, researchers have attempted to link decreased kidney functions with the biochemical, morphologic, and clinical manifestations of SHPT. The task has proved to be difficult because both the excretory and endocrine functions of the kidney are impaired in CRE In addition, the treatment of CRF and its complications contribute to the pathogenesis of SHPT, complicating the complete explanation of the pathophysiology of SHPT. The past 30 years have witnessed a dramatic improvement in our understanding of the factors involved in the pathogenesis of renal SHPT. The first landmarks were the

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development of the radioimmunoassay" for PTH fragments and later an immunoradiometric assay for intact PTH(l-84). Understanding some factors in the pathogenesis of SHPT, such as hypocalcemia, hyperphosphatemia, decreased 1,25(OHhD 3 levels, altered PTH metabolism, skeletal resistance to PTH, and the changed set-point in PTH production, provided the initial body of knowledge to help rationally treat these patients. The other advances took place at the biomolecular and genetic levels. They include the discovery of receptors for calcium and calcitriol in the parathyroid cells, their regulation, and the implications of polymorphism; the identification of the PTH gene; and the demonstration of monoclonality in some parathyroid hyperplasia nodules. Increased PTH levels cause, besides the classic skeletal disorders, many clinical manifestations of SHPT. A PTHmediated elevation of cytosolic ionized free calcium (Ca 2+;) is responsible for much of the generalized organ dysfunction in CRF.7 It also has to be taken into account that the assay used for the dosage of "intact PTH" has also been found to detect "7-84" fragments, with a potentially inhibitory effect on the action of the whole hormone, Intact PTH assays also react with non-(l-84)PTH, large carboxyltenninal (C) fragments with a partially preserved aminotenninal (N) structure. They account for up to 50% of intact PTH in renal failure and may be implicated in PTH resistance." The following are the main pathogenic factors linking CRF and SHPT.

Before Kidney Transplantation HYPOCALCEMIA

Hypocalcemia is not a primary event in CRF but a consequence of hyperphosphatemia, bone resistance to PTH, and low circulating calcitriol, each playing a dominant role in different stages of SHPT. The fact that serum calcium is normal in more that 50% of patients with CRp9 is explained

Metabolic Complications of Secondary Hyperparathyroidism - -

by the gradually increasing PTH secretion to maintain serum calcium levels. PTH raises the serum calcium level through its effects on bone and kidney; calcitriol produces similar effects by working in concert with PTH on bone and by enhancing calcium absorption in the gastrointestinal tract. High serum concentrations of calcium inhibit the synthesis of preproPTH messenger RNA (mRNA) and secretion of PTHlO by the parathyroid cells. PTH stimulates the synthesis of calcitriol by enhancing renal Iu-hydroxylase activity, whereas calcitriol inhibits the synthesis and secretion of PTH by impairing PTH gene expression. I I Parathyroid gland becomes hyperplastic in response to prolonged hypocalcemia. 12 Hypocalcemia is a potent stimulator of PTH mRNA synthesis. This stimulation, however, is independent of the cytosolic calcium concentration of the parathyroid cell. Although little is known about the regulation of parathyroid cell proliferation, constant stimulation of PTH mRNA synthesis is associated with the development of parathyroid hyperplasia.P:'" DIMINISHED SYNTHESIS OF CALCITRIOL

The kidney produces calcitriol," the most active metabolite of vitamin D. The synthesis of calcitriol from 25-(OH)D3by the renal enzyme Iu-hydroxylase is stimulated by PTH, by hypocalcemia per se, and by hypophosphatemia. Calcitriol exerts its actions on mineral metabolism through the bone, the gut, the parathyroid glands, and the kidney. On the bone, calcitriol works in concert with PTH to mobilize calcium by enhancing osteoclastic activity and recruiting stem cells to differentiate into osteoclasts. It also has an indirect action in ossification, probably by recruiting cells into osteoblasts, which in tum are responsible for bone mineralization." Calcitriol promotes the intestinal absorption of calcium by enhancing the expression of the calciumbinding protein (calbindin)." On the parathyroid glands, calcitriol inhibits PTH synthesis and secretion by increasing the sensitivity of the parathyroid cell to calcium.'? inhibiting PTH gene expression.V'P and inhibiting parathyroid cell proliferation." Calcitriol also appears to upregulate its own receptor in the parathyroid gland." In addition, the hypercalcemic effect of calcitriol indirectly inhibits PTH synthesis and secretion. On the kidney, calcitriol promotes phosphorus excretion." There is considerable evidence that patients with advanced renal failure, despite elevated serum PTH levels, have reduced or even undetectable levels of calcitriol.Pv" although in mild uremia calcitriol levels are only slightly reduced or even normal. 25.26 The reduction of renal mass and the hyperphosphatemia are the main reasons for calcitriol deficiency. A relative resistance of lre-hydroxylase to the effect of PTH has also been advocated." Extrarenal production of calcitriol from macrophages, keratinocytes, and aortic endothelial cells might compensate for the decrease in renal production." but this occurs only after high doses of 25-(OH)D 3. Although the metabolic clearance rate of calcitriol is also decreased in CRF, it does not compensate for the low calcitriol production.r" The decreasing ability of the failing kidney to hydroxylate 25-hydroxyvitamin D causes an absolute or relative

503

deficiency of calcitriol that plays a key role in the genesis of SHPT. 23.24 Low calcitriol levels impair the mobilization of calcium from the bone and the absorption of calcium by the intestine. Its suppressive effect on PTH secretion is lifted." and the renal reabsorption of phosphate is enhanced. In addition, low levels of calcitriol may lower the response of the parathyroid glands to serum ionized calcium.P Calcitriol receptors are diminished in the parathyroid glands of CRF patients, rendering the glands less responsive to the inhibitory action of 1,25-(OH)zD3, and therefore contribute to the development of SHPT.3' PHOSPHATE RETENTION

First proposed by Neil Bricker32.33 as the clue for the "tradeoff' hypothesis, the role of phosphate retention as a major factor in the pathogenesis of hypocalcemia and SHPT was emphasized by Slatopolsky and coworkers.Y''? An imbalance between dietary intake of phosphate and the decreased renal excretory capacity leading to phosphate retention and directly to SHPT is not likely to be the initial pathogenic event-" because hyperphosphatemia is not demonstrable in early CRF during fasting or after an oral phosphate load." The origin of hyperphosphatemia in the CRF patient is doubled. The dietary intake of phosphate, greatly increased in the patient taking phosphate, adds to the effect of reduced excretion of phosphate by an insufficient kidney subject to the stimulus of increasing levels of PTH. The original observation that reducing the phosphate intake in proportion to the decrease of glomerular filtration prevented the progression of SHPT led to the theory that hyperphosphatemia caused SHPT by directly lowering ionized calcium. Upon revision, it has been shown that in patients with a moderate degree of CRF, phosphate restriction suppresses PTH secretion by increasing serum calcitriol through a direct effect on the kidney." However, studies in patients and dogs with advanced renal insufficiency have demonstrated that phosphate per se, independent of the levels of calcitriol or ionized calcium, can stimulate the secretion of PTH.20 Phosphorus induces hyperplasia of the parathyroid glands independent of calcium and calcitriol and by a post-transcriptional mechanism increases PTH synthesis and secretion.P On the other hand, intracellular phosphate retention, which may develop as renal insufficiency ensues, may interfere with the action and production of calcitriol," adding the effect of phosphate retention to that of diminished calcitriol production. RESISTANCE OF BONE TO PARATHYROID HORMONE EFFECT

PTH exerts one of its main actions by inducing bone remodeling and liberating calcium to the extracellular compartment. The osteoblast has PTH receptors and binding of PTH activates osteoclasts, probably in concert with calcitriol. In the presence of an increased concentration of PTH, infusion of PTH did not cause as much increase in serum calcium. 4o-42 The mechanisms responsible for this blunted calcemic response include (1) low levels of calcitriol,43.44 which prevent activation of osteoclasts; (2) phosphate retention," either through a direct effect or by diminishing calcitriol production; and (3) downregulation of PTH bone receptors by high levels ofPTH.45 The latter is increasingly recognized

504 - - Parathyroid Gland to play a major role in the decreased response to PTH in renal failure." The progressive bone resistance to the calcemic effect of PTH sets up an endless loop of increased need for PTH to maintain serum calcium levels, causing parathyroid hyperplasia and resulting in a progressively demineralized bone matrix.

transplant recipients may continue to have persistent HPT and hypercalcemia. 12 The following are some of the factors that may prevent the involution of the hyperplastic parathyroid gland even after the primary stimulus (i.e., kidney failure) has been removed.

PARATHYROID HORMONE SET-POINT CHANGES

Renal function rarely returns completely to normal" and it is possible that the mild degree of renal insufficiency slows or prevents the involution of parathyroid glands. In some series, an inverse correlation between serum PTH levels and creatinine clearance suggests that impaired renal function is responsible for post-transplantation SHPT.55.56

The PTH set-point is defined as the serum calcium concentration that decreases the maximal PTH level by 50%.46 In early CRF, there is a shift in the PTH set-point rendering the parathyroid relatively insensitive to the suppressive effects of calcium.P''? In advanced CRF and in patients having maintenance hemodialysis, changes in the set-point appear to be dependent on the particular form of their bone disease and calcitriol status.'? Changes in the set-point may be a function of changes in the parathyroid cell calcium receptor" mediated by low levels of calcitriol.20 Specifically, it has been suggested that a calcium-sensing receptor gene polymorphism (codon G990R) influences the responsiveness of the parathyroid gland to changes of extracellular ionic calcium in uremic patients. The glands of patients with the GG genotype of the calcium-sensing receptor gene may be more sensitive to extracellular ionic calcium changes." The vitamin D parathyroid receptors are also diminished. The parathyroid cell becomes more resistant to the suppressive effects of calcium and of calcitriol, and therefore excessive PTH is secreted at a given serum calcium concentration.

IMPAIRED GRAFT FUNCTION

PARATHYROID AUTONOMY

Initially, some authors have postulated autonomous parathyroid activity, when PTH production could no longer be regulated by serum calcium (or the set-point was altered so that hypercalcemia was considered "normal" by the parathyroid glands). NONSUPPRESSIBLE PARATHYROID HORMONE SECRETION

Kidney transplantation is the best treatment for SHPT.48 The hyperfunction of the parathyroid glands, however, may continue or even become apparent after kidney transplantation.

The recognition that the PTH secretion could not be totally suppressed by calcium infusion in these patients led to the concept of nonsuppressible PTH secretion. In this theory, the parathyroid cells are not autonomous but instead diminish their PTH production to a minimum after transplantation. The increased PTH level is then the result of an increased number of parathyroid cells, each secreting a minimum amount of PTH that cannot be suppressed even when the serum calcium level is elevated." This nonsuppres sible PTH secretion then also increases calcitriol production by the transplanted kidney, leading to hypercalcemia.57

PREVALENCE

SLOWINVOLUTION OF PARATHYROID GLANDS

The prevalence of persistent SHPT after kidney transplantation has been reported to be 8% to 50%,49-52 depending on when hypercalcemia is assessed and how SHPT is treated before and after kidney transplantation. Absence of hypercalcemia does not mean normal parathyroid function. Elevated intact PTH and abnormal bone biopsy persist in 50% to 70% of recipients with a longterm graft.50,53 Hypercalcemia of more than 1 year is found in one third of the transplant recipients. The hypercalcemia resolves in 50% of the patients in the first month after kidney transplantation, 85% on the first 6 months, and 95% after 6 months. The hypercalcemia is not dependent on age, postoperative medication, preoperative serum calcium, or alkaline phosphatase levels/" Hypercalcemia after transplantation is due to the continuous hyperfunction of hyperplastic parathyroid glands. In patients with a well-functioning kidney transplant, factors such as calcitriol deficiency, hyperphosphatemia, and skeletal resistance of PTH action are no longer present. Although the prevalence of hypercalcemia in patients after kidney transplantation has decreased because of better control of SHPT before transplantation, some renal

The nonsuppressible PTH secretion theory depends on an increased parathyroid mass that involutes slowly. In a detailed review, Parfitt" outlined possible reasons for this slow involution, including the low rate of parathyroid cell turnover inherent in the parathyroid gland, the inefficiency of cell deletion mechanisms, and the slow rate at which parathyroid glands become smaller in response to hypercalcemia.

After Kidney Transplantation

INSUFFICIENT CALCITRIOL SECRETION

Vitamin D metabolism is usually normal within I week after transplantation, irrespective of the onset of diuresis or the dose of cyclosporine A,52 However, vitamin D metabolism may remain impaired in 20% of kidney transplant recipients/" perpetuating after kidney transplantation the most important pathogenic factor of SPTH. PARATHYROID HORMONE SET-POINT

There is insufficient information about the PTH set-point in patients after transplantation with or without hypercalcemia, but it is likely that a PTH set-point is restored slowly after transplantation. Many patients are found to have high intact PTH for calcium levels after kidney transplantation.

Metabolic Complications of Secondary Hyperparathyroidism - -

Clinical Manifestations of Secondary Hyperparathyroidism Replacement of the kidney's excretory function by dialysis has prolonged life, but it has also revealed the extent and importance of its endocrine functions." Patients with CRF have considerable morbidity and mortality. Classic clinical manifestations of SHPT come from bones (pain, deformities, fractures), from metastatic calcifications, and from skin (pruritus, calciphylaxis). Patients with CRF also suffer from a wide range of organ dysfunctions that were attributed to a "uremic toxin." As we begin to understand the physiopathology of CRF, we recognize that many organ derangements are the consequences of the effects of high PTH levels on cellular metabolism.

Bone Disease Musculoskeletal problems remain among the main limitations of the quality of life of patients with renal failure, in particular those treated with long-term maintenance dialysis. The mechanical problems caused by uremic bone disease include fractures of long bones, crush vertebral fractures, and rib fractures. Bone pain is a common manifestation, insidious in appearance and more frequent in the lower back, hips, and legs. In children, growth retardation is common and may be worsened by other factors such as chronic acidosis, malnutrition, and low levels of somatomedin.w" Skeletal deformities are common in uremic children because of the intense remodeling. In adults, deformities arise mainly from vertebral fractures producing kyphosis and lumbar scoliosis. TYPES OF BONE DISEASE

Histologic skeletal abnormalities develop early in patients with chronic renal disease. Bone resorption, the most common abnormality, occurs in several locations (subperiosteal, subchondral, trabecular, endosteal, and subligamentous), whereas brown tumors and periosteal reaction are less common. Osteosclerosis primarily affects the axial skeleton, and associated osteoporosis and osteomalacia cause generalized osteopenia. Bone biopsies reveal increased PTH activity on bone in half of the patients whose glomerular filtration rate has fallen to 50% of normal or less. In the early stages, mild hyperparathyroid bone disease is seen. When the glomerular filtration rate falls to between 20 and 40 mL/min, bone biopsies show a mineralization defect." Youth, female gender, tubulointerstitial types of nephropathy, and a long duration of uremia appear to be independent risk factors for the development of bone disease." Bone disorders in renal failure have a wide spectrum of histologic types, including the classic osteitis fibrosa, osteomalacia, a mixed form (with features of both osteitis fibrosa and osteomalacia), aluminum osteodystrophy, and adynamic bone disease. The form and severity of the bone disease depend on the gender and age of the patient; the severity and duration of the CRF; the metabolic acidosis; the characteristics of the dialysis; the calcitriol and PTH levels; the dietary calcium, phosphate, and aluminum load; additional medications (specially steroids); and the associated endocrine

505

diseases (frequently diabetes mellitus). In addition, parathyroidectomy and renal transplantation can suddenly modify the precarious adaptation of the long-deranged mineral metabolism. In addition to the defects in bone formation and mineralization, patients receiving long-term hemodialysis may have bone deposits of ~2-microglobulin, which per se cause bone disease and increase the risk of fractures.f High-Turnover Hyperparathyroid Bone Disease. Osteitis fibrosa cystica (although no inflammatory process was ever identified) is the result of long-standing hyperparathyroidism. Seen in 5% to 30% of dialyzed patients, it rarely arises before initiation of dialysis.v' It is characterized by an increase in the osteoblast surface, an increased number of osteoclasts and osteoblasts, and accelerated bone resorption and bone formation. Woven osteoid is increased, with a random arrangement of collagen instead of the normal lamellar pattern and deposition of amorphous calcium phosphate instead of hydroxyapatite.f In advanced cases, collagen deposition produces fibrosis and cysts (hence fibrosa cystica) replacing the bone marrow. The resulting structure, even with an increased bone mass, consists mainly of frail woven bone prone to fractures. Low-TurnoverBoneDisease. The other end of the spectrum is associated with a relative PTH deficiency, a decrease in the osteoblast surface, and paucity of bone cells, with a profound decrease in the number of active remodeling sites. Aluminum overload contributes significantly to low-turnover bone disease, and it occurs in 30% to 85% of these patients.v' Patients with low-turnover bone disease tend to become hypercalcemic, have aging of bone caused by stunted bone remodeling and microfractures, and are at higher risk for fractures.P The term low-turnover aluminum-associated bone disease (LTAABD) has been used to describe this histologic lesion.P Other factors that reduce bone turnover, such as parathyroidectomy, diabetes." and medication, can account for a significant proportion of low-turnover bone disease. Patients with high-turnover hyperparathyroid bone disease and LTAABD present with similar clinical and laboratory features; therefore, differentiating these two bone abnormalities is often difficult. An erroneous diagnosis of osteitis fibrosa cystica may lead to parathyroidectomy that exacerbates aluminum deposition and low-turnover bone disease." Within this group, two subgroups can be identified. When reduced mineralization is coupled with a parallel decrease in bone formation, the end result is "adynamic uremic bone disease." When reduced mineralization precedes or is more pronounced than the decreased collagen deposition, "lowturnover osteomalacia" is the consequence. 12 The use of peritoneal dialysis with a supraphysiologic level of calcium in the dialysate, use of calcium-based phosphate binders, and diabetes appear to be independent pathogenic factors for the development of adynamic uremic bone disease." Most patients with uremic bone disease, however, have a mixed form (mixed uremic osteodystrophy) with or without aluminum deposition. DIAGNOSIS OF UREMIC OSTEODYSTROPHY

No serum biochemical or other noninvasive test can diagnose unequivocally renal osteodystrophy or can distinguish different forms of the disorder with reasonable sensitivity

506 - - Parathyroid Gland and specificity. Bone biopsies remain the surest and most rational approach." Hypercalcemia, for example, may be present in patients with either low-turnover osteomalacia or hyperparathyroid bone disease. Although the desferrioxamine test was once advocated for the diagnosis of aluminum overload/'? it has proved useful in only a small fraction of those who have low serum PTH levels and gives false-negative results in many patients.l? Also, the radiographic findings are not specific and the radiographic signs of oxalosis can mimic those of hyperparathyroid bone disease." Positron emission tomography (PET) scanning of bone using fluoride has been advocated to differentiate low-turnover from highturnover renal osteodystrophy and to provide quantitative estimates of bone cell activity that correlate with histomorphometric data. 10

Extraskeletal Calcification There are three kinds of extraskeletal calcification: visceral, periarticular, and vascular. Visceral calcifications may involve the lungs (causing restrictive lung disease), myocardium.TP mitral valve," kidneys, skeletal muscle, breast." and stomach. Penile calcification may produce impotence, and its prevalence is probably underestimated.P Patients with visceral calcifications have hyperphosphatemia, an elevated calcium-phosphorus product, and high levels of PTH.43 Periarticular calcification produces calcific periarthritis and small-joint effusions, and radiography usually shows the calcification around the joint. Vascular calcification, in both large and small vessels, occurs in 20% of patients with endstage CRF76 and may cause falsely elevated blood pressure readings.f Calcium deposits on the conjunctiva can cause a red eye syndrome. Parathyroidectomy rarely affects vascular calcification but usually diminishes nonvascular calcium deposits."

Pruritus Pruritus affects up to 85% of patients receiving hemodialysis, and it may be a major and distressing symptom. Although dramatic improvement of pruritus has been repeatedly observed after parathyroidectomy.P''" PTH does not seem to be directly involved in its patbogenesis.v-f Serum phosphate, calcium, and magnesium and especially their ionic products may cause pruritus or are markers of an as yet unknown prurogen.v-"

Calciphylaxis Calciphylaxis, an uncommon syndrome of disseminated calcification, is a severe complication of SHPT. It results in soft tissue calcification and vascular medial calcinosis leading to ischemic tissue necrosis. Patients present with painful, violaceous, mottled lesions that progress to skin and subcutaneous tissue necrosis, nonhealing ulcers, and gangrene. Lesions are characteristically located in the hands and fingers, lower extremities, and sometimes lower abdomen. Gangrene of fingers and toes frequently requires amputation, produces nonhealing wounds, and can lead to sepsis and death." Patients usually have a high Ca-P product but not necessarily extremely high PTH levels. It has been

described after kidney transplantation and also after recurrent SHPT.62 The prognosis for patients with calciphylaxis is dismal, with mortality approaching 50%. When signs and symptoms of calciphylaxis are recognized, the patient should be treated with phosphate binders and timely parathyroidectomy'v" A mathematical expression involving the Ca-P product and the alkaline phosphatase and PTH levels has been developed to help identify high-risk patients.t"

Anemia Normochromic, normocytic anemia is a prominent complication of CRF. In addition to decreased erythropoietin production, iron deficiency, systemic infections, aluminum toxicity, and increased hemolysis are contributing factors in some patients. Increased PTH levels may cause anemia by inhibition of erythropoiesis." shortening red blood cell survival, and inducing bone marrow fibrosis." Parathyroidectomy improves the hematocrit in many patients with SHPT.89-91 Recombinant human erythropoietin is used to treat anemia in CRF patients. The dose of erythropoietin required to achieve an adequate hematocrit response may depend on the severity of SHPT and the extent of bone marrow fibrosis.f? Hypertension is its most serious side effect.

Insulin Resistance Treatment of SHPT by correcting phosphate retention improves glucose intolerance with increased insulin secretion." Diabetic patients with CRF have lower serum calcium and intact PTH levels than nondiabetic patients. Osteitis fibrosa is noted radiologically in a third of nondiabetic patients but in none of the diabetic patients. Because of the lower PTH level, low-turnover bone disease is a special problem for the diabetic patient receiving dialysis." Insulin secretion may be impaired in CRF related to SHPT.95 The impaired insulin secretion in association with peripheral resistance to the action of insulin causes glucose intolerance in CRF. The impaired insulin secretion induced by excess PTH may be related to the effect of PTH on the pancreatic islets to increase intracellular calcium. A calcium channel blocker prevents calcium accumulation in the islet cells, antagonizes the effect of PTH, reverses the abnormalities in insulin release, and normalizes glucose tolerance in animals with CRF.96 Calcitriol modulates secretion of insulin by the beta cell. The regulation of insulin secretion in uremia is affected directly by the low calcitriollevel and indirectly by the low PTH level, both independently of serum calcium."?

Hypertension Arterial hypertension is a cause and also a consequence of CRF. Cytosolic calcium metabolism is altered in the saltdependent type of essential hypertension and also in CRF patients. Patients with CRF and overt SHPT have more severe hypertension'" and a higher intracellular calcium content?' than uremic patients without bone resorption and SHPT. Parathyroidectomy lowers blood pressure in a significant proportion of patients with SHPT.l00 Calcitriol causes

Metabolic Complications of Secondary Hyperparathyroidism - - 507

hypertension,'?' whereas PTH is a vasodilator and calcium has a hypotensive effect. An identified parathyroid hypertensive factor,102,103 a 3000-d protein-lipophospholipid.Pv'P' may be the cause of hypertension in genetically hypertensive rats, 106 salt-sensitive low-renin essential hypertension in humans, 107 and hypertension associated with primary hyperparathyroidism. 107.108 This parathyroid hypertensive factor is secreted by the parathyroid gland!'? and its secretion is inhibited by calcium. 110 The role of parathyroid hypertensive factor in SHPT, however, has not been studied.

Hyperlipemia Hyperlipidemia is common in CRF, but the underlying mechanisms are not clearly defined. Experimental and clinical data have shown that SHPT may be the cause of hypertriglyceridemia. Excess PTH reduces postheparin lipoprotein lipase activity in plasma, impairing lipid removal from the circulation.I? There is a significant positive correlation between serum levels of alkaline phosphatase and triglycerides in patients with SHPT. Serum triglycerides may become normal after parathyroidectomy in some patients with hypertriglyceridemia.'!' Both hyperlipemia and hyperphosphatemia promote atherosclerosis and may explain the high prevalence of coronary heart disease in CRF patients.U?

Impaired Phagocytosis Polymorphonuclear leukocytes in patients with CRF have elevated basal levels of cytosolic calcium, reduced ATP content, and impaired phagocytosis. Excess PTH seems to cause these abnormalities and may be prevented by either reducing the levels of PTH or blocking its action with verapamil. 113

Clinical Manifestations of Secondary Hyperparathyroidism after Kidney Transplantation Although post-transplantation SHPT most often follows an asymptomatic course, it can cause significant morbidity and give rise to serious complications.F' Symptoms resemble those of primary hyperparathyroidism such as increased bone resorption, nephrolithiasis, and pancreatitis. Increased bone resorption may persist'!" and osteopenia may be present for as long as 96 months after transplantation because of preexisting osteodystrophy, SHPT, and steroids given to control graft rejection.57. I 15 Steroid-induced osteopenia is more intense in the spine than in cortical bone.P Avascular necrosis of the hip joint, highly prevalent among transplant recipients, correlates more with steroid therapy than with the degree of SHPT. Nephrolithiasis occurs in 5% to 10% of transplanted kidneys and may appear years after transplantation. It may arise as an asymptomatic radiologic finding, as painless hematuria because the grafted kidney is denervated, or as painless ureteral obstruction causing oliguria and hydronephrosis.V!" Although it can be precipitated by other factors, SHPT is the main cause of nephrolithiasis in transplanted kidneys. Hypercalciuria, common in hypercalcemic transplant recipients, also predisposes to stone formation.P

Pancreatitis occurs in 2% to 6% of kidney transplant recipients. Among those with hypercalcemia, acute pancreatitis has a prevalence of 11%.117 Hypercalcemia is a more important cause of acute pancreatitis than immunosuppressive therapy, gallstones, alcoholism, or steroids in these

patients.V!"

Summary SHPT after chronic kidney disease can lead to clinically significant bone disease. Additional consequences include soft tissue and vascular calcification, cardiovascular disease, and arteriole calcification, and it may contribute to the increased risk of cardiovascular morbidity and mortality among uremic patients. The pathogenesis of SHPT comprises decreased 1,25-(OHhD3 levels, hyperphosphatemia, altered PTH metabolism, skeletal resistance to PTH, and possibly gene-mediated changes in the sensitivity of the parathyroid cell to the effects of calcium and calcitriol. The treatment of CRF and its complications may also contribute to the pathogenesis of SHPT. After kidney transplantation, impaired graft function, some level of parathyroid autonomy, nonsuppressible PTH secretion, and a slow involution of parathyroid glands may cause persistent parathyroid overgrowth.

REFERENCES I. Coe FL, Canterbury JM, Firpo 11, Reiss E. Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J Clin Invest 1973; 52:134. 2. Breslau NA. Update on secondary forms of hyperparathyroidism. Am J Med Sci 1987;294:120. 3. Riggs BL, Gallagher JC, DeLuca HF, et aJ. A syndrome of osteoporosis, increased serum immunoreactive parathyroid hormone, and inappropriately low serum 1,25-dihydroxyvitamin D. Mayo Clin Proc 1978;53:701. 4. Nordenstrom J, Strigard K, Perbeck L, et aJ. Hyperparathyroidism associated with treatment of manic-depressive disorders by lithium. Eur J Surg 1992;158:207. 5. Albright F, Baird P, Cope 0, Bloomberg E. Studies on the physiology of the parathyroid glands. IV. Renal complications of hyperparathyroidism. Am J Med Sci 1934;187:49. 6. Berson S, Yalow R. Immunoassay of bovine and human parathyroid hormone. Proc Nat! Acad Sci USA 1963;49:613. 7. Massry SG, Fadda GZ. Chronic renal failure is a state of cellular calcium toxicity. Am J Kidney Dis 1993;21:81. 8. Nguyen-Yamamoto L, Rousseau L, Brossard JH, et al. Origin of parathyroid hormone (PTH) fragments detected by intact-PTH assays. Eur J EndocrinoI2002;147:123. 9. Coburn JW, Popovtzer MM, Massry SG, Kleeman CR. The physicochemical state and renal handling of divalent ions in chronic renal failure. Arch Intern Med 1969;124:302. 10. Backdahl M, Howe JR, Lairmore TC, Wells SA Jr. The molecular biology of parathyroid disease. World J Surg 1991;15:756. 11. Russell J, Lettieri D, Sherwood LM. Suppression by 1,25(OH)2D3 of transcription of the pre-proparathyroid hormone gene. Endocrinology 1986; 119:2864. 12. Felsenfeld AJ, Llach F. Parathyroid gland function in chronic renal failure. Kidney Int 1993;43:771. 13. Shvil Y, Naveh-Many T, Barach P, Silver J. Regulation of parathyroid cell gene expression in experimental uremia. J Am Soc Nephrol 1990;1:99. 14. Akerstrom G, Rastad J, Ljunghall S, et aJ. Cellular physiology and pathophysiology of the parathyroid glands. World J Surg 1991;15:672. 15. Fraser D, Kodicek E. Unique biosynthesis by kidney of a biologically active vitamin D metabolite. Nature 1970;228:764.

508 - - Parathyroid Gland 16. Holick M. Vitamin D. Biosynthesis, metabolism, and mode of action. In: DeGroot LJ (ed), Endocrinology, 2nd ed. Philadelphia, WB Saunders, 1989, p 902. 17. Delmez lA, Tindira C, Grooms P, et al. Parathyroid hormone suppression by intravenous 1,25-dihydroxyvitamin D. A role for increased sensitivity to calcium. 1 Clin Invest 1989;83:1349. 18. Rahamimov R, Silver 1. The molecular basis of secondary hyperparathyroidism in chronic renal failure. Isr 1 Med Sci 1994;30:26. 19. Slatopolsky E, Lopez-Hilker S, Delmez 1, et al. The parathyroidcalcitriol axis in health and chronic renal failure. Kidney Int Suppl 1990;29:S41. 20. Slatopolsky E, Brown A, Dusso A. Pathogenesis of secondary hyperparathyroidism. Kidney Int Suppl 1999;73:S14. 21. Szabo A, Merke 1, Beier E, et al. 1,25(OHh vitamin D3 inhibits parathyroid cell proliferation in experimental uremia. Kidney Int 1989;35:1049. 22. Puschett JB, Beck WS Jr, Parathyroid hormone and 25-hydroxyvitamin D3: Synergistic and antagonistic effects on renal phosphate transport. Science 1975;190:473. 23. Portale AA, Morris RC lr. Pathogenesis of secondary hyperparathyroidism in chronic renal insufficiency. Miner Electrolyte Metab 1991;17:211. 24. Ritz E, Matthias S, Seidel A, et al. Disturbed calcium metabolism in renal failure-Pathogenesis and therapeutic strategies. Kidney Int SuppI1992;38:S37. 25. luttmann lR, Buurman Cl, De Kam E, et al. Serum concentrations of metabolites of vitamin D in patients with chronic renal failure (CRF). Consequences for the treatment with l-alpha-hydroxy derivatives. Clin Endocrinol (Oxf) 1981;14:225. 26. Cheung AK, Manolagas SC, Catherwood BD, et al. Determinants of serum 1,25(OHhD levels in renal disease. Kidney Int 1983;24:104. 27. Prince RL, Hutchison BG, Dick I. The regulation of calcitriol by parathyroid hormone and absorbed dietary phosphorus in subjects with moderate chronic renal failure. Metabolism 1993;42:834. 28. Dusso A, Finch 1, Delmez 1, et al. Extrarenal production of calcitriol. Kidney Int Suppl 1990;29:S36. 29. Hsu CH, Patel S. Factors influencing calcitriol metabolism in renal failure. Kidney Int 1990;37:44. 30. Fukagawa M, Kaname S, Igarashi T, et al. Regulation of parathyroid hormone synthesis in chronic renal failure in rats. Kidney Int 1991; 39:874. 31. Brown AI, Dusso A, Lopez-Hilker S, et al. 1,25-(OHhD receptors are decreased in parathyroid glands from chronically uremic dogs. Kidney Int 1989;35:19. 32. Bricker NS. On the pathogenesis of the uremic state. An exposition of the "trade-off hypothesis." N Engl 1 Med 1972;286:1093. 33. Bricker NS, Slatopolsky E, Reiss E, Avioli LV. Calcium, phosphorus, and bone in renal disease and transplantation. Arch Intern Med 1969;123:543. 34. Coburn 1, Kanis 1, Popovtzer M, et al. Pathophysiology and treatment of uremic bone disease. Calcif Tissue Int 1983;35:712. 35. Delmez lA, Fallon MD, Harter HR, et al. Does strict phosphorus control precipitate renal osteomalacia? 1 Clin Endocrinol Metab 1986; 62:747. 36. Lopez-Hilker S, Galceran T, Chan YL, et al. Hypocalcemia may not be essential for the development of secondary hyperparathyroidism in chronic renal failure. 1 Clin Invest 1986;78: 1097. 37. Slatopolsky E, Caglar S, Gradowska L, et al. On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using "proportional reduction" of dietary phosphorus intake. Kidney Int 1972;2:147. 38. Ritz E, Malluche HH, Krempien B, et al. Pathogenesis of renal osteodystrophy: Roles of phosphate and skeletal resistance to PTH. Adv Exp Med Bioi 1978;103:423. 39. Llach F, Massry SG. On the mechanism of secondary hyperparathyroidism in moderate renal insufficiency. 1 Clin Endocrinol Metab 1985;61:601. 40. Evanson 1M. The response to the infusion of parathyroid extract in hypocalcaemic states. Clin Sci 1966;3 I :63. 4 I. Rodriguez M, Martin-Malo A, Martinez ME, et al. Calcemic response to parathyroid hormone in renal failure: Role of phosphorus and its effect on calcitriol. Kidney Int 1991;40:1055. 42. Massry SG, Coburn JW, Lee DB, et al. Skeletal resistance to parathyroid hormone in renal failure. Studies in 105 human subjects. Ann Intern Med 1973;78:357.

43. Salusky I, Coburn 1. The renal osteodystrophies. In: DeGroot LJ (ed), Endocrinology, 2nd ed. Philadelphia, WB Saunders, 1989, p 1032. 44. Rodriguez M, Felsenfeld AI, Llach F. Calcemic response to parathyroid hormone in renal failure: Role of calcitriol and the effect of parathyroidectomy. Kidney Int 1991;40:1063. 45. Rosenblatt M, Kronenberg H, Potts 1. Parathyroid hormone. Physiology, chemistry, biosynthesis, secretion, metabolism, and mode of action. In: DeGroot LJ (ed), Endocrinology, 2nd ed. Philadelphia, WB Saunders, 1989, p 848. 46. Felsenfeld AI, Rodriguez M, Dunlay R, Llach F. A comparison of parathyroid-gland function in haemodialysis patients with different forms of renal osteodystrophy. Nephrol Dial Transplant 1991;6:244. 47. Yokoyama K, Shigematsu T, Tsukada T, et al. Calcium-sensing receptor gene polymorphism affects the parathyroid response to moderate hypercalcemic suppression in patients with end-stage renal disease. Clin NephroI2002;57:131. 48. Alfrey AC, lenkins D, Groth CG, et al. Resolution of hyperparathyroidism, renal osteodystrophy and metastatic calcification after renal homotransplantation. N Engl 1 Med 1968;279:1349. 49. Lins LE. Renal function in hypercalcemia after renal transplantation. Scand 1 Urol Nephrol SuppI1977;(42):159. 50. Sitges-Serra A, Esteller E, Ricart Ml, Caralps A. Indications and late results of subtotal parathyroidectomy for hyperparathyroidism after renal transplantation. World 1 Surg 1984;8:534. 51. Pletka PG, Strom TB, Hampers CL, et al. Secondary hyperparathyroidism in human kidney transplant recipients. Nephron 1976;17:371. 52. Saha HH, Salmela KT, Ahonen PI, et al. Sequential changes in vitamin D and calcium metabolism after successful renal transplantation. Scand 1 Urol NephroI1994;28:21. 53. Straffen AM, Carmichael Dl, Fairney A, et al. Calcium metabolism following renal transplantation. Ann Clin Biochem 1994;31:125. 54. David DS, Sakai S, Brennan BL, et al. Hypercalcemia after renal transplantation. Long-term follow-up data. N Engl 1 Med 1973;289:398. 55. Christensen MS, Nielsen HE. The clinical significance of hyperparathyroidism after renal transplantation. Scand 1 Urol Nephrol Suppl 1977;(42):130. 56. Garvin PI, Castaneda M, Linderer R, Dickhans M. Management of hypercalcemic hyperparathyroidism after renal transplantation. Arch Surg 1985;120:578. 57. Sitges-Serra A, Caralps-Riera A. Hyperparathyroidism associated with renal disease. Pathogenesis, natural history, and surgical treatment. Surg Clin North Am 1987;67:359. 58. Parfitt AM. Hypercalcemic hyperparathyroidism following renal transplantation: Differential diagnosis, management, and implications for cell population control in the parathyroid gland. Miner Electrolyte Metab 1982;8:92. 59. Malluche HH, Faugere Me. Renal osteodystrophy. N Engl 1 Med 1989;321:317. 60. Salusky IB, Goodman WG. Renal osteodystrophy in dialyzed children. Miner Electrolyte Metab 1991;17:273. 61. Cundy T, Hand Dl, Oliver DO, et al. Who gets renal bone disease before beginning dialysis? Br Med 1 (Clin Res Ed) 1985;290:271. 62. Onishi S, Andress DL, Maloney NA, et al. Beta 2-microglobulin deposition in bone in chronic renal failure. Kidney Int 1991;39:990. 63. Malluche H, Faugere MC. Renal bone disease 1990: An unmet challenge for the nephrologist. Kidney Int 1990;38:193. 64. Chazan lA, Libbey NP, London MR, et al. The clinical spectrum of renal osteodystrophy in 57 chronic hemodialysis patients: A correlation between biochemical parameters and bone pathology findings. Clin Nephrol 1991;35:78. 65. Malluche HH, Monier-Faugere Me. Risk of adynamic bone disease in dialyzed patients. Kidney Int Suppl 1992;38:S62. 66. Pei Y, Hercz G, Greenwood C, et al. Renal osteodystrophy in diabetic patients. Kidney Int 1993;44:159. 67. Sherrard Dl. The role of aluminum in renal osteodystrophy. Mayo Clin Proc 1993;68:510. 68. Hercz G, Pei Y, Greenwood C, et al. Aplastic osteodystrophy without aluminum: The role of "suppressed" parathyroid function. Kidney Int 1993;44:860. 69. Milliner DS, Nebeker HG, Ott SM, et al. Use of the deferoxamine infusion test in the diagnosis of aluminum-related osteodystrophy. Ann Intern Med 1984;101:775. 70. lulian BA, Faugere MC, Malluche RH. Oxalosis in bone causing a radiographical mimicry of renal osteodystrophy. Am J Kidney Dis 1987;9:436.

Metabolic Complications of Secondary Hyperparathyroidism - - 509 71. Mako J, Lengyel M, Szucs J. Intracardiac calcification in patients under chronic haemodialysis. Int Urol Nephrol 1987;19:441. 72. Rostand SG, Sanders PC, Rutsky EA. Cardiac calcification in uremia. Contrib NephroI1994;106:26. 73. Forman MB, Virmani R, Robertson RM, Stone WJ. Mitral anular calcification in chronic renal failure. Chest 1984;85:367. 74. Sommer G, Kopsa H, Zazgornik J, Salomonowitz E. Breast calcifications in renal hyperparathyroidism. AJR Am J Roentgenol 1987;148:855. 75. Dalal S, Gandhi VC, Yu AW, et al. Penile calcification in maintenance hemodialysis patients. Urology 1992;40:422. 76. Cassidy MJ, Owen JP, Ellis HA, et al. Renal osteodystrophy and metastatic calcification in long-term continuous ambulatory peritoneal dialysis. Q J Med 1985;54:29. 77. De Francisco AM, Cassidy MJ, Owen JP, et al. Ectopic calcification. The role of parathyroid hormone. Proc Eur Dial Transplant Assoc Eur RenAssoc 1985;21:888. 78. Massry SG, Popovtzer MM, Coburn JW, et al. Intractable pruritus as a manifestation of secondary hyperparathyroidism in uremia. Disappearance of itching after subtotal parathyroidectomy. N Engl J Med 1968;279:697. 79. Albertucci M, Zielinski CM, Rothberg M, et al. Surgical treatment of the parathyroid gland in patients with end-stage renal disease. Surg GynecolObstet 1988;167:49. 80. Demeure MJ, McGee DC, Wilkes W, et al. Results of surgical treatment for hyperparathyroidism associated with renal disease. Am J Surg 1990;160:337. 81. Carmichael AJ, McHugh MM, Martin AM, Farrow M. Serological markers of renal itch in patients receiving long term haemodialysis, Br Med J (Clin Res Ed) 1988;296:1575. 82. Stahle-Backdahl M, Hagermark 0, Lins LE, et al. Experimental and immunohistochemical studies on the possible role of parathyroid hormone in uraemic pruritus. J Intern Med 1989;225:411. 83. Chou FF, Ho JC, Huang SC, Sheen-Chen SM. A study on pruritus after parathyroidectomy for secondary hyperparathyroidism. J Am Coli Surg 2000;190:65. 84. Duh QY, Lim RC, Clark OH. Calciphylaxis in secondary hyperparathyroidism. Diagnosis and parathyroidectomy. Arch Surg 1991;126:1213; discussion, 1218. 85. Roe SM, Graham LD, Brock WB, Barker DE. Calciphylaxis: Early recognition and management. Am Surg 1994;60:81. 86. Levin A, Mehta RL, Goldstein MB. Mathematical formulation to help identify the patient at risk of ischemic tissue necrosis-A potentially lethal complication of chronic renal failure. Am J Nephrol 1993; 13:448. 87. McGonigle RJ, Wallin JD, Husserl F, et al. Potential role of parathyroid hormone as an inhibitor of erythropoiesis in the anemia of renal failure. J Lab Clin Med 1984;104:1016. 88. Massry SG. Pathogenesis of the anemia of uremia: Role of secondary hyperparathyroidism. Kidney Int SuppI1983;16:S204. 89. Grutzmacher P, Radtke HW, Fassbinder W, et aI. Effect of secondary hyperparathyroidism on the anaemia of end-stage renal failure: In vivo and in vitro studies. Proc Eur Dial Transplant Assoc 1983; 20:739. 90. Urena P, Eckardt KU, Sarfati E, et al. Serum erythropoietin and erythropoiesis in primary and secondary hyperparathyroidism: Effect of parathyroidectomy. Nephron 1991;59:384. 91. Zingraff J, Drueke T, Marie P, et al. Anemia and secondary hyperparathyroidism. Arch Intern Med 1978; 138: 1650. 92. Rao DS, Shih MS, Mohini R. Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med 1993;328:171. 93. Mak RH, Turner C, Haycock GB, Chantler C. Secondary hyperparathyroidism and glucose intolerance in children with uremia. Kidney Int SuppI1983;16:S128. 94. Vincenti F, Arnaud SB, Recker R, et al. Parathyroid and bone response of the diabetic patient to uremia. Kidney Int 1984;25:677.

95. Fadda GZ, Akmal M, Premdas FH, et al. Insulin release from pancreatic islets: Effects ofCRF and excess PTH. Kidney Int 1988;33:1066. 96. Fadda GZ, Akmal M, Soliman AR, et al. Correction of glucose intolerance and the impaired insulin release of chronic renal failure by verapamil. Kidney Int 1989;36:773. 97. Quesada JM, Martin-Malo A, Santiago J, et aI. Effect of calcitriol on insulin secretion in uraemia. Nephrol Dial Transplant 1990;5:1013. 98. London GM, De Vernejoul MC, Fabiani F, et al. Secondary hyperparathyroidism and cardiac hypertrophy in hemodialysis patients. Kidney Int 1987;32:900. 99. Raine AE, Bedford L, Simpson AW, et al. Hyperparathyroidism, platelet intracellular free calcium and hypertension in chronic renal failure. Kidney Int 1993;43:700. 100. Pizzarelli F, Fabrizi F, Postorino M, et al. Parathyroidectomy and blood pressure in hemodialysis patients. Nephron 1993;63:384. 101. Bukoski RD, Kremer D. Calcium-regulating hormones in hypertension: Vascular actions. Am J Clin Nutr 1991 ;54:220S. 102. Pang PK, Lewanczuk RZ. Parathyroid origin of a new circulating hypertensive factor in spontaneously hypertensive rats. Am J Hypertens 1989;2:898. 103. Pang PK, Lewanczuk RZ, Benishin CG. Parathyroid hypertensive factor. J Hypertens Suppl 1990;8:S155. 104. Benishin CG, Lewanczuk RZ, Pang PK. Purification of parathyroid hypertensive factor from plasma of spontaneously hypertensive rats. Proc Nat! Acad Sci USA 1991;88:6372. 105. Benishin CG, Lewanczuk RZ, Shan J, Pang PK. Purification and structural characterization of parathyroid hypertensive factor. J Cardiovasc Pharmacol 1994;23(Suppl 2):S9. 106. Pang PK, Benishin CG, Lewanczuk RZ. Parathyroid hypertensive factor, a circulating factor in animal and human hypertension. Am J Hypertens 1991;4:472. 107. Lewanczuk RZ, Benishin CG, Shan J, Pang PK. Clinical aspects of parathyroid hypertensive factor. J Cardiovasc Pharmacol 1994; 23(Suppl 2):S23. 108. Lewanczuk RZ, Pang PK. Expression of parathyroid hypertensive factor in hypertensive primary hyperparathyroid patients. Blood Press 1993;2:22. 109. Pang PK, Benishin CG, Shan J, Lewanczuk RZ. PHF: The new parathyroid hypertensive factor. Blood Press 1994;3: 148. 110. Lin CM, Saito K, Tsujino T, Yokoyama M. Calcium supplementation inhibits the expression of parathyroid hypertensive factor in DOCAsalt hypertensive rats. Am J Hypertens 1994;7:201. III. Nishizawa Y, Miki T, Okui Y, et al. Deranged metabolism of lipids in patients with chronic renal failure: Possible role of secondary hyperparathyroidism. Jpn J Med 1986;25:40. 112. Ritz E, Deppisch R, Stier E, Hansch G. Atherogenesis and cardiac death: Are they related to dialysis procedure and biocompatibility? Nephrol Dial Transplant I994;9(Suppl 2):165. 113. Chervu I, Kiersztejn M, Alexiewicz JM, et al. Impaired phagocytosis in chronic renal failure is mediated by secondary hyperparathyroidism. Kidney IntI992;41:1501. 114. Pietschmann P, Vychytil A, Woloszczuk W, Kovarik J. Bone metabolism in patients with functioning kidney grafts: Increased serum levels of osteocalcin and parathyroid hormone despite normalisation of kidney function. Nephron 1991;59:533. 115. Almond MK, Kwan JT, Evans K, Cunningham 1. Loss of regional bone mineral density in the first 12 months following renal transplantation. Nephron 1994;66:52. 116. Guest G, Tete MI, Beurton D, Broyer M. [Urinary lithiasis after kidney transplantation. Experience at a pediatric center.] Arch Fr Pediatr 1993;50: 15. 117. Frick TW, Fryd DS, Sutherland DE, et al. Hypercalcemia associated with pancreatitis and hyperamylasemia in renal transplant recipients. Data from the Minnesota randomized trial of cyc1osporine versus antilymphoblast azathioprine. Am J Surg 1987;154:487. 118. Sitges-Serra A, Alonso M, de Lecea C, et al. Pancreatitis and hyperparathyroidism. Br J Surg 1988;75: 158.

Surgical Approach to Secondary Hyperparathyroidism Juan J. Sancho, MD, PhD • Antonio Sitges-Serra, MD, PhD

Indications for Surgery Pretransplantation Parathyroidectomy (PIX) is indicated when medical treatment fails to control progressive secondary renal hyperparathyroidism (SHPT) (Table 57_1).1-3 Clinical manifestations include persistence or worsening of skeletal symptoms, pruritus, and extraskeletal calcifications." Because high parathormone (PTH) levels may worsen many disorders associated with chronic renal failure (CRF), other potential indications include hypertension, anemia, deranged myocardial function, and peripheral neuropathy.' High intact PTH (iPTH) (1-84) levels and a proven highturnover bone disease are prerequisites for considering a CRF patient with SHPT for surgery>" Calciphylaxis is an absolute indication for immediate PTX.5.9

Post-Transplantation PTX is indicated in some patients after kidney transplantation because of clinical manifestations similar to those of primary hyperparathyroidism: hypercalcemia plus nephrolithiasis, acute pancreatitis, changes in mental status (lethargy, irritability, confusion), or overt bone disease.'? Mild hypercalcemia alone does not appear to be a serious threat to the patient with a transplanted kidney, but impaired renal function in the presence of high PTH and hypercalcemia should be an indication for PTX, 11.12 as is the association of kidney stones and long-standing hypercalcemia.13,14 Whether asymptomatic hypercalcemia alone is an indication for PTX in renal transplant recipients is controversial. Post-transplantation hypercalcemia can arise with four different patterns: (1) subacute severe hypercalcemia, (2) transient hypercalcemia, (3) persistent hypercalcemia, and (4) hypercalcemia appearing after a period of normocalcemia.v'> The indications for surgery are summarized in Table 57-2.

510

SUBACUTE SEVERE HYPERCALCEMIA

Now an exceptional occurrence, severe hypercalcemia (serum calcium greater than 13 mg/dL) usually arises shortly after renal transplantation. It requires prompt PTX, especially if it threatens graft function. J 5-18 TRANSIENT HYPERCALCEMIA

Hypercalcemia after kidney transplantation resolves spontaneously in two thirds of the patients; 85% of them become normocalcemic during the first year. lO,17 In addition to overt post-transplantation SHPT, hypercalcemia can be caused by hypophosphatemia.l'' and the latter is exacerbated by the normally functioning kidney and high levels of PTH from a still hyperplastic parathyroid glands.'? Resorption of calcium phosphate salts may explain hypercalcemia and hyperphosphatemia in some patients. 15,16 Moreover, a preexisting vitamin D intoxication can be unmasked by the transplanted kidney. For the aforementioned reasons, the mild hypercalcemia present during the first 6 to 12 months after kidney transplantation is not an indication for surgery. PERSISTENT HYPERCALCEMIA

Whether the state of hypercalcemia is considered permanent depends on the investigators; the criteria range from 6 months to 6 years after transplantation. The old liberal approach of PTX for patients with more than 6 months of hypercalcemia-P has progressively been replaced by a more conservative approach in which the clinical status and the kidney function are closely monitored' and PTX is not even considered for 2 years if the graft is functioning. In any case, the longer the duration of hypercalcemia, the less likely it is to resolve spontaneously. Only 25% of cases of hypercalcemia persisting more than 12 months after transplantation resolve spontaneously." Two groups of patients may be considered for surgery for asymptomatic persistent hypercalcemia: those with

Surgical Approach to Secondary Hyperparathyroidism - -

511

and acute pancreatitis, or graft failure. I? When a previously normocalcemic transplant recipient develops hypercalcemia, graft failure should be ruled out. If graft failure is not the cause of hypercalcemia, PTX should be considered to prevent the development of complications of hyperparathyroidism or graft failure.

Preoperative Care

hypercalcemia that is not likely to resolve spontaneously and those with hypercalcemia lasting more than 2 years. A serum calcium level of 12 mg/dl," and borderline hyperphosphatemia 10 are good predictors of hypercalcemia that will not resolve spontaneously. The tolerable limits of serum calcium in persistent hypercalcemia vary among authors and are between 11.0 and 13.0 mg/dL. 3,1O,15,16,18 Elevated serum alkaline phosphatase levels have also been advocated as an independent predictor of persistent hypercalcemia. 3,1O,15,16,18 A declining alkaline phosphatase level after transplantation may, however, be due to inhibition of osteoblasts by steroids and thus would be an unreliable marker of bone resorption after transplantation." Some authors did not find elevated serum alkaline phosphatase predictive of persistent hypercalcemia.'? There may be a sound set of reasons for withholding PTX in those patients (fear of precipitating an adynamic bone disease or a high surgical risk), but expecting its spontaneous resolution is certainly not one of them." Prophylactic PTX in asymptomatic patients with persistent hypercalcemia may reduce the incidence of subsequent nephrolithiasis, acute pancreatitis, and vascular calcifications that are potentially graft and life threatening. I? RELAPSING HYPERCALCEMIA

Relapsing hypercalcemia is a rare condition. The few cases reported have associated complications, such as nephrolithiasis

Preoperative preparation of dialysis patients includes control of hyperkalemia, hypomagnesemia, and hypervolemia and careful evaluation and treatment of hypertension and cardiovascular disease.P Patients should receive oral calcitriol (1 ug) before surgery to avoid severe postoperative hypocalcemia. Patient should be dialyzed no longer than 1 day before PTX and then again no later than 2 days after the operation. When PTX is performed after kidney transplantation, immunosuppressive medication does not have to be interrupted in the perioperative period. Replacement steroid doses should be administered."

Localization Localization studies of the parathyroid glands are discussed in detail elsewhere in this book. Some issues, however, are unique to SHPT. Because image-based localizing tests depend on gland size and patients with SHPT tend to have large glands, the specificity and positive predictive value of computed tomography (CT) scanning, ultrasonography, and thallium-technetium (Tl-Tc) scintigraphy are much higher for SHPT than for primary hyperplasia." Ultrasonography has found to be useful for screening and follow-up of SHPT.26,2? It has a reported sensitivity of 45% to 70%.28,29 When large glands are not found by ultrasonography in patients with severe SHPT, they are usually situated in the superior mediastinum, behind the trachea or esophagus, or deep within the neck. 29 CT scanning and magnetic resonance imaging should then be the studies of choice.

512 - - Parathyroid Gland Although Tl-Tc scintigraphy also has greater success in finding the parathyroids in patients with SHPT than in those with primary hyperplasia." its sensitivity is only 30% to 55%.25.31,32 CT scanning has a sensitivity of only 50% in SHPT,25.28.31.32 but it is better than ultrasonography in localizing glands in the mediastinum.P Finally, 99mTc sestamibi-P'T subtraction scanning is positive in 88% of cases but has an overall sensitivity of only 67% for the localization of all hyperplasic glands, in relation to the functional status of the glands and not their weight'"; it is sometimes extremely useful in identifying an ectopic or supernumerary gland, or both.P

Surgical Management The critical factor for successful PTX is a highly skilled surgeon experienced in parathyroid surgery. The second most important factor is the localization of all parathyroid tissue," and that is closely linked to the former. All efforts should be made to locate all parathyroid glands, knowing that in 15% of these patients a fifth'" or even a sixth gland may be hidden in an ectopic situation. The patient is placed in a semi seated Kocher position. A standard collar incision is made and meticulous hemostasis is maintained throughout the procedure. Some authors routinely divide the strap muscles to obtain better exposure." but it is usually not necessary. The thyroid gland is widely exposed, the middle thyroid vein is ligated and transected, and the thyroid lobe is retracted medially and the carotid sheath laterally. The recurrent laryngeal nerve is exposed. The search for the parathyroid glands is then started, first in their normal location. The principle of "not removing anything before seeing everything" certainly applies here. All four, or more, parathyroid glands should be exposed and a confirmatory frozen section of each one obtained. Approximately 80% of the superior parathyroid glands are located within a circumscribed area of 1 inch above the intersection of the recurrent laryngeal nerve and the inferior thyroid artery. The glands are frequently secluded in the connective tissue that binds the posterior edge of the thyroid lobe to the larynx. The posterior thyroid capsule should be incised and the superior pole vessels divided if the upper glands are not found. To find the lower glands, the inferior poles of the thyroid should be cleared from fat and all tissue within I inch from the inferior pole of the thyroid dissected free and removed. Approximately 15% of lower glands are found in the thoracic inlet within the thymus. Regardless of the glands found, the thymus is routinely resected to ensure removal of possible supernumerary glands, an ectopic fourth or fifth gland (10% of the cases"), or rudimentary parathyroid tissue. The prethymic fascia extending from the middle cervical fascia is incised to identify the thymus. The thymus is then mobilized upward, using a small gauze swab to gently dissect the surrounding soft tissues from it. Veins draining the thymus into the innominate vein should be carefully ligated to avoid bleeding." When a gland is not found in its orthotopic location or within the thymus, the relatively avascular paraesophageal, paralaryngeal, retroesophageal, and retropharyngeal regions

should be carefully dissected." Next, the carotid sheath should be incised from its emergence from the mediastinum to the bifurcation. Finally, if a gland is still missing, a thyroid lobectomy is considered. Although true intrathyroidal parathyroid glands occur in only 2%, some parathyroid glands are so closely attached to the thyroid capsule that thyroid lobectomy may be required to identify them." Once all the parathyroid glands have been exposed, the subsequent steps depend on the procedure chosen. If subtotal PTX is planned, the smallest parathyroid is selected. The nonvascular pole of the gland is excised, leaving in place a 40- to 60-mg remnant. If there are doubts about the viability of the remnant, the gland is completely excised and the next best gland is selected in tum. All the remaining glands must be left in place until a viable, properly sized, well-colored remnant has been obtained. Only then are the remaining glands resected. We usually try to leave the remnant from a superior gland. The upper glands commonly have good vascular attachments to the thyroid capsule, and blood supply to lower glands may be interrupted during thymectomy. Lower gland remnants can also descend into the mediastinum, making an eventual reoperation more difficult.f The remnant is marked with nonreabsorbable material (ideally a titanium clip and a long silk thread). If only three parathyroid glands are found after exhaustive search, all three are removed. Thirty percent of the patients can be expected to have persistent hyperparathyroidism if this contingency arises.!? If total PTX and autotransplantation are planned, all four glands are resected and the most suitable gland is selected to obtain the autograft." Using glands with nodularity for the graft carries a high risk of graft-dependent recurrence.v" A 40- to 60-mg portion of the gland is sliced into l-mm fragments and 10 to 20 fragments are placed into several separate intramuscular pockets in the nondominant forearm, as far as possible from present and planned arteriovenous fistula location. The muscle pockets are closed with nonreabsorbable material to facilitate localization in case reoperation for recurrence is needed. Although exceptional, parathyromatosis is a potential cause of unexpected recurrence.f Care should be taken, therefore, to avoid breaking the parathyroid gland capsule and spilling parathyroid cells on the operative field. Intraoperative measurement of iPTH 15 or 30 minutes after removing all parathyroid tissue using a quick assay is found to be valuable where available, signaling either the end of the procedure or an overlooked fifth gland. 44.45 Cryopreservation should be routine in case permanent hypoparathyroidism develops. The technique and results obtained with cryopreserved parathyroid tissue are discussed elsewhere in this book.

Type Of Surgical Procedure The two accepted surgical procedures for the management of SHPT are subtotal parathyroidectomy (sPTX) and total PTX with parathyroid autotransplantation (PTX + AT). Total PTX46.47 is still supported by some groups on the basis of lower recurrences, but in these patients the bone does not mineralize in the absence of PTH and the patient must

Surgical Approach to Secondary Hyperparathyroidism - - 513

undergo life-long treatment with vitamin D and oral calcium.' The rationale for choosing a procedure to treat parathyroid hyperplasia and the relative merits and risks of each approach are discussed in detail in a separate chapter.

Subtotal Versus Autotransplantation Trials There are many reports supporting one procedure versus the other, but trials dealing specifically with SHPT are scarce. In a prospective randomized trial, Rothmund and coworkers'" found that PTX + AT was superior to sPTX in a group of 40 patients. During a mean follow-up of nearly 4 years, four patients in the sPTX group developed recurrence. Bone pain was alleviated in a significantly higher proportion of patients with PTX + AT. The other clinical responses were similar in both groups. One criticism of the study is that they left a larger remnant (60 to 80 mg) than the size recommended by other authors (40 to 60 mg). When evaluating this trial, one should keep in mind that the author's team was well known for their previous excellent results in a large series of PTX + AT. 49 There are several reports comparing both techniques'v-' in a retrospective sequential design. They found both techniques to have similar results, but the authors recommended one procedure over the other on the basis of theoretical merits. Proye and coworkers considered the technique less important than the accuracy of indication for operation and the complete

localization of all parathyroid tissue'" because one third to one half of the recurrences arise from an overlooked gland (ectopic or supernumerary, or both) in the neck. Different ways to report results make comparison among the reports of a single technique inappropriate (Table 57-3). In assessing the merit of each technique, one should keep in mind that most authorities find the technique they routinely use and have more experience with to be most appropriate.

Subtotal Parathyroidectomy The success of sPTX depends mainly on the size and viability of the remnant. Remnants that are nodular are more likely to grow and cause recurrent disease. sPTX has the theoretical advantage of inducing less postoperative hypocalcemia because the remnant continues to function. If persistent or recurrent hyperparathyroidism occurs, the gland is in the neck or, exceptionally, in the mediastinum. The main disadvantage is that reoperations are tedious and carry an increased risk of recurrent laryngeal nerve injury. The overall results from large series showed that 10% to 16% had postoperative hypercalcemia, 8% required reoperation because of remnant growth, and 4% to 25 % had hypocalcemia longer than 12 months after operation. Compared with PTX + AT, successful sPTX provided less immediate relief of bone pain but carried less risk of postoperative low-turnover bone disease. ss-s8

514 - - Parathyroid Gland

Total Parathyroidectomy and Autotransplantation AS THE TECHNIQUE OF CHOICE

Success of total PTX and autotransplantation depends mainly on the absence of nodularity of the gland from which the graft is obtained and the number and weight of the fragments implanted. Graft-dependent recurrence is three times higher when implanting a nodular gland instead of a diffusely hyperplastic one.59 Most published series did not consider this as a source of variability and therefore may have had higher recurrence rates than are theoretically possible. The advantage of autotransplantation is that if hyperparathyroidism recurs, the graft can be partially resected under local anesthesia. Nevertheless, reresection may be necessary and sometimes a tumor-like growth develops in the implant, making it difficult to remove. The Casanova test requires total ischemic blockade of the arm bearing the parathyroid graft and measuring PTH levels proximally and distally to the blockade. It is used to assess graft function after PTX + AT or to determine the site of recurrence/" Published series show a 5% to 38% rate of postoperative hypercalcemia, 2% to 6% rate of recurrence requiring graft resection, and 5% to 30% rate of hypocalcemia lasting more than 12 months. 21,49,61-65 AS AN ALTERNATIVE TECHNIQUE

Even surgeons who routinely perform sPTX for SHPT use PTX + AT in some selected cases: when thyroidectomy is necessary because of thyroid disease, when the viability of the remnant is in doubt in sPTX, or when the remnant overgrows and causes recurrence.e'>'

Complications of Parathyroidectomy The mortality after PTX for SHPT is less than 1%.4 Hyperkalemia is the single most preventable cause of death. Infection, cardiac complications not related to hyperkalemia, acute hypocalcemia, pancreatitis, and respiratory complications are other miscellaneous causes of mortality. TRANSIENT HYPOCALCEMIA

Hypocalcemia occurs in 20% to 85% of patients after PTX for SHPT. These patients usually develop the classic symptoms of numbness, paresthesias, and tetany cramps the day after PTX if hypocalcemia is not prevented. The causes of hypocalcemia include increased deposition of calcium in bone ("hungry bone" syndrome), uncoupling of bone formation and resorption." hypoparathyroidism resulting from failure of the parathyroid remnant or autograft, and hypomagnesemia.?" Hypocalcemia is more common in patients with more severe preoperative bone disease and can be anticipated in those with elevated serum levels of alkaline phosphatase." Serum potassium, calcium, phosphate, and magnesium should be carefully monitored. Intravenous calcium gluconate in 10% solution or diluted in 5% dextrose may be needed if the serum calcium falls below 7.5 mg/dL. Once the acute episode is controlled or if the hypocalcemia is mild, oral calcium is given in doses of up to 6 g of elemental calcium per day.24 Phosphate binders should be adjusted to maintain serum phosphate concentration between

3.5 and 5.0 mg/dL. Oral calcitriol (0.5 to 4Ilg/day) should be given in addition to calcium to control hypocalcemia.s? When postoperative hypocalcemia is likely, prophylactic calcium and calcitriol administration can be started before or immediately after surgery. Calcitriol (2 ug) given during dialysis has been used for 5 days before the operation to prevent postoperative hypocalcemia.' Patients receiving peritoneal dialysis can be given intraperitoneal calcium therapy to control hypocalcemia.v Supplementation with elemental magnesium at 1 mEq/kg per day should be started if the serum magnesium concentration drops below 1.5 mg/dL. 24 If not properly treated, hypocalcemia can lead to tetany and convulsions, especially during the later hours of hemodialysis. Hypocalcemic seizures can cause multiple fractures.' PERMANENT HYPOPARATHYROIDISM

The prevalence of permanent hypoparathyroidism varied greatly from 0%48 to 73%2 in early series but is most commonly between 4% and 12%. Parathyroid autotransplants can fail and cause hypocalcemia up to 2 years after surgery.'? It is difficult to assess the exact percentage of hypoparathyroidism because of retrospective analysis and reporting heterogeneity (see Table 57-3). Patients with hypoparathyroidism need vitamin D and calcium supplementation for life. The hypocalcemic symptoms can be exaggerated after a kidney transplantation reversing the acidemia. Hypercalcemia can also occur because of vitamin D intoxication. PERSISTENCE AND RECURRENCE

The prevalence of persistent or recurrent hyperparathyroidism is between 2% and 12%. In one third to one half of the cases, the recurrence is due to an incomplete first operation: less than four glands were found, cervical thymectomy was not performed, or there were supernumerary glands in the neck or mediastinum.P These patients have hypercalcemia, elevated iPTH levels, and persistence or worsening of clinical manifestations. If sPTX was the initial operation, reexploration of the neck and PTX + AT are indicated. If PTX + AT was the initial operation, the Casanova test should be performed. Graft resection or re-exploration of the neck is then indicated, depending on the site of recurrence. In all cases of repeated neck operations, imaging studies should be done to localize the recurrent disease. Reoperations for hyperparathyroidism are treated in detail in another chapter of this book. Some authors suggest that the recurrent tumor can be injected with ethanol under ultrasonographic guidance, but recurrent nerve injury has been reported. 64•69-71

Clinical Course after Successful Parathyroidectomy Clinical Manifestations The overall clinical result is considered good in 70% to 85% of the patients. Bone pain improves in few days in 60% to 80% of patients, joint pain in 85%, and malaise in 75%.4Abdominal pain and irritated eyes are less likely to improve." Muscle weakness is relieved in one third of the patients and radiologic

Surgical Approach to Secondary Hyperparathyroidism - -

signs improve in 95%.48 Itching decreases overnight in almost all patients and disappears in 60% to 80%.4,48 Successful PTX improves nonvisceral calcification in 50% to 60% but does not change arterial calcification despite reduction in the Ca-P product and PTH. Small peripheral arterial calcification may even develop or progress in as many as 56% of the patients after PTX.65

Bone Disease A rapid decrease in serum parathyroid hormone level after PTX appears to suppress bone resorption as well as cause a transient marked increase in bone formation and an increase in normal lamellar osteoid seams." PTX decreases resorption surfaces and osteoclast number as well as bone formation rate." A much debated issue is the development of aluminumrelated osteomalacia after PTX. Some reports showed that PTX did not enhance accumulation of bone aluminum or increase the prevalence of clinical bone disease during dialysis.I" whereas other reports clearly demonstrated aluminum accumulation in bone after PTX.75 If aluminum is available to bone (through ingestion of phosphate binders or through the dialysate) or if there was an aluminum-related bone disease before surgery, it deposits in the low-turnover post-PTX bone. If, however, vitamin D levels are maintained and calcium is available, no low-turnover aluminum-related bone disease should arise. Symptomatic osteomalacia after PTX usually indicates that surgery was unnecessary and that the hypercalcemia was due to aluminum toxicity. The bone mass density of the lumbar spine can be significantly increased with postoperative supplementation with vitamin D and calcium."

Calcium Metabolism Immediately after PTX, serum PTH and calcium concentrations decline abruptly. Serum alkaline phosphatase, usually elevated before surgery, increases in the immediate postoperative period and then declines with time." A strong correlation has been noted between the degree of hypocalcemia after the operation and the level of serum alkaline phosphatase before the operation.?" Circulating levels of calcitriol also decrease after PTX, further contributing to hypocalcemia."

Anemia Anemia improves in CRF patients after PTX.80 PTX increases serum erythropoietin and blood reticulocytes in 50% of the patients. 81,82 Normalizing levels of PTH, extraor intracellular calcium and phosphorus, and increased tissue sensitivity to erythropoietin after PTX could all be responsible." ,83,84

Summary Before kidney transplantation, PTX is indicated when medical treatment fails to control progressive hyperparathyroidism. High PTH levels and high-turnover bone disease

515

are prerequisites for surgically treating this condition. Calciphylaxis is an absolute indication. The main posttransplantation indication is a persistent or symptomatic hypercalcemia. The keys to a successful surgery are to locate all parathyroid glands and leave 40 to 60 mg of viable tissue as a remnant in the neck or as an autotransplant in the forearm. In any case, minute details of the surgical technique influence the outcome. The most frequent postoperative sequel is persistent or recurrent hyperparathyroidism.

REFERENCES 1. Hognestad J, Flatmark A. Hyperparathyroidism in uremia and after kidney transplantation. Scand J Urol Nephrol SuppI1977:137. 2. Lundgren G, Asaba M, Magnusson G, et al. The role of parathyroidectomy in the treatment of secondary hyperparathyroidism before and after renal transplantation. Scand J Urol Nephrol Suppl 1977;(42): 149. 3. Diethelm AG, Edwards RP, Whelchel JD. The natural history and surgical treatment of hypercalcemia before and after renal transplantation. Surg Gynecol Obstet 1982;154:481. 4. Demeure MJ, McGee DC, Wilkes W, et al. Results of surgical treatment for hyperparathyroidism associated with renal disease. Am J Surg 1990; 160:337. 5. Llach F. Parathyroidectomy in chronic renal failure: Indications, surgical approach and the use of calcitriol. Kidney Int Suppl 1990;29:S62. 6. Muirhead N, Catto GR, Edward N, et al. Suppression of secondary hyperparathyroidism in uraemia: Acute and chronic studies. Br Med J (Clin Res Ed) 1984;288:177. 7. DeVita MV, Rasenas LL, Bansal M, et al. Assessment of renal osteodystrophy in hemodialysis patients. Medicine (Baltimore) 1992; 71:284. 8. Malluche HH, Monier-Faugere MC. The role of bone biopsy in the management of patients with renal osteodystrophy. J Am Soc Nephrol 1994;4:1631. 9. Duh QY, Lim RC, Clark OH. Calciphylaxis in secondary hyperparathyroidism. Diagnosis and parathyroidectomy. Arch Surg 1991;126:1213; discussion, 1218. 10. D' Alessandro AM, Melzer JS, Pirsch JD, et al. Tertiary hyperparathyroidism after renal transplantation: Operative indications. Surgery 1989; 106:1049; discussion 1055. 11. Chatterjee SN, Friedler RM, Berne TV, et al. Persistent hypercalcemia after successful renal transplantation. Nephron 1976;17:1. 12. Chatterjee SN, Massry SG, Friedler RM, et al. The high incidence of persistent secondary hyperparathyroidism after renal homotransplantation. Surg Gynecol Obstet 1976;143:440. 13. Christensen MS, Nielsen HE. The clinical significance of hyperparathyroidism after renal transplantation. Scand J Urol Nephrol Suppl 1977;(42):130. 14. Pieper R, Alveryd A, Lundgren G, et al. Secondary hyperparathyroidism and its sequelae in renal transplant recipients. Long term findings in a series of conservatively managed patients. Scand J Urol Nephrol SuppI1977;(42):I44. 15. Parfitt AM. Hypercalcemic hyperparathyroidism following renal transplantation: Differential diagnosis, management, and implications for cell population control in the parathyroid gland. Miner Electrolyte Metab 1982;8:92. 16. David DS, Sakai S, Brennan BL, et al. Hypercalcemia after renal transplantation. Long-term follow-up data. N Engl J Med 1973;289:398. 17. Sitges-Serra A, Esteller E, Ricart MJ, Caralps A. Indications and late results of subtotal parathyroidectomy for hyperparathyroidism after renal transplantation. World J Surg 1984;8:534. 18. Sitges-Serra A, Gores P, Hesse U, et al. Serum calcium as an early indicator for surgical treatment of hyperparathyroidism after renal transplantation. World J Surg 1986; 10:661. 19. Pletka PG, Strom TB, Hampers CL, et al. Secondary hyperparathyroidism in human kidney transplant recipients. Nephron 1976;17:371. 20. Blohme I, Eriksson A. Parathyroidectomy after renal transplantation. Scand J Urol Nephrol SuppI1977;(42):134. 21. Garvin PJ, Castaneda M, Linderer R, Dickhans M. Management of hypercalcemic hyperparathyroidism after renal transplantation. Arch Surg 1985; 120:578.

516 - - Parathyroid Gland 22. Cundy T, Kanis JA. Rapid suppression of plasma alkaline phosphatase activity after renal transplantation in patients with osteodystrophy. Clin Chim Acta 1987;164:285. 23. Clark O. Endocrine Surgery of the Thyroid and Parathyroid Glands. St. Louis, CV Mosby, 1985. 24. Sitges-Serra A, Caralps-Riera A. Hyperparathyroidism associated with renal disease. Pathogenesis, natural history, and surgical treatment. Surg Clin North Am 1987;67:359. 25. Kohri K, Ishikawa Y, Kodama M, et al. Comparison of imaging methods for localization of parathyroid tumors. Am J Surg 1992; 164:140. 26. Gladziwa U, Ittel TH, Dakshinamurty KV, et al. Secondary hyperparathyroidism and sonographic evaluation of parathyroid gland hyperplasia in dialysis patients. Clin Nephrol 1992;38: 162. 27. Takebayashi S, Matsui K, Onohara Y, Hidai H. Sonography for early diagnosis of enlarged parathyroid glands in patients with secondary hyperparathyroidism. AJR Am J RoentgenoI1987;148:911. 28. Takagi H, Tominaga Y, Uchida K, et al. Comparison of imaging methods for diagnosing enlarged parathyroid glands in chronic renal failure. J Comput Assist Tomogr 1985;9:733. 29. Clark OH, Stark DA, Duh QY, et al. Value of high resolution real-time ultrasonography in secondary hyperparathyroidism. Am J Surg 1985; 150:9. 30. Okerlund MD, Sheldon K, Corpuz S, et al. A new method with high sensitivity and specificity for localization of abnormal parathyroid glands. Ann Surg 1984;200:381. 31. Rademaker P, Meijer S, Piers DA. Parathyroid localization by 201TP9mTc subtraction scintigraphy: Results in secondary hyperparathyroidism. Acta Endocrinol (Copenh) 1990;123:402. 32. Torregrosa JV, Fernandez-Cruz L, Canalejo A, et al. (99m)Tcsestarnibi scintigraphy and cell cycle in parathyroid glands of secondary hyperparathyroidism. World J Surg 2000;24: 1386. 33. Duh QY, Sancho n, Clark OH. Parathyroid localization. Clinical review. Acta Chir Scand 1987;153:241. 34. Wei JP, Burke GJ, Mansberger AR Jr. Prospective evaluation of the efficacy of technetium 99m sestamibi and iodine 123 radionuclide imaging of abnormal parathyroid glands. Surgery 1992;112:1111; discussion, 1116. 35. Rossi R, Cady B. Surgery of parathyroid glands. In: Cady B, Rossi RL (eds), Surgery of the Thyroid and Parathyroid Glands, 3rd ed. Philadelphia, WB Saunders, 1991, p 283. 36. Wells SA Jr, Gunnells JC, Shelburne JD, et al. Transplantation of the parathyroid glands in man: Clinical indications and results. Surgery 1975;78:34. 37. Krause MW, Hedinger CEo Pathologic study of parathyroid glands in tertiary hyperparathyroidism. Hum Pathol 1985;16:772. 38. Ohta K, Manabe T, Katagiri M, Harada T. Expression of proliferating cell nuclear antigens in parathyroid glands of renal hyperparathyroidism. World J Surg 1994;18:625; discussion 628. 39. Wallfelt CH, Larsson R, Gylfe E, et al. Secretory disturbance in hyperplastic parathyroid nodules of uremic hyperparathyroidism: Implication for parathyroid autotransplantation. World J Surg 1988; 12:431. 40. Tominaga Y, Tanaka Y, Sato K, et al. Recurrent renal hyperparathyroidism and DNA analysis of autografted parathyroid tissue. World J Surg 1992;16:595; discussion 602. 41. Tanaka Y, Seo H, Tominaga Y, et al. Factors related to the recurrent hyperfunction of autografts after total parathyroidectomy in patients with severe secondary hyperparathyroidism. Surg Today 1993;23:220. 42. Niederle B, Horandner H, Roka R, Woloszczuk W. Morphologic and functional studies to prevent graft-dependent recurrence in renal osteodystrophy. Surgery 1989;106:1043. 43. Kollmorgen CF, Aust MR, Ferreiro JA, et al. Parathyromatosis: A rare yet important cause of persistent or recurrent hyperparathyroidism. Surgery 1994;116:Ill. 44. Chou FF, Lee CH, Chen JB, et al. Intraoperative parathyroid hormone measurement in patients with secondary hyperparathyroidism. Arch Surg 2002;137:341. 45. Proye CA, Goropoulos A, Franz C, et al. Usefulness and limits of quick intraoperative measurements of intact (1-84) parathyroid hormone in the surgical management of hyperparathyroidism: Sequential measurements in patients with multiglandular disease. Surgery 1991;110:1035. 46. Kaye M, D'Amour P, Henderson J. Elective total parathyroidectomy without autotransplant in end-stage renal disease. Kidney Int 1989;35:1390.

47. Ockert S, Willeke F, Richter A, et al. Total parathyroidectomy without autotransplantation as a standard procedure in the treatment of secondary hyperparathyroidism. Langenbecks Arch Surg 2002;387:204. 48. Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy versus total parathyroidectomy and autotransplantation in secondary hyperparathyroidism: A randomized trial. World J Surg 1991;15:745. 49. Rothmund M, Wagner PK. Total parathyroidectomy and autotransplantation of parathyroid tissue for renal hyperparathyroidism. A one- to six-year follow-up. Ann Surg 1983;197:7. 50. Gasparri G, Camandona M, Abbona GC, et al. Secondary and tertiary hyperparathyroidism: Causes of recurrent disease after 446 parathyroidectomies. Ann Surg 2001;233:65. 51. Takagi H, Tominaga Y, Uchida K, et al. Subtotal versus total parathyroidectomy with forearm autograft for secondary hyperparathyroidism in chronic renal failure. Ann Surg 1984;200:18. 52. Welsh CL, Taylor GW, Cattell WR, Baker LR. Parathyroid surgery in chronic renal failure: Subtotal parathyroidectomy or autotransplantation? Br J Surg 1984;71:591. 53. Malmaeus J, Akerstrom G, Johansson H, et al. Parathyroid surgery in chronic renal insufficiency. Subtotal parathyroidectomy versus total parathyroidectomy with autotransplantation to the forearm. Acta Chir Scand 1982;148:229. 54. Proye C, Carnaille B, Sautier M. Hyperparathyroidism in patients with chronic renal failure: Subtotal parathyroidectomy or total parathyroidectomy with autotransplantation? Experience with 121 cases. J Chir (Paris) 1990;127:136. 55. Delmonico FL, Wang CA, Rubin NT, et al. Parathyroid surgery in patients with renal failure. Ann Surg 1984;200:644. 56. Decker PA, Cohen EP, Doffek KM, et al. Subtotal parathyroidectomy in renal failure: Still needed after all these years. World J Surg 2001;25:708. 57. Yu I, DeVita MV, Komisar A. Long-term follow-up after subtotal parathyroidectomy in patients with renal failure. Laryngoscope 1998; 108:1824. 58. Kim HC, Cheigh JS, David DS, et al. Long term results of subtotal parathyroidectomy in patients with end-stage renal disease. Am Surg 1994;60:641. 59. Tominaga Y, Uchida K, Haba T, et al. More than 1,000 cases of total parathyroidectomy with forearm autograft for renal hyperparathyroidism. Am J Kidney Dis 2001;38(4 Suppll):SI68. 60. Casanova D, Sarfati E, De Francisco A, et al. Secondary hyperparathyroidism: Diagnosis of site of recurrence. World J Surg 1991;15:546; discussion 549. 61. Albertucci M, Zielinski CM, Rothberg M, et al. Surgical treatment of the parathyroid gland in patients with end-stage renal disease. Surg Gynecol Obstet 1988;167:49. 62. Benz RL, Schleifer CR, Teehan BP, et al. Successful treatment of postparathyroidectomy hypocalcemia using continuous ambulatory intraperitoneal calcium (CAlC) therapy. Perit Dial Int 1989;9:285. 63. Mozes MF, Soper WD, Jonasson 0, Lang GR. Total parathyroidectomy and autotransplantation in secondary hyperparathyroidism. Arch Surg 1980;115:378. 64. Page B, Zingraff J, Souberbielle JC, et al. Correction of severe secondary hyperparathyroidism in two dialysis patients: Surgical removal versus percutaneous ethanol injection. Am J Kidney Dis 1992;19:378. 65. de Francisco AM, Ellis HA, Owen JP, et al. Parathyroidectomy in chronic renal failure. Q J Med 1985;55:289. 66. Coen G, Mazzaferro S, De Antoni E, et al. Procollagen type I C-terminal extension peptide serum levels following parathyroidectomy in hyperparathyroid patients. Am J Nephrol 1994;14:106. 67. Clair F, Leenhardt L, Bourdeau A, et al. Effect of calcitriol in the control of plasma calcium after parathyroidectomy. A placebo-controlled, double-blind study in chronic hemodialysis patients. Nephron 1987; 46:18. 68. Cattan P, Halimi B, Aidan K, et al. Reoperation for secondary uremic hyperparathyroidism: Are technical difficulties influenced by initial surgical procedure? Surgery 2000;127:562. 69. Giangrande A, Castiglioni A, Solbiati L, Allaria P. Ultrasound-guided percutaneous fine-needle ethanol injection into parathyroid glands in secondary hyperparathyroidism. Nephrol Dial Transplant 1992;7:412. 70. Giangrande A, Castiglioni A, Solbiati L, et al. Chemical parathyroidectomy for recurrence of secondary hyperparathyroidism. Am J Kidney Dis 1994;24:421. 71. Solbiati L, Giangrande A, De Pra L, et al. Percutaneous ethanol injection of parathyroid tumors under US guidance: Treatment for secondary hyperparathyroidism. Radiology 1985;155:607.

Surgical Approach to Secondary Hyperparathyroidism - - 517 72. Yajima A, Ogawa Y, Takahashi HE, et aJ. Changes of bone remodeling immediately after parathyroidectomy for secondary hyperparathyroidism. Am J Kidney Dis 2003;42:729. 73. Charhon SA, Berland YF, Olmer MJ, et al. Effects of parathyroidectomy on bone formation and mineralization in hemodialyzed patients. Kidney Int 1985;27:426. 74. Dahl E, Nordal KP, Halse J, Flatrnark A. Pretransplant parathyroidectomy in renal failure: Effects on bone histology and aluminum deposits during dialysis and after kidney transplantation. Scand J Urol Nephrol 1992;26:283. 75. Felsenfeld AJ, Harrelson lM, Gutman RA, et aI. Osteomalacia after parathyroidectomy in patients with uremia. Ann Intern Med 1982;96:34. 76. Yano S, Sugimoto T, Tsukamoto T, et aJ. Effect of parathyroidectomy on bone mineral density in hemodialysis patients with secondary hyperparathyroidism: Possible usefulness of preoperative determination of parathyroid hormone level for prediction of bone regain. Horm Metab Res 2003;35:259. 77. Urena P, Basile C, Grateau G, et aI. Short-term effects of parathyroidectomy on plasma biochemistry in chronic uremia. Kidney Int 1989;36:120.

78. Chandran PK, Ulahannan TJ, Skiles M. Biochemical changes following parathyroidectomy. Int J Artif Organs 1993;16:700. 79. Fanti P, Smith AJ, Price PA, et aJ. Effects of parathyroidectomy on circulating levels of I alpha, 25-dihydroxyvitarnin D and bone Gla protein in dialyzed patients. J Clin Endocrinol Metab 1986;62:869. 80. Zingraff J, Drueke T, Marie P, et aJ. Anemia and secondary hyperparathyroidism, Arch Intern Med 1978;138:1650. 81. Urena P, Eckardt KU, Sarfati E, et aJ. Serum erythropoietin and erythropoiesis in primary and secondary hyperparathyroidism: Effect of parathyroidectomy. Nephron 1991;59:384. 82. Barbour GL. Effect of parathyroidectomy on anemia in chronic renal failure. Arch Intern Med 1979;139:889. 83. Yasunaga C, Matsuo K, Yanagida T, et aJ. Early effects of parathyroidectomy on erythropoietin production in secondary hyperparathyroidism. Am J Surg 2002;183:199. 84. Washio M, Iseki K, Onoyama K, et aJ. Elevation of serum erythropoietin after subtotal parathyroidectomy in chronic haemodialysis patients. Nephrol Dial Transplant 1992;7:121.

Parathyroid Reoperations Chung Yau Lo, MB, BS(HK), MS(HK), FRCS(Edin), FACS • Jon A. van Heerden, MB, ChB, MS(Surg)[Minn], FRCS(C), FACS

The prospect of an imminent, initial, cervical exploration for biochemically proven hyperparathyroidism (HPT) invariably results in a release of endogenous endorphins in the experienced endocrine surgeon. In stark contrast, the prospect of cervical re-exploration for the same disease, by the same endocrine surgeon, invariably results in an increase in the secretion of fractionated urinary catecholamines. What is the reason for these opposite reactions when operating for the same disease entity in the same anatomic region of the body? In the first instance, the surgeon can accurately predict that the operation will usually be a technically easy one, that the cure rate (return to a normocalcemic state) will be high (>98%) both short and long term, and that the operative procedure will be accompanied by a negligible operative mortality and morbidity.' We have, at times, jokingly stated that the surgical team should in fact reimburse the patient for being allowed to perform the operation. In direct contrast, the surgeon can accurately predict that in a sizable percentage of patients undergoing reoperation, the surgical procedure will be a technically demanding one (a "no-fun case"), that the success rate will be 10% to 15% lower than in the primary procedure, and that the operative and postoperative complications will be considerably higher. It is fairly obvious that there would be no need for reoperative surgical procedures for HPT if the initial exploration was uniformly successful. This is unfortunately not the case, and it behooves all of us to re-examine the causes for initial failed cervical exploration and the overall approach to this challenging group of patients.

Causes of Failed Initial Exploration for Hyperparathyroidism HPT following a prior cervical or mediastinal exploration for hypercalcemia can be divided arbitrarily into persistent (defined as hypercalcemia recurring within 6 months after initial operation) or recurrent (hypercalcemia recurring after 6 months of normocalcemia following initial operationj.i-'

518

The former denotes missed pathology and the latter refers to newly developed pathology. The distinction of these two categories has been loosely applied since it is possible that a physiologically insignificant amount of hyperfunctioning tissue that was present at the first operation could proliferate and produce a biochemical recurrence several years later? It has been estimated that 2% to 10% of surgical failures may be attributed to an incorrect diagnosis." However, this is much less of a problem today with the advent of a reliable radioimmunoassay for intact parathyroid hormone (PTH). In patients with renal disease, PTH clearance is compromised by impaired renal clearance and may lead to spurious elevations of PTH levels if the hormone is measured by assays that fail to detect intact PTH molecular structures. In such circumstances, the measurement of PTH using doubleantibody methods will help resolve this issue. Another, albeit rare, diagnostic pitfall are patients with benign familial hypocalciuric hypercalcemia (BFHH). This disorder is associated with moderate hypercalcemia and normal or slightly elevated blood PTH levels. BFHH can be diagnosed by a positive family history of hypercalcemia at times associated with unsuccessful parathyroid surgery, a 24-hour urinary calcium excretion of less than 100 mg, and the calculated value of calcium-to-creatinine clearance ratio of less than 0.01. 4 Other causes of hypercalcemia (intake of thiazide diuretics or lithium, vitamin D intoxication, sarcoidosis, multiple myeloma, malignancy, and paraneoplastic syndromes) rarely cause confusion today in the diagnosis of primary HPT. This is largely due to the accuracy and sensitivity of the currently available intact PTH assays. In contrast to the incorrect diagnosis of primary HPT, inexperience on the part of the surgeon is a major cause of surgical failure because of the lack of knowledge regarding parathyroid embryology and knowing the usual "hiding places" of the parathyroid glands; the inability to recognize and excise an abnormal gland; failure to recognize and adequately treat multiple gland disease; failure to locate an ectopic gland; the presence of supernumerary glands; errors on frozen section examination; incomplete excision of invasive parathyroid carcinoma; or parathyromatosis (i.e., multiple nodules of hyperfunctioning parathyroid tissue scattered

Parathyroid Reoperations - -

through the neck and mediastinum) due most often to spillage of diseased tissue during removal or rarely due to abnormal embryologic development. The anatomy and embryologic descent of the parathyroid glands are variable in 20% of patients.' Inability to recognize an anomalous location of an abnormal gland or the inability to perform a bloodless, thorough dissection of the neck is a common cause for failed cervical exploration by the inexperienced endocrine surgeon, Although multiple-gland disease accounts for 5% to 15% of patients undergoing initial exploration, up to 37% of patients who come to reoperation have multiple-gland disease rather than a single adenoma. 2,3,6,7 This heterogeneous group of patients includes patients with familial HPT and multiple endocrine neoplasia (MEN) types I and 2. The logistic difficulty in diagnosing some of these rare conditions can be attributed to a negative family history and the disparity of size of the enlarged glands, although all are hypercellular (unequal or asymmetrical hyperplasia). In general, the location and excision of an adenoma, visual identification of all parathyroid glands, and biopsy of a second suspicious gland constitute a safe and effective strategy for most patients with primary HPT undergoing initial operation. In multiple-gland hyperplasia, it is vitally important to adequately reduce the amount of functioning parathyroid tissue to prevent recurrence without being overly aggressive and creating an aparathyroid state with the need for chronic calcium and vitamin D supplementationa regimen that is unpleasant for the patients and that has a poor rate of patient compliance. Subtotal parathyroidectomy (3.5-g1and resection: leaving ±50 mg viable parathyroid tissue) or total parathyroidectomy with immediate forearm reimplantation is considered the treatment of choice for patients with familial HPT.8,9 The incidence of supernumerary ("fifth") glands in 1% to 6% of patients with MEN 1 adds further surgical difficulty. Routine transcervical thymectomy for the possible removal of a supernumerary fifth gland is indicated in all patients with MEN 1. Undoubtedly, failure to identify multiple-gland disease and to remove adequate functioning parathyroid tissue, the presence of supernumerary and ectopic glands, regrowth of remnant glands, or autograft hyperfunction invariably lead to persistent or recurrent hypercalcemia." Despite the success of this approach, there is a steady push toward a more limited, or focused, cervical exploration, often under local anesthesia and increasingly on an outpatient basis.' Considerable interest has been focused on the adoption of minimally invasive approaches including endoscopic, video-assisted, and radio-guided parathyroidectomy for primary HPT.IO,II Application of these techniques depends on an accurate preoperative sestamibi scanning or the use of intraoperative gamma probe technology to locate the adenoma as well as the increasing availability of the intraoperative "quick" PTH assay to confirm surgical success, However, the fact that there are numerous types of minimally invasive parathyroidectomy, and that no firmly established method has been accepted as the standard technique, makes evaluation and comparison with the open approach difficult. 10 These new approaches should be evaluated carefully and compared objectively with the excellent results obtained when surgical expertise alone is used. 1 In addition,

519

these techniques can be applied only to selected patients'<" and have potential pitfalls that could result in surgical failure. 14 Persistent or recurrent HPT occurs in a small but significant proportion of patients after the initial exploration and continues to pose a management dilemma and technical challenge to the surgeon. The newer techniques and technology need to be particularly carefully evaluated in this complex subset of patients with HPT.

Approach to the Reoperative Patient Confirmation of Diagnosis When the initial operation fails to return a patient to the normocalcemic state or if hypercalcemia recurs after initial but temporary postoperative normocalcemia, the patient joins a special selective group of patients quite distinct from patients being considered for primary operation. It is extremely important that the diagnosis of primary HPT be reconfirmed rigorously. The confirmation of primary HPT should be based only on the stringent criterion of elevated, or inappropriately elevated, PTH in the presence of elevated ionized serum calcium. In some instances of suspected primary HPT, another cause for hypercalcemia may be present, such as sarcoidosis, vitamin D excess, metastatic malignant disease, multiple myeloma, and so forth. A repeated careful history taking and physical examination should be conducted. A detailed family history usually helps determine whether multiple-gland disease or BFHH should be suspected. Patients with a positive family history of less severe disease and failed cervical explorations should raise the suspicion of BFHH. A selection of pertinent diagnostic tests should be tailored to the individual patient to confirm or refute the clinical suspicion. When faced with this complex subgroup of patients, the surgeon and the endocrinologist thus need to ask and answer the simple question: "Does this patient have unequivocal primary HPT?"

Evaluation of Indications Versus Risk of Reoperation In a classic study by Purnell and associates" of a large number of patients with asymptomatic HPT being followed without operation, it was clearly demonstrated that 20% developed compelling indications for operation within 5 years. Parathyroidectomy for asymptomatic HPT results in normalization of biochemical values and bone density, and approximately one quarter of those who did not undergo operation did have some progression for periods of up to 10 years. 16 Cervical exploration seems justified in all patients with documented primary HPT since normocalcemia is restored in more than 95% of patients, mortality is nearly nil, and morbidity is rare when the operation is performed by an experienced endocrine surgeon. 1 However, in contrast with patients with primary HPT, this liberal indication should be reconsidered cautiously in patients with recurrent or persistent primary HPT. In the reoperative situation, the obliteration of tissue planes by scar tissue leads to a greater risk of injuring surrounding structures (laryngeal nerve or normal

520 - - Parathyroid Gland multifactorial cardiac risk scheme (Table 58_2).18 In patients with severe underlying cardiovascular diseases as exemplified by high ASA class or Goldman scores, the potential benefit of subjecting the patient to reoperation should be balanced against the surgical risk. It is in this group of selected patients that medical or nonoperative intervention may be considered as an alternative to surgical treatment, albeit rarely.

Review Previous Operative Notes and Pathology Reports

parathyroid glands) and an even higher chance of operative failure compared with the initial exploration. The risk of subjecting a patient to a second surgical procedure that may be an operative failure is frustrating to both the surgeon and patient. The statement, "The second most difficult decision in surgery is to advise operation-the most difficult decision, though, is the one to reoperate!" by Organ is seldom more true than in reoperative parathyroid surgery. Once the diagnosis has been reconfirmed by pertinent laboratory tests, the potential benefit of re-exploration is weighed against the operative risk in the individual patient. Some suggest that patients with asymptomatic mild hypercalcemia with serum calcium levels below 12 mg/dL (normal, 7.9 to 10.1 mg/dL) should be followed up at least 3 to 6 months after failed initial exploration." During this period of observation, initial operative tissue injury will slowly heal, mature, and facilitate subsequent re-exploration. In addition, a small number of patients with apparently failed primary operations revert to a normocalcemic state within a few months after operation and may remain so. This may be due to inadvertent devascularization of the abnormal parathyroid gland during mobilization. Similarly, the decision to reoperate should be considered in conjunction with the objective assessment of operative risk of the patient using the American Society of Anesthesiologists (ASA) physical status classification (Table 58-1) and the Goldman

Once the diagnosis of persistent or recurrent primary HPT is biochemically reconfirmed, indications exist to warrant reoperation, and there is no contraindication to surgery, collection and careful review of all surgical and pathologic information about the initial exploration is mandatory. It is of paramount importance for the surgeon who is to undertake the re-exploration, and not only the endocrinologist, to evaluate the operative dictation regarding the prior exploration. It is important to determine whether the initial operation was thorough enough to conclude that the missing glandes) is most likely in the mediastinum or whether the exploration was of such a nature that, in all likelihood, the offending glands remain in the neck (this is by far the most common occurrence). The previous operative record should be carefully studied, and if there is any uncertainty, the initial operating surgeon should be contacted to clarify the findings. The histopathologic slides of resected specimens should be subjected to review and verification by an experienced endocrine pathologist. The finding of abnormal parathyroid tissue in the first operation may point to inadequate treatment of multiple-gland disease. In many instances, careful and objective assessment of preceding operative and pathologic details can give valuable clues as to the thoroughness of prior exploration, the expected anatomic location of the missing gland, the underlying parathyroid pathology (missing adenoma, hyperplasia, ectopic gland, supernumerary gland, or recurrent carcinoma) and help in the subsequent identification of the abnormal parathyroid glandes).

Parathyroid Reoperations - - 521

Consider Alternative Therapeutic Modalities: Medical Versus Ablative Therapy For patients who are not operative candidates because. of prohibitive medical comorbidity or excessiv~ reopera~lVe morbidity and for those who refuse reoperation, medical therapy and other nonoperative intervention should be considered when there is a compelling indication to treat the hypercalcemic state. Although there is currently no eft:ective medical therapy for primary HPT, adequate hydratlOn~ a furosemide diuretic, and phosphate therapy (as the last choice when not contraindicated) may help to reduce serum calcium levels. Estrogen may also be helpful in postmenopausal women with osteopenia or osteoporosis. Fine-needle aspiration of suspected hyperfunctioning parathyroid tissue to obtain tissue for cytologic examination or fluid for PTH assay can be performed under ultrasonography (US) or computed tomography (CT) guidance. 19,20 This technique ~an, be combined with alcohol ablation of the hyperfunctioning gland" once the lesion has been confirmed ~ither cyto.lo.gically or biochemically. Partial ablation of a smgle remammg enlarged gland may be possible to avoid aparathyroid state." In addition, angiographic ablation of the hyperactive parathyroid gland with ionic contrast material has ~lso bee.n reported." This technique is applicable for poor-risk surgical patients with persistent HPT or those with mediastinal parathyroid adenomas to avoiid me diIan sternotomy. 23 However, the role of nonoperative ablation of hyperfunctioning parathyroid gland is still not well established. Nerve injury has been associated with alcohol injection and no tissue is available for cryopreservation, autotransplantation, or histology. These nonoperative procedures should be reserved for highly selected patients and performed by experts in this specialized area, after in-depth consultation between the surgeon, the endocrinologist, and the radiologist who is to perform the procedure. Close follow-up of serum calcium level is required, and repeat treatments may be necessary because recurrence of hypercalcemia is likely."

Plan Appropriate Cost-Effective Localizing Modalities Although the role of routine preoperative localizing studies in patients with primary HPT undergoing an initial conventional operation remains controversial because of the extremely high success rate achieved by an experienced surgeon without the aid of localizing studies,'? there are clear-cut indications for preoperative localizing studies prior to secondary exploration,2.3.5-8.20,24-29 particularly when the initial exploration was thorough. Localization tests should, however, never be performed to confirm the diagnosis of primary HPT. They should only be performed once the diagnosis of persistent or recurrent primary HPT is reconfirmed and reoperation is deemed feasible. Preoperative localization in such patients may shorten operative time, improve surgical results, and reduce operative complications. In the past, many modalities of noninvasive or invasive imaging were applied preoperatively to localize the parathyroid glands, including barium esophagography, selenomethionine and 1131 scanning, cine-esophagraphy, thyroid

lymphography, and thermography, all with limited success rates. Table 58-3 shows the different preoperative localizing studies currently employed for parathyroid localization with their rates of accuracy in various reported series. 2.3,6,7,20.24-30 For patients who have previously undergone a limited initial cervical exploration, US using a lO-MHz small-part probe often detects a missed cervical gland, o~ on occas~on, a thyroid nodule that may represent an intrathyroidal parathyroid adenoma. This noninvasive, inexpensive m.odality should be employed as t~e initial.loca~izi~g mod~hty ~f choice. A drawback of US IS that visualization behmd air (the trachea) or bone (the clavicles) is extremely limited, and good results are only obtained by an experienced ultrasonographer. Radionuclide isotope imaging with technetium 99m sestarnibi-iodine 123 imaging (TSS) may complement US in detecting abnormal glands in the neck and is particularly useful as an adjunct to US in localizing abnormal parathyroid tissue in patients with mediastinal a~~ singl~gland disease.'? A combination of US and sestamibi sca~ IS recommended as the initial, and perhaps only, preoperatIve localization test in reoperations for suspected parathyroid adenomas." CT scan and magnetic resonance imaging (MRI) should be reserved for patients if both of these imaging techniques have failed and when the abnormal gland is suspected to be located in the mediastinum. Invasive procedures, including selective angiography or selective venous sampling for PTH, should be performed extremely rarely, in highly selected patients, and only if other noninvasive measures fail to localize the abnormal glandes). Figure 58-1 summarizes the algorithm for management of persistent or recurrent primary HPT before reoperation.

Operative Aspects Cervical Exploration At the time of initial cervical exploration, it is generally recommended that ideally all four glands should be identified and the abnormal glandes) be removed. However, in the reoperative situation, the objective is to locate the abnormal gland and remove it without disturbing (and perhaps devascularizing) normal glands. Prolonged attempts to identify

522 - - Parathyroid Gland Persistent/recurrent primary HPT

+ +

Confirm diagnosis

Evaluate operative indications ~

/ No

Yes

Observation

Assess operative risk (ASA and Goldman class)

+

+

/'

~

Low risk

High risk

Localizing studies, assess operative records, review prior pathology

Ablative or medical therapy

+

+

+

Cervical ± mediastinal exploration

FIGURE 58-1. Algorithm for management of persistent or recurrent primary hyperparathyroidism (HPT). ASA = American Society of Anesthesiologists.

normal parathyroid glands embedded in scarred tissue invariably result in their devascularization and destruction. Re-exploration generally returns the surgeon to the neck unless there is compelling evidence in the preoperative evaluation that the missing gland is located in the mediastinum since the neck remains by far the most common site of previously missed glands; in addition, ectopic glands in the superior mediastinal thymus (the second most common site for a missed gland) can almost always be retrieved via a standard cervical incision. A generous incision should be made through the previous operative incision if it is appropriately placed, followed by elevation of ample skin flaps. Exposure via the lateral approach by entering a plane lateral to the strap muscles and medial to the sternal head of the sternocleidomastoid muscle can avoid the scarred median tissue. The tracheoesophageal groove and retrothyroid regions, where most of the missed glands reside, can be entered via this previously undissected plane. The initial exploration should be directed toward those target areas as suggested by localization studies, combined with evaluation of previous operative and pathologic findings. The recurrent laryngeal nerve should be identified whenever possible and traced generously to preserve its integrity once the thyroid gland is reflected medially to expose the retrothyroid area. The commonly found "anomalous" positions of an inferior gland include the posterior or lateral surface of the thyroid gland beneath a thin layer of thyroid capsule, the thyrothymic ligament, and the thymic tongue in the anterosuperior mediastinum. Arrested descent of the inferior parathyroid gland ("parathymus") during embryologic development may leave the gland high in the neck, sometimes as far superiorly as the angle of the mandible.

The inferior gland in this location is thus superior to the superior parathyroid gland. A search along the embryologic descent path of the inferior parathyroid gland should be made from the angle of the mandible to the superior mediastinum. The carotid sheath should be opened and explored. The superior mediastinum can be quite thoroughly explored via the cervical incision, removing a major portion of the thymus gland. For suspected abnormal superior glands, the superior thyroid pedicle should be ligated and divided to facilitate exposure of the posterior aspect of the superior thyroid pole. The retroesophageal area should be thoroughly explored by entering this space immediately superior to the inferior thyroid artery. Inserting a finger into this space toward the posterosuperior mediastinum allows for accurate digital palpation of a space where large glands are often missed by an inexperienced surgeon at the initial operation. A superior gland descending in this groove may thus be located inferior to the inferior parathyroid gland. The contralateral side should be explored in a similar manner if exploration of the first side is negative. If exploration fails after a thorough bilateral search, thyroid lobectomy should be considered on the side of greater suspicion searching for the rare true intrathyroid parathyroid adenoma. Most of these glands can be suspected because of a nodule seen by US. A staged mediastinal exploration can be considered after appropriate mediastinal localization studies have been performed. It is prudent that all suspicious tissue removed be sent for frozen section and that an intraoperative dialogue (correlating the operative findings and histopathology) with an experienced pathologist ensue; this dialogue is crucial.

Mediastinal Exploration The surgeon should be satisfied that a thorough and complete cervical re-exploration has been performed before proceeding to mediastinal exploration unless there is compelling evidence from preoperative localization studies that the missing gland is located in the mediastinum. The mediastinum is entered by a partial or complete sternal split or via a thoracoscopic approach. Once the mediastinum is opened, the search for the parathyroid should begin with the thymus gland. Most mediastinal parathyroid glands are located intrathymically at the level of innominate vein in the anterior superior mediastinum. A small number are situated low in the anterosuperior mediastinum between the thymus and pleura, adjacent to the great vessels along the aortic arch or in the aorticopulmonary window. Occasionally, a missing superior gland may be located in the posterosuperior mediastinum in the retroesophageal space, posterior to the carina, or in the right subpulmonary artery space.

Intraoperative Localization Several intraoperative localization tests, including intraoperative US, methylene blue staining, intraoperative venous sampling for PTH measurement, and gamma probe examination have been described in the reoperative situation. Intraoperative US performed by an experienced radiologist can help guide dissection." It images more abnormal glands than preoperative US and may help locate an intrathyroid or

Parathyroid Reoperations - - 523

retrothyroid parathyroid gland encased in scar tissue or an ectopic gland within the carotid sheath. The use of intraoperative methylene blue injection has not been as helpful in reoperative cases as in initial operations because of the relative nonspecificity of the test.' The rapid intraoperative PTH assay enables the surgeon to perform selective venous sampling intraoperatively and to localize and lateralize an abnormal gland by detecting an increase in PTH level on the side of the tumor. In addition, this technique enables the surgeon to confidently confirm the adequate removal of hyperfunctioning tissue, especially in multiple-gland disease, and improve the overall surgical success rate." Minimally invasive radio-guided parathyroidectomy using the gamma probe allows a directed dissection with a small incision and is associated with a high success rate in patients with positive sestamibi scans requiring reoperation."

Cryopreservation and Autotransplantation Cryopreservation of a portion of excised parathyroid tissue in the reoperative situation has been regarded as stateof-the-art practice to correct postexploration hypocalcemia. A portion of the parathyroid gland is sliced into pieces and cryopreserved for future delayed autotransplantation in the event that the patient develops permanent hypoparathyroidism postoperatively. Controversy exists whether to perform immediate autotransplantation after removal of all parathyroid tissue in the reoperative situation and thus achieve a 90% success rate when using fresh parathyroid tissue in comparison to a 50% success rate when delayed transplantation is employed." However, it is generally advantageous to delay transplantation to observe the biochemical response after operation unless three or four parathyroid glands have already been removed. The presence of a fifth supernumerary gland or the possibility of persistent hypercalcemia makes us cautious about immediate autotransplantation. Although cryopreservation plays an integral role in reoperative parathyroid surgery, the rate of cryopreservation usage is low. and unfortunately not all patients are rendered normocalcemic after autotransplantation of cryopreserved parathyroid tissue."

Brief Review of Results of Reoperative Parathyroid Surgery A summary of results reported by referral centers with extensive experience in parathyroid reoperations is shown in Table 58-4. Some of these results included all patients with persistent or recurrent HPT, but others, such as at the National Institutes of Health, only included patients with sporadic disease and one abnormal gland. From 1989 to 1997 at the Mayo Clinic, 124 patients with benign persistent or recurrent primary HPT underwent 106 cervical explorations (86%), 9 mediastinal explorations alone (7%), and 9 (7%) combined cervical-mediastinal explorations.i" In this series, US had an accuracy of 65%, a sensitivity of 75%, and a positive predictive value of 78%. Sestamibi scanning was accurate in 67% with a sensitivity of 82% and a positive predictive value of 79%. CT scanning of the mediastinum was accurate in 53% and had a sensitivity of 40% and a positive predictive value of 80%. Cure of hypercalcemia was achieved in 88% of patients. Morbidity was incurred in 15% of patients, with permanent hypoparathyroidism accounting for most of the morbidity (89%). Immediate forearm autotransplantation was performed in 13 patients, and 4 (32%) patients remained hypoparathyroid. Delayed autotransplantation was carried out in 4 patients with a 25% graft success rate. Neither cure rates nor operative morbidity have changed appreciably over the past 2 decades despite the application of sestamibi scanning and intraoperative PTH monitoring.P Multiple-gland disease continues to represent the principal cause of failure in reoperative parathyroid surgery and most missed abnormal glands reside in normal anatomic locations. Of the 15 patients who remained hypercalcemic following their reoperative surgery, 11 (73%) had multiple-gland disease based on previous records, histologic examination, and preoperative localization tests. The overwhelming majority of glands removed were in normal anatomic positions (76%) in the neck. Of glands not in a normal position (n = 26), 8 were found in the mediastinum, 7 were intrathyroidal,

524 - - Parathyroid Gland

6 were within the carotid sheath, 3 were anterior to the trachea, and 2 were retroesophageal. The anatomic site of disease at reoperation is well documented in various large series and is shown in Table 58-5.

Although the success rate of reoperation in experienced hands ranges from 82% to 98%, the fact that more than 40% of missing glands were found in normal anatomic positions challenges all surgeons who operate on primary HPT to strive for cure in the primary operation rather than submitting a patient to the risk of a reoperation-or rendering the reoperative endocrine surgeon to chronic excessive catecholamine secretion.

Illustrative Cases

FIGURE 58-2. Ultrasonography of the neck showing a suspicious enlarged parathyroid gland posterior to the lower pole of the right lobe of the thyroid (see Case I).

Parathyroid Reoperations - -

525

Summary Patients with persistent or recurrent PHPT may present a challenge, even for the experienced parathyroid surgeon. Surgeons must reconfirm the diagnosis, consider the risks and benefits of reoperation, and review the operative note(s), pathology report(s), and results of the localization tests. The success rate of reoperation is quite good, especially in a patient whose tumor is identified by the preoperative localization tests, but the complication rate is appreciably higher than during initial parathyroid operations.

REFERENCES

Reoperative Pearls • • • • • • • •

Reconfirm the diagnosis of HPT The surgeon must review prior operative notes Assess patient risk factors Pathologist must re-review prior pathology slides Missed gland usually is in the neck Judicious, cost-effective parathyroid gland localization Consider lateral cervical approach Remember that if the inferior gland is missing, look superior to the superior gland for the inferior gland and, similarly, if the superior gland is the missing one, look inferior to the inferior for the superior gland.

FIGURE 58-3. Radionuclide scintiscan demonstrating a suspicious uptake in the anterior mediastinum near the left main bronchus (see Case 2).

1. van Heerden JA. Endocrine surgery. JAm Coll Surg 1998;186:141. 2. Clark OH, Way LW, Hunt TK. Recurrent hyperparathyroidism. Ann Surg 1976;184:391. 3. Brennan MF, Norton JA. Reoperation for persistent and recurrent hyperparathyroidism. Ann Surg 1985;201:40. 4. Marx SJ, Stock JL, Attie MF, et al. Familial hypocalciuric hypercalcemia: Recognition among patients referred after unsuccessful parathyroid exploration. Ann Intern Med 1980;92:351. 5. Wang C-A. Parathyroid re-exploration: A clinical and pathological study of 112 cases. Ann Surg 1977;186:140. 6. Levin KE, Clark OH. The reasons for failure in parathyroid operations. Arch Surg 1989;124:911. 7. Shen W, Duren M, Morita E, et al. Reoperation for persistent or recurrent primary hyperparathyroidism. Arch Surg 1996;131:861. 8. Hellman P, Skogseid B, Oberg K, et al. Primary and reoperative parathyroid operations in hyperparathyroidism of multiple endocrine neoplasia type I. Surgery 1998;124:993. 9. Kivlen MH, Bartlett DL, Libutti SK, et al. Reoperation for hyperparathyroidism in multiple endocrine neoplasia type I. Surgery 2001; 130:991. 10. Reeve ST, Babidge WJ, Parkyn RF, et al. Minimally invasive surgery for primary hyperparathyroidism: Systematic review. Arch Surg 2000;135:481. 11. Miccoli P. Minimally invasive surgery for thyroid and parathyroid diseases. Surg Endosc 2002;16:3. 12. Perrier ND, Ituarte PH, Morita E, et al. Parathyroid surgery: Separating promise from reality. J Clin Endocrinol MetaboI2002;87:1024. 13. Burkey SH, van Heerden JA, Farley DR, et al. Will directed parathyroidectomy utilizing the gamma probe or intraoperative parathyroid hormone assay replace bilateral cervical exploration as the preferred operation for primary hyperparathyroidism? World J Surg 2002; 26:914. 14. Jaskowiak NT, Sugg SL, Helke J, et al. Pitfalls of intraoperative parathyroid hormone monitoring and gamma probe localization in surgery for primary hyperparathyroidism. Arch Surg 2002;137:659. 15. Purnell DC, Scholz DA, Smith LH, et al. Treatment of primary hyperparathyroidism. Am J Med 1974;56:800. 16. Silverberg SJ, Shane E, Jacobs TP, et al. A lO-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N EnglJ Med 1999;341:1249. 17. Consensus Development Conference Panel. Diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus Development Conference Statement. Ann Intern Med 1991; 114:593. 18. Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med 1977; 297:845. 19. Gooding GA, Clark OH, Stark DD, et al. Parathyroid aspiration biopsy under ultrasound guidance in the postoperative hyperparathyroid patient. Radiology 1985;155:193. 20. Thompson GB, Grant CS, Perrier ND, et al. Reoperative parathyroid surgery in the era of sestamibi scanning and intraoperative parathyroid hormone monitoring. Arch Surg 1999;134:699. 21. Harman CR, Grant CS, Hay ill, et al. Indications, technique, and efficacy of alcohol injection of enlarged parathyroid glands in patients with primary hyperparathyroidism. Surgery 1998;124:1011.

526 - - Parathyroid Gland 22. Miller DL, Doppman JL, Chang R, et al. Angiographic ablation of parathyroid adenomas: Lessons from a IO-year experience. Radiology 1987;165:601. 23. McIntyre RC Jr, Kumpe DA, Liechty RD. Re-exploration and angiographic ablation for hyperparathyroidism. Arch Surg 1994;129:499. 24. Grant CS, van Heerden lA, Charboneau JW, et al. Clinical management of persistent and/or recurrent primary hyperparathyroidism. World I Surg 1986;10:555. 25. Cheung PSY, Borgstrom A, Thompson NW. Strategy in reoperative surgery for hyperparathyroidism. Arch Surg 1989;124:676. 26. Carty SE, Norton IA. Management of patients with persistent or recurrent primary hyperparathyroidism. World I Surg 1991;15:716. 27. Akerstrom G, Rudberg C, Grimelius L, et al. Causes of failed primary exploration and technical aspects of re-operation in primary hyperparathyroidism. World I Surg 1992;16:562. 28. Jarhult I, Nordenstrom I, Perbeck L. Reoperation for suspected primary hyperparathyroidism. Br I Surg 1993;80:453.

29. Weber CI, Sewell CW, McGarity We. Persistent and recurrent sporadic primary hyperparathyroidism: Histopathology, complications, and results of operation. Surgery 1994;116:982. 30. Thompson GB, Mullan BP, Grant CS, et al. Parathyroid imaging utilizing technetium-99m-sestamibi: An initial institutional experience. Surgery 1994;116; 966. 31. Feingold DL, Alexander HR, Chen CC, et al. Ultrasound and sestamibi scan as the only preoperative imaging testes in reoperation for parathyroid adenomas. Surgery 2000;128:1103. 32. Irvin GL III, Molinari AS, Figueroa C, et al. Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Ann Surg 1999;229:874. 33. Norman I, Denham D. Minimally invasive radio-guided parathyroidectomy in the reoperative neck. Surgery 1998;124:1088. 34. Caccitolo lA, Farley DR, van Heerden lA, et al. The current role of parathyroid cryopreservation and autotransplantation in parathyroid surgery. Surgery 1997;122:1062.

Hypoparathyroidism and Pseudohypoparathyroidism Mary Ruppe, MD • Martha A. Zeiger, MD • Suzanne Jan de Beur, MD

Hypoparathyroidism can result from either decreased secretion of parathyroid hormone (PTH) or target organ resistance to PTH. The etiologies of decreased secretion of PTH include the destruction of the parathyroid glands as a complication of head and neck surgery; genetic defects, such as mutations in the PTH or the calcium-sensing receptor genes; developmental defects, such as DiGeorge's syndrome; autoimmune destruction, as in the polyglandular autoimmune endocrinopathies (autoimmune polyendocrinopathy--candidiasisectodermal dystrophy [APECED] syndrome); and infiltrative diseases, such as hemochromatosis or Wilson's disease. In contrast with true hypoparathyroidism, hypocalcemia and hyperphosphatemia in pseudohypoparathyroidism (PHP) is accompanied by an elevated serum level of PTH and results from resistance to the action of PTH rather than to PTH deficiency. The etiology of the hormone resistance observed in this group of related syndromes is a G-protein defect that results in impaired signaling in a variety of receptors, including the PTH receptor. Hypomagnesemia, depending on the severity and duration, may also result in either decreased secretion of or resistance to PTH.

HypoparathyroidismPostsurgical Surgical destruction of the parathyroid glands is the most common cause of hypoparathyroidism. Hypoparathyroidism can occur after any surgical procedure that involves the anterior neck but is most commonly seen as a complication of parathyroid surgery or thyroid surgery, or after extensive resection for head and neck cancer. Trauma to the parathyroid vascular pedicles or inadvertent removal of the glands leads to either transient or permanent hypoparathyroidism. Estimates of the incidence of post-thyroidectomy hypoparathyroidism vary widely, ranging from 6.9% to 46% for transient and 0.4% to 33%\ for permanent hypoparathyroidism. A survey by the American College of Surgeons reported an incidence of hypoparathyroidism following total thyroidectomy of 8%.2 A multicenter prospective trial of

5846 patients undergoing total thyroidectomy revealed an incidence of transient hypoparathyroidism of 7.3% and permanent hypoparathyroidism of 1.5%. J Characteristics of the surgical procedure associated with an increased risk of hypoparathyroidism were a greater extent of surgical resection and central rather than peripheral thyroid artery ligation, the latter of which is less likely to preserve the vascular supply to the parathyroid glands. Following total thyroidectomy, more experienced surgeons report fewer complications, including hypoparathyroidism.' Surgical removal of hyperfunctioning parathyroid tissue often results in transient hypoparathyroidism because the remaining normal parathyroid tissue had been previously suppressed by hypercalcemia. Postsurgical hypoparathyroidism is usually manifest within the first 24 to 48 hours following surgery. Generally, calcium values and parathyroid responsiveness improve within 1 week after surgery. If the preexisting hyperparathyroidism resulted in excessive bone resorption, then a more severe, protracted form of postparathyroidectomy hypocalcemia referred to as "hungry bones" may ensue. Once the PTH-stimulated bone resorption is halted by parathyroidectomy, then calcium and phosphorus are rapidly deposited into the bones, precipitating symptomatic hypocalcemia and hypophosphatemia. Patients with preoperative evidence of parathyroid bone disease such as osteitis fibrosa cystica, resorption of the distal phalanges, an elevated alkaline phosphatase, or those with renal osteodystrophy are at high risk for developing hungry bone syndrome and should be monitored carefully for the development of postoperative hypocalcemia and treated aggressively. Hungry bone syndrome is typically associated with more severe, symptomatic hypocalcemia and may require treatment for several weeks to months before biochemical parameters normalize. An elevated serum PTH level distinguishes hypocalcemia of hungry bones from other forms of post-parathyroidectomy hypocalcemia (Table 59-1). The typical signs and symptoms associated with hypocalcemia are neuromuscular irritability, including perioral or acral paresthesias; muscle cramps that may progress to carpopedal spasm, laryngospasm, bronchospasm, or even

527

528 - - Parathyroid Gland

tetany; and central nervous system deficits as subtle as mood lability or as profound as stupor. Simple bedside maneuvers such as the Chvostek's sign and Trousseau's sign can reveal the presence of neuromuscular irritability. Chvostek's sign is described as circumoral twitching following tapping of the facial nerve. This sign is present in 10% to 30%4 of normal individuals; therefore, if it is to be used as a postoperative marker of hypocalcemia, it is important to verify that it is not present preoperatively. Trousseau's sign is carpal spasm that is elicited after inflation of a blood pressure cuff to 20 mm Hg above the patient's systolic blood pressure for 3 minutes. Severe hypocalcemia may also manifest as prolongation of the QT interval or nonspecific changes on an electrocardiogram. Treatment decisions for postoperative hypoparathyroidism are based on the degree of hypocalcemia, the rapidity of its development, and severity of the symptoms. In severe cases (calcium level < 7.5 mg/dL or severe symptoms), intravenous administration of calcium salts is required. A recommended approach includes using 10 ampules of calcium gluconate (90 mg of elemental calcium per lO-mL ampule) in I L of 5% dextrose with an initial infusion rate of 100 mL/hour. With frequent monitoring of serum calcium levels (usually every I to 2 hours), the infusion rate is titrated to keep the calcium level in the low-normal range. Once stabilized, the patient may be converted to a regimen of oral calcium and calcitriol as described later. If the patient is asymptomatic with mild hypocalcemia (7.5 to 8.5 mg/dL), oral therapy consisting of up to 1000 mg of elemental calcium every 6 hours and 0.25 to 2.0 ug/day of calcitriol [I,25-(OH)z]vitamin D3 should be instituted. As with intravenous therapy, the oral doses can be titrated to keep the calcium in the low-normal range. Magnesium levels should be monitored and repleted because hypomagnesemia results in both impaired PTH secretion and PTH resistance. In most cases, treatment with calcium and vitamin D is short term and necessary only until the residual parathyroid tissue begins to function.

Pseudohypoparathyroidism PHP is a heterogeneous group of disorders characterized by hormone resistance-the hallmark of which is PTH resistance. Typically, these patients present with hypocalcemia and hyperphosphatemia that is due to impaired target tissue responsiveness to PTH rather than PTH deficiency. Two genetically distinct forms of PHP type I have been described. The more common variant, termed PHP type La, is an autosomal dominant disorder with resistance to multiple

hormones (PTH, thyroid-stimulating hormone, luteinizing hormone, gonadotropin hormone-releasing hormone) and a constellation of developmental defects termed Albright's hereditary osteodystrophy (AHO). These defects include short stature, obesity, round facies, brachymetacarpia, subcutaneous ossification, and mental deficiency.' Patients with PHP type Ia have mutations in maternal GNASl alleles that abrogate expression or activity of G; the heterotrimeric G protein that couples receptors to activation of adenylyl cyclase." Identical mutations in paternal alleles are associated with AHO and normal hormone responsiveness, a variant termed pseudo-pseudohypoparathyroidism (PPHP).7 PHP type lb is a less common and clinically distinct variant of PHP that has also been linked to the GNASllocus. 8.9 Subjects with PHP Ib lack features of AHO, show renal resistance to PTH as the only manifestation of hormone resistance, and have normal Gsa activity in tissue. PHP Ib arises as a result of an imprinting defect that affects expression of GNASl in the proximal renal tubule and is the basis for this disorder. Specifically, patients with PHP lb have paternal-specific patterns of cytosine methylation within differentially methylated regions of maternally inherited GNASl alleles.'? The specific genetic mutation(s) that accounts for this methylation defect is unknown. Biochemically, PHP l a and lb lead to functional hypoparathyroidism. Laboratory evaluation reveals hypocalcemia, hyperphosphatemia, and elevated levels of PTH (Table 59-2). In addition, individuals with PHP la may also manifest biochemical evidence of hypothyroidism, gonadotropin resistance, and growth hormone deficiency. In contrast, individuals with PPHP do not exhibit hormone resistance and have normal calcium, phosphorus, and PTH levels. Confirmation of the diagnosis of PHP l a or lb can be accomplished by monitoring urinary cyclic adenosine monophosphate and phosphate excretion following infusion of PTH. 11 Although a reliable diagnosis of PHP Ia may be made on clinical grounds, the molecular genetic diagnosis of PHP l a requires identification of heterozygous inactivating mutations in GNASl. This genetic test is now available at several centers. There is currently no commercially available genetic test for PHP lb. The basic principles associated with the treatment of PHP are similar to those for postoperative hypoparathyroidism, with the mode of treatment being dictated by the severity of the hypocalcemia, the rapidity of development of the hypocalcemia, and the presence of signs and symptoms of hypocalcemia. Intravenous infusion of calcium is required in patients with acute hypocalcemic crises. Long-term maintenance therapy consists of oral administration of calcium and vitamin D.

Hypoparathyroidism and Pseudohypoparathyroidism - -

Summary Hypoparathyroidism is most commonly caused by surgery for parathyroid disease, thyroid disease, or extensive head and neck tumors. Patients with hypoparathyroidism often display signs and symptoms of hypocalcemia and exhibit diminished serum calcium, elevated serum phosphorus, and reduced serum PTH. In contrast, patients with the rare disorder PHP manifest functional hypoparathyroidism with hypocalcemia and hyperphosphatemia, yet they exhibit elevated PTH levels due to PTH resistance rather than PTH deficiency. The basis of the PTH resistance is decreased Gsa activity, resulting in impaired signaling through a number of hormonal receptors, including the PTH receptor. Severe hypocalcemia resulting from any cause can be life threatening; therefore, establishing the appropriate diagnosis and initiating prompt therapy are critical. Close monitoring is indicated to determine if long-term therapy is necessary.

REFERENCES I. Thomusch 0, Machens A, Sekulla C, et al. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: A multivariate analysis of 5846 consecutive patients. Surgery 2003; 133:180. 2. Foster RS. Morbidity and mortality after thyroidectomy. Surg Gynecol Obstet 1978;146:423.

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3. Sosa J, Bowman H, Tielsch 1. The importance of surgeon experience for the clinical and economic outcomes from thyroidectomy. Ann Surg 1998;228:320. 4. Hoffman E. The Chvostek sign: A clinical study. Am J Surg 1958: 96:33. 5. Albright F, Burnett CH, Smith PH. Pseudohypoparathyroidism: An example of "Seabright-Bantam syndrome." Endocrinology 1942: 30:922. 6. Patten JL, Johns DR, Valle D, et al. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright's hereditary osteodystrophy. N Engl J Med 1990;322:1412. 7. Levine MA, Jap TS, Mauseth RS, et al. Activity of the stimulatory guanine nucleotide-binding protein is reduced in erythrocytes from patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism: Biochemical, endocrine, and genetic analysis of Albright's hereditary osteodystrophy in six kindreds. J Clin Endocrinol Metab 1986;62:497. 8. Juppner H, Schipani E, Bastepe M, et al. The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20qI3.3. Proc Nat! Acad Sci USA 1998;95: 11798. 9. Jan de Beur SM, O'Connell JR, Peila R, et al. Refinement of the pseudohypoparathyroidism type Ib locus to a region including GNASI at 20q13.3. J Bone Miner Res 2003;18:424. 10. Liu J, Litman D, Rosenberg MJ, et al. A GNASI imprinting defect in pseudohypoparathyroidism type lB. J Clin Invest 2000;106:1167. II. Mallette LE, Kirkland JL, Gagel RF. Synthetic human parathyroid hormone (1-34) for the study of pseudohypoparathyroidism. J Clin Endocrinol Metab 1988;67:964.

Cryopreservation of Parathyroid Tissue Andrew Saxe, MD • Glenn Gibson, BA

Historical Aspects

Technical Issues

The earliest English language reference to cryopreserving parathyroid tissue that we have been able to establish is by Blumenthal and Walsh in 1950. 1 Their study was designed to evaluate the histologic appearance of previously frozen thyroid autotransplants in guinea pigs. They compared autotransplants with and without thyrotropin and preservation at -70°C with preservation at -190°C. They concluded that the lower temperature better preserved thyroid architecture. In a single preparation, however, a parathyroid gland previously maintained at -70°C appeared "well preserved" and "similar to a parathyroid observed in a control autotransplant." The study did not include functional analysis of the frozen thyroid or parathyroid tissue. To facilitate studies of the emerging science of cryobiology, Russel and colleagues- investigated technical aspects of cryopreserving tissue. They recognized the need for a functional assessment of success and used parathyroid tissue because they could measure reversal of hypocalcemia in parathyroidectomized rats. They emphasized the value both of using glycerol as a cryoprotectant and of a slow, -1°C/min freezing rate. Their work was repeated by Huggins and Abo.' who emphasized the importance of removing the cryoprotectant after thawing and before reimplantation. The "modem" era of clinically applicable parathyroid cryopreservation was ushered in by Wells and Christiansen." They were able to demonstrate in rats that parathyroid tissue frozen at -1°C/min in autologous serum and dimethyl sulfoxide (DMSO) as a cryoprotectant could function as assessed by restoration of normocalcemia and return of hypocalcemia on removal of the transplant. For a more complete discussion of other investigators' contributions to the history of developing clinically useful parathyroid cryopreservation, the reader is referred to reviews by Saxe' and Niederle and colleagues.f

Saxe and coworkers 7 explored methodologic aspects of cryopreserving human parathyroid tissue. They quantitated the rate of freezing of parathyroid tissue under a variety of conditions, including placing tissue directly into vaporphase liquid nitrogen, directly into a -70°C freezer, into a programmable freezer, and into an ethanol bath placed in a -70°C freezer. They demonstrated that when using the inexpensive ethanol bath method, the freezing rate was influenced by the volume of ethanol but not by the number of vials being frozen or by the mass of tissue within each cryopreservation vial (100 mg tissue versus 200 mg tissue per vial). By measuring the in vitro viability of cell suspensions derived from patients' samples maintained as long as 50 months, they concluded that there was no difference in cell viability between fresh tissue and tissue frozen by any technique that used a -1°C/min freezing rate. Wagner and colleagues" demonstrated increased necrosis of parathyroid tissue frozen at -2°C/min compared with that of tissue frozen at -1°C/min. Saxe and coworkers 7 also found no difference in viability among samples from the same patient assessed at varying times after cryopreservation and no difference in viability between cryopreserved adenoma and hyperplastic parathyroid tissue.

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Our Current Cryopreservation Technique Tissue is harvested in the operating room as promptly as possible and placed immediately in chilled, sterile RPMI-I640 culture medium for transport to the laboratory. If medium is not available, saline is a better alternative than water. Under a laminar flow hood, using sterile technique, tissue is bathed in chilled RPMI-I640 in a Petri dish on ice, and adherent fat and capsule are stripped from the parathyroid parenchyma. The tissue is divided (freehand) into cubes,

Cryopreservation of Parathyroid Tissue - -

approximately 1 to 2 mm per side. Two solutions are prepared on ice in separate test tubes: 20% (by volume) solutions of autologous serum and of DMSO in RPMI-1640. These can be conveniently prepared by placing 4 mL of RPMI -1640 in each of two test tubes on ice and adding 1 mL of autologous serum to the first and 1 mL of DMSO to the second. If large amounts (several grams) of tissue are to be cryopreserved, 2 mL of serum or DMSO added to 8 mL of RPMI-I640 is suggested. Before introducing tissue to the vial, 0.6 mL of the 20% serum solution is added to each 2.0-mL cryopreservation vial (Coming, Coming, NY) on ice. Approximately 20 pieces of tissue are added to each cryopreservation vial while the vials are kept on ice. After tissue has been placed in all vials, 0.6 mL of the 20% DMSO solution is added to each vial in the same order so that chilled DMSO is added to tissue that has been chilled by the 20% serum RPMI1640. Vials are mixed by gentle agitation and then left on ice for 5 minutes. If fewer than 18 vials are to be stored, we now use a Mr. Frosty Cryo 1°C Freezing Container (Nalge, Rochester, NY) by adding 250 mL of chilled isopropyl alcohol (kept overnight in a 4°C refrigerator) to the reservoir and placing the device in a -70°C freezer overnight. At a convenient time the next day, we transfer the vials for longterm storage in a -135°C freezer. If an electric -135° freezer is not available, storage in vapor-phase nitrogen is satisfactory. If more than 18 vials are to be stored, we place the vials in a test tube rack that is placed in a metal pan with internal dimensions of approximately 29 x 18 em, to which is added 1000 mL of chilled (4°C refrigerator overnight) ethanol. The pan volume-ethanol ratio does influence freezing rate. The pan is covered with aluminum foil and placed in a -70°C freezer overnight.

Our Technique for Thawing the Tissue A tube of 20% patient's serum (by volume) in RPMI-I640 is prepared as previously discussed and placed on ice. Cryopreservation vials are removed from the long-term storage freezer and placed in a 37°C water bath. The vials are gently agitated until the ice has nearly completely melted and only a core of frozen RPMI-I640 remains. At that point, the vial is opened and 0.5 mL of freshly prepared serum-RPMI-1640 solution is added. The vial is returned to the water bath and agitated until the ice crystal is completely melted. Then, 0.5 mL of the liquid vial contents is aspirated with a sterile pipette and replaced with 0.5 mL of fresh serum-RPMI-I640. The vial is now placed on ice and the cycle of aspirating vial contents and replacing with fresh serum-RPMI-I640 is repeated three times. The intention is to dilute the DMSO while the tissue remains chilled. After the vial contents have been exchanged four times, the tissue is removed, placed in a fresh container with fresh RPMI1640, and kept on ice until used. If the tissue is to be used as an autotransplant, a piece is submitted for bacteriologic culture and for frozen section to confirm its identity as parathyroid. We have given patients perioperative antibiotics prophylactically. Using blunt dissection, several pockets are created in the selected muscle and then observed for hemostasis. In an absolutely dry pocket, 5 to 10 pieces of gland tissue are inserted, and the pocket

531

is closed with nonabsorbable material that can serve as a marker for relocating the pocket if necessary. We believe that a hematoma in the pocket may interfere with revascularization of the tissue fragments. Typically, 20 pieces of tissue are transplanted. Almost certainly, some cases of graft failure are due to transplantation of insufficient viable tissue. At present, however, there is no rapid method for assessing the function of cryopreserved tissue on a "per unit mass" basis and no practical method, therefore, for determining the correct number of pieces to be placed in the muscle pockets.

Variations of Cryopreservation Variations on this technique of cryopreservation have been introduced periodically. Basile and colleagues? reported successfully cryopreserving rat parathyroid tissue and, in a single case, human parathyroid tissue using Waymouth's solution in place of RPMI-I640 and placing cryopreservation vials with tissue into a -80°C freezer (without chilled ethanol) for 16 hours before long-term storage in liquid nitrogen. Kapur and associates'? placed rat parathyroid tissue in 15% DMSO-Hanks basic salt solution in a -20°C freezer for 24 hours and were able to demonstrate function in 7 of 10 animals that underwent autotransplantation with cryopreserved tissue. The rates of viability of cryopreserved parathyroid tissue in vitro and in vivo are displayed in Table 60-1.

Evaluation of Function Assessing the function of transplants with fresh parathyroid tissue can be difficult because normocalcemia attributed to transplanted tissue may be due to residual in situ parathyroid tissue. Evaluating the function of cryopreserved transplants is usually more straightforward because patients receive cryopreserved grafts only for well-established hypoparathyroidism. In this setting, one may reasonably consider that return of serum calcium, parathyroid hormone, or urine cyclic adenosine monophosphate (cyclic AMP) toward normal after these transplants is a reflection of successful cryopreservation. Clinical results with cryopreserved autotransplants are displayed in Table 60-2. Several studies also provide confidence that cryopreserved parathyroid tissue retains the same (but not necessarily normal) physiology that it displays in the fresh state (Table 60-3). Several investigators have demonstrated preservation of calcium-mediated suppression of parathyroid hormone (Fig. 60_1).11.15 McHenry and coauthors" reported that parathyroid tissue cryopreserved as tissue pieces better preserved calcium-mediated suppression than the same tissue first dispersed and cryopreserved as cell suspensions. Wagner and colleagues'? found that cryopreservation preserved the parathyroid hormone secretory rate (parathyroid hormone release per 105 viable cells) but that the number of nonviable cells varied with both freezing rate and other poorly understood factors. Saxe and Gibson" found no difference between fresh and cryopreserved human parathyroid tissue with respect to lithium-stimulated tritiated thymidine incorporation. On the other hand,

532 - - Parathyroid Gland

Hetrakul and coworkers'? reported loss of mitochondrial activity as assessed by sestamibi uptake in cryopreserved versus fresh human parathyroid tissue. Although few studies have been designed to address the question directly, there is evidence from several investigators that the length of storage does not affect the viability or function of cryopreserved parathyroid tissue.4 ,7,1I,1 Z,15, 18-Z3 It appears that tissue is lost during the freezing and thawing processes rather than by attrition during storage.

Indications for Transplantation with Cryopreserved Tissue The indications for autotransplantation with cryopreserved tissue are straightforward: persistent, "permanent" hypocalcemia in patients for whom cryopreserved tissue is available. There is no fully agreed-on definition of permanent hypocalcemia; however, dependence on oral calcium and vitamin D

Cryopreservation of Parathyroid Tissue - -

for 6 months seems reasonable. Patients with disabling symptoms may undergo transplantation sooner," Measurement of parathyroid hormone to distinguish postoperative parathyroid hormone deficiency from "bone hunger" is warranted before the physician embarks on autotransplantation. Although routine cryopreservation is difficult to justify because of the low incidence of postoperative hypocalcemia, surgeons managing patients at higher risk for hypocalcemia should be knowledgeable about techniques of cryopreservation and parathyroid transplantation, and their institutions should have appropriate facilities. An informal survey of several clinical investigators reported rather similar impressions: resected parathyroid tissue is cryopreserved, if ever, only from patients at high risk for postoperative hypoparathyroidism, and only a handful of patients have undergone autotransplantation with cryopreserved tissue. As discussed in Chapter 59, patients well recognized as being at higher risk for postoperative hypoparathyroidism are those undergoing

IN VITRO PTH RELEASE BY HUMAN PARATHYROID CELLS 100

0--0 FRESH (n = 5)

::J'

~

<

::E 75

o-

6 CRYOPRESERVED (n = 5)

\

~

::E

\

u.. 50

0

L\ 'I

~ ~

::I: 25 lo,

0.4

"

-6

0.8 Ionized Ca++[mM]

FIGURE 60-1. Comparison of suppression of parathyroid hormone (PTH) release in vitro in both fresh tissue (0) and after 20 to 220 days of cryopreservation of tissue (l»; mean of five patients at each point. (From Brennan MF, Brown EM. Prediction of in vivo function of human parathyroid tissue autografts by in vitro testing. World J Surg 1980;4:748.)

533

reoperative thyroid surgery, those who have multiple hyperplastic parathyroid glands resected, and those undergoing reoperation for persistent or recurrent hyperparathyroidism.

Thyroid Disease Transplantation with cryopreserved tissue does not playa role in either primary or secondary operations for thyroid disease. Recognition that parathyroid tissue has become devascularized warrants immediate transplantation of the tenuous parathyroid to the sternocleidomastoid muscle. Frozen section analysis of a small piece of the tissue to be transplanted is mandatory. As pointed out by Lahey.>' it can be difficult to distinguish a lymph node with metastatic thyroid cancer from a parathyroid gland.

Multiple-Gland Disease: Initial Surgery Multiple-gland disease can be anticipated in patients with multiple endocrine neoplasias, familial disease, and secondary hyperparathyroidism. Two surgical strategies are widely used: (1) subtotal (3.5-gland excision) parathyroidectomy leaving tissue attached to its native blood supply and (2) total parathyroidectomy and autotransplantation to forearm muscles or subcutaneously. Regardless of the strategy selected, cryopreservation of resected parathyroid tissue as a backup is warranted. Autotransplantation with fresh tissue is not uniformly successful, as reflected by an incidence of postoperative hypoparathyroidism of approximately 10% in patients undergoing total parathyroidectomy with immediate autotransplantation.' Autotransplantation with biopsy-proven cryopreserved tissue offers the patient a second chance to be free from calcium supplements.

Reoperative Parathyroid Surgery An important part of planning reoperative parathyroid surgery is the review of operative and pathology notes by the surgeon and the review of resected tissue by a pathologist. Should it be determined that the patient's only functioning parathyroid tissue is a single remaining adenoma, resection with immediate transplantation of a portion of the adenoma and

534 - - Parathyroid Gland

cryopreservation of the remaining tissue are preferred over angiographic ablation. Another situation that may be anticipated by a review of operative documents and histologic slides is that of reoperation for multiple-gland disease. Saxe and Brennan" reported a 54% incidence of spontaneous normocalcemia and a 12% incidence of persistent hypercalcemia in 26 such patients who underwent attempted total parathyroidectomy without immediate autotransplantation. Of particular interest were 13 patients who had histologically documented four-gland resections. Fully 69% of those patients remained normocalcemic (seven patients) or hypercalcemic (two patients) without calcium supplementation or autotransplantation. This indicates that in this setting even patients undergoing intentional removal of all parathyroid tissue may (unpredictably) have residual tissue. The seven normocalcemic patients might well have become hypercalcemic had they received immediate autotransplants. The authors concluded that for patients undergoing intentional "total parathyroidectomy" at reoperation for multiple-gland disease, a prediction of inevitable hypocalcemia is unwarranted and immediate autotransplantation with fresh tissue is unwise. They recommended restricting autotransplantation (with cryopreserved tissue) to patients with documented hypoparathyroidism.

Research Cryopreservation of parathyroid tissue has utility beyond autotransplantation for treatment of hypoparathyroidism. Research using parathyroid tissue can be facilitated by harvesting tissue on the day of resection for use at a time convenient to the investigator. Access to a "bank" of cryopreserved tissue frees the investigator from the vagaries of the operating room schedule and permits accumulation of masses of tissue sufficient to perform complex experiments. It also permits comparison of several patients' tissues in a single experiment as well as the same patient's tissue in several experiments. Cryopreserved tissue has been used in the investigation of several aspects of physiology: comparison of hormone release in adenoma versus hyperplasia," effect of lithium on thymidine incorporation," parathyroid immunology.Pr" effect of cimetidine on hormone secretion.i? effect of phorbol ester on hormone secretion," mitochondrial incorporation

of sestamibi.!? and generation of microcapsules of parathyroid tissue.'? In general, cryopreservation appears to preserve parathyroid function, although there does appear to be a difference in preservation of estrogen receptors in fresh versus cryopreserved human parathyroid tissue (Table 60-4),31 For in vitro experiments, we have used the following protocol for preparation of cell suspensions. Thawed tissue is placed in 10 mL of a 0.5-mg/mL collagenase (Boehringer Mannheim, Indianapolis, IN) in RPMI-I640 solution. The culture tube containing the tissue is placed in a 37°C shaking water bath and agitated gently (92/min) for 30 to 60 minutes. Because the viability of cryopreserved cells is variable, we have used an additional step to remove necrotic cells and enrich the proportion of viable cells. A stock solution of isotonic Percoll (Pharmacia, Uppsala, Sweden) is made by mixing Percoll with lOx phosphate-buffered saline (PBS). Working solutions of 25% and 75% stock solutions are made by dilution in PBS. In a 12- x 75-mm culture tube, 1.5-mL portions of the 25% and 75% stock solutions are added below the parathyroid cell suspension using a spinal needle, and the tube is centrifuged at 450 g for 15 minutes. The superficial 0.5 mL containing debris and necrotic cells is discarded. Of the remaining Percoll gradient, 1.5 mL is aspirated, diluted with 3.5 mL of culture medium, recentrifuged, and resuspended in whatever solution is to be used for the experiment.

Conclusion In conclusion, techniques for preparing and transplanting cryopreserved parathyroid tissue have been presented. Surgeons who perform parathyroid surgery should be familiar with these techniques. The success rate of using this technique is about 70% (see Table 60-2) versus better than 90% with autotransplantation of fresh parathyroid autografts.

REFERENCES I. Blumenthal HT, Walsh LB. Survival of guinea pig thyroid and parathyroid autotransplants previously subjected to extremely low temperatures. Proc Soc Exp BioI Med 1950;73:62. 2. Russel PS, Wood ML, Gittes RF. Preservation of living tissue in the frozen state: A study using parathyroid tissue. J Surg Res 1961; I:23. 3. Huggins CE, Abo S. Preservation of rat parathyroid glands by freezing. In: Norman JC (ed), Organ Perfusion and Preservation. New York, Appleton-Century-Crofts, 1968, p 739.

Cryopreservation of Parathyroid Tissue - 4. Wells SA, Christiansen C. The transplanted parathyroid gland: Evaluation of cryopreservation and other environmental factors which affect its function. Surgery 1974;75:49. 5. Saxe A. Parathyroid transplantation: A review. Surgery 1984;95:507. 6. Niederle B, Roka R, Brennan ME The transplantation of parathyroid tissue in man: Development, indications, technique, and results. Endocr Rev 1982;3:245. 7. SaxeAW, Gibson GW. Kay S. Characterization of a simplified method of cryopreserving human parathyroid tissue. Surgery 1990;108:1033. 8. Wagner PK, Seesko HG, Rothmund M. Replantation of cryopreserved human parathyroid tissue. World J Surg 1991;15:751. 9. Basile C, Drueke T, Lacour B, et al. Total parathyroidectomy and delayed autotransplantation using a simplified cryopreservation technique: Human and animal studies. Am J Kidney Dis 1984;3:366. 10. Kapur MM, Mehta SN, Moulik BK, et al. Parathyroid preservation and transplantation. Indian J Med Res 1976;64: 1793. II. Herrera MF, Grant CS, van Heerden JA, et al. The effect of cryopreservation on cell viability and hormone secretion in human parathyroid tissue. Surgery 1992;112:1096. 12. Wagner PK, Rumpelt HI, Krause U, et al. The effect of cryopreservation on hormone secretion in vitro and morphology of human parathyroid tissue. Surgery 1986;99:257. 13. Saxe AW. The effect of phorbol ester on in vitro release of parathyroid hormone from abnormal human parathyroid cell. Surgery 1987;102:932. 14. Brennan MF, Brown EM. Prediction of in vivo function of human parathyroid tissue autografts by in vitro testing. World J Surg 1980;4:747. 15. McHenry CR, Stenger DB, Calandro NK. The effect of cryopreservation on parathyroid cell viability and function. Am J Surg 1997;174:481. 16. Saxe AW, Gibson G. Lithium increases tritiated thymidine uptake by abnormal human parathyroid tissue. Surgery 1991;110:1067. 17. Hetrakul N, CivelekAC, Stagg CA, Udelsman R. In vitro accumulation of technetium 99m-sestamibi in human parathyroid mitochondria. Surgery 200 I; 130:10II. 18. Goudet P, Cougard P, Zeller V, et al. Transplantation of human cryopreserved adenomatous and hyperplastic parathyroid tissue to the hypocalcemic nude mouse. World J Surg 1993;17:628. 19. Brennan MF, Brown EM, Spiegel AM, et al. Autotransplantation of cryopreserved parathyroid tissue in man. Ann Surg 1979;189:139. 20. Rothmund M, Wagner PK. Assessment of parathyroid graft function after autotransplantation of fresh and cryopreserved tissue. World J Surg 1984;8:527. 21. Saxe AW, Spiegel AM, Marx SJ, et al. Deferred parathyroid autografts with cryopreserved tissue after reoperative parathyroid surgery.Arch Surg 1982;117:538. 22. Smeds S, Trulsson L, Garovoy M, et al. Survival of human parathyroid tissue xenotransplanted in nude mice after 9 to 55 months' cryopreservation. APMIS 1999;107:445. 23. Tanaka Y, Fuahashi H, Imai T, et al. Functional and morphometric study of cryopreserved human parathyroid tissue transplanted into nude mice. World J Surg 1996;20:692. 24. Lahey PH, The transplantation of parathyroids in partial thyroidectomy. Surg Gynecol Obstet 1926;42:508. 25. Saxe AW, Brennan MF. Reoperative parathyroid surgery for primary hyperparathyroidism caused by multiple-gland disease: Total

26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

43. 44.

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parathyroidectomy and autotransplantation with cryopreserved tissue. Surgery 1982;91:616. Brown EM, Gardner DG, Brennan MF, et al. Calcium-regulated parathyroid hormone release in primary hyperparathyroidism: Studies in vitro with dispersed parathyroid cells. Am J Med 1979;66:923. Saxe A, Gibson G, Elfont E. In vitro assessment of parathyroid immunogenicity: The effect of cryopreservation. Surgery 1990; I08:56. Martin L, Viennet G, Racadot E, et al. Antigenicite des adenomes parthyroidiens humains frais, cryopreserves et conserves en milieu liquide. Pathol BioI (Paris) 1998;46:315. Saxe AW, Chen SL, Marx SJ, et al. In vitro studies of parathyroid hormone release: Effect of cimetidine. Surgery 1982;92:793. Kobayashi S, Amano J, Minoru F, et al. Microcapsulated parathyroid tissue in vitro. Biomed Pharmacother 2000;54(Suppl 1):66. Saxe AW, Gibson GW, Russo IH, et al. Measurement of estrogen and progesterone receptors in abnormal human parathyroid tissue. Calcif Tissue Int 1992;51:344. Walgenbach S, Rosniatowski R, Bittinger F,et al. Modified cryopreservation and xenotransplantation of human parathyroid tissue. Langenbecks Arch Surg 1999;384:277. Brennan MF, Brown EM, Sears HF, et al. Human parathyroid cryopreservation: In vitro testing of function by parathyroid hormone release. Ann Surg 1978;187:87. Ulrich F, Steinmuller T, Rayes N, et al. Cryopreserved human parathyroid tissue: Cell cultures for in vitro testing of function. Transplant Proc 2001;33:666. Leight GS, Parker GA, Sears HF, et al. Experimental cryopreservation and autotransplantation of parathyroid glands: Technique and demonstration of function. Ann Surg 1978;188:16. Sonoda T, Ohkawa T, Takeuchi M, et al. Successful parathyroid preservation: Experimental study. Surgery 1968;64:791. Caccitolo JA, Farley DR, van Heerden JA, et al. The current role of parathyroid cryopreservation and autotransplantation in parathyroid surgery: An institutional experience. Surgery 1997;122:1062. Carty SE, Norton JA. Management of patients with persistent or recurrent primary hyperparathyroidism. World J Surg 1991;15:716. Higgins RM, Richardson AJ, Ratcliffe PJ, et al. Total parathyroidectomy alone or with autograft for renal hyperparathyroidism? Q J Med 1991;79:323. Mozes MF, Soper WD, Jonasson 0, et al. Total parathyroidectomy and autotransplantation in secondary hyperparathyroidism. Arch Surg 1980;115:378. Tolloczko T, Wozniewic B, Sawicki A, et al. Cultured parathyroid cell transplantation without immunosuppression in the treatment of surgical hypoparathyroidism. Transplant Proc 1994;26: 190I. Walgenbach S, Junginger T, Kohler H, Wandel E. Diagnostik von Dysfunktionen replantierten Nebenschilddrugenwebes durch seitengetrennte analyse des intakten parathomons im kubitalvenenblut. Med Klin (Munich) 1995;90:8. Wells SA, Gunnells JC, Gutman RA, et al. The successful transplantation of frozen parathyroid tissue in man. Surgery 1977;81:86. Wells SA, Farndon JR, Dale JK, et al. Long-term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surg 1980;192:451.

Hypercalcemia of Malignancy and Parathyroid Hormone-Related Protein Gordon J. Strewler, MD

Hypercalcemia is a relatively common complication of malignant tumors, occurring in 5% to 10% of all cancers. The incidence of hypercalcemia in malignancy is 15 cases per 100,000 person-years, about one half the incidence of primary hyperparathyroidism, 1 and it is the most common cause of hypercalcemia in hospitalized patients.? In 1924, Zondek and colleagues' first described hypercalcemia as a complication of cancer, and in 1941 Albright! proposed that hypercalcemia may be caused by humoral factors rather than direct resorption of bone by metastatic tumor. Our understanding of the causation and treatment of the syndrome of hypercalcemia in malignancy has burgeoned rapidly since 1980.5.6

Clinical Syndrome of Hypercalcemia in Malignancy The onset of hypercalcemia in malignancy is usually rapid, and hypercalcemia is often manifested as confusion, stupor, nausea, vomiting, or dehydration. The offending neoplasm is almost always evident clinically, even when hypercalcemia is its initial manifestation. Thus, physical examination, a chest radiograph, complete blood count, and urinalysis disclose the underlying tumor in about 98% of patients. Given these characteristics, it is not surprising that malignancy is the most common cause of hypercalcemia in hospitalized patients but is a rare cause of hypercalcemia in an office practice, which is dominated by patients with primary hyperparathyroidism and other forms of chronic, minimally symptomatic hypercalcemia. Because hypercalcemia usually occurs in advanced malignancy, the prognosis is poor, with a median survival of only 4 to 8 weeks after the discovery of hypercalcemia.' Exceptions to this rule are breast carcinoma and multiple myeloma. In both these disorders, successful therapy for the underlying malignancy may provide long survival in the hypercalcemic patient.

536

Tumors Causing Hypercalcemia Table 61-1 shows the frequency of individual tumors in collected series of patients with hypercalcemia. The most common single cause of hypercalcemia is lung carcinoma. Lung carcinomas with squamous or large-cell histology produce hypercalcemia frequently, but small-cell carcinoma almost never does." About two thirds of lung cancer patients have bone metastasis when hypercalcemia develops. In the remainder, hypercalcemia clearly has a humoral basis, usually humoral secretion of the parathyroid hormone-related protein (PTHrP), as discussed later. Together, lung carcinoma, breast carcinoma, and multiple myeloma account for more than 50% of all cases of malignancy-associated hypercalcemia. Among other solid tumors, the most common are squamous carcinomas of the esophagus and female reproductive tract and renal carcinoma. Gastrointestinal tumors and prostate carcinoma are less common causes of hypercalcemia. Among hematologic malignancies, hypercalcemia is common in multiple myeloma but distinctly uncommon in lymphomas and leukemia.

Pathogenesis of Hypercalcemia Parathyroid Hormone-Related Protein By far the most common cause of hypercalcemia in cancer is secretion of a protein similar to parathyroid hormone (PTH).5,6 The PTHrP is a distinct gene product with sequence homology to PTH only in a limited domain at the aminoterminal end of the molecule, where 8 of the first 13 amino acids in the two proteins are identical (Fig. 61-1). Although tightly circumscribed, this region of homology is critical, for the aminoterminal domain is the region required for activation of the receptor shared by the two proteins, the PTH-PTHrP receptor. Overall, PTHrP is 139 to 173 amino acids long compared with the 84-amino acid PTH molecule.

Hypercalcemia of Malignancy and Parathyroid Hormone-Related Protein - - 537

The two are cousins not only structurally but also in ancestry; shared features of gene structure and chromosomal location indicate that their genes arose from a common ancestral gene," Because PTH and PTHrP share a receptor, it can be anticipated that their biologic actions and the clinical syndrome they produce will be similar.'? Both produce humoral hypercalcemia by increasing resorption of bone throughout the skeleton and by increasing the renal resorption of calcium, and both produce relative hypophosphatemia through a phosphaturic effect at the kidney," Most tumors that produce PTHrP, such as squamous and renal carcinomas (see Table 61-1), cause hypercalcemia without bone metastasis in a large fraction of cases (Table 61-2). Even in squamous and renal carcinoma patients who do have bone metastasis, the primary cause of hypercalcemia is probably humoral secretion of PTHrP because the serum level of PTHrP is better correlated with the serum calcium and phosphorus than is the number or size of bone metastases. Overall, about 80% of hypercalcemic cancer patients have increased serum levels of PTHrP, which can be measured in two-site, aminoterrninal, or midregion assays (Fig. 61_2).11-15 This group includes most solid tumor patients but only a few

FIGURE 61-1. Primary structures of the aminoterminal part of parathyroid hormonerelated protein (PTHrP) and of parathyroid hormone. The human sequences I to 34 are compared. Identical amino acids are highlighted.

patients with multiple myeloma, lymphoma, or leukemia. However, one leukemia, the adult T-cell leukemia syndrome, produces hypercalcemia in an extraordinarily high percentage of cases (about 60%) by direct secretion of PTHrP from malignant T Iymphocytes.ls" This is of particular interest because the adult T-cell leukemia syndrome, which is rare in the United States but endemic in Japan and the Caribbean basin, is caused by infection with a retrovirus, human T-cell leukemia-lymphoma virus (HTLV) type 1. It appears that a protein encoded in the genome ofHTLV-1 can directly activate transcription of the PTHrP gene in T cells. 19 It is likely that, in addition to humoral hypercalcemia, PTHrP can produce local osteolytic hypercalcemia by direct activation of osteoclasts in the vicinity of bone metastases. The best example is breast carcinoma. Unlike most other solid tumors, breast carcinoma produces hypercalcemia mainly in patients with extensive bone metastases (see Table 61-2). About 50% of these patients have elevated serum levels of PTHrP,11-15 presumably indicative of humoral hypercalcemia. However, metastases to bone are immunohistochemically positive for PTHrP in 92% of cases compared with 17% of nonosseous metastases." This suggests either that tumor cells that secrete PTHrP have an advantage in bone (perhaps because they induce local resorption) or that the bone environment induces the expression of PTHrP. In either case, PTHrP could act locally to produce osteolysis. Transfection of the PTHrP gene into breast carcinoma cells increases the number of bone metastases, and animals with such metastases are hypercalcemic but do not have increased levels of circulating PTHrp.21 On the basis of this evidence, it seems likely that PTHrP can act as either a humoral factor or a local osteolytic factor in breast carcinoma. Secretion of PTHrP also causes hypercalcemia in a few benign conditions. The best example is pheochromocytoma. 22,23 Hypercalcemia can also be a part of the watery diarrhea with hypokalemic alkalosis syndrome produced by tumors that secrete vasoactive intestinal peptide. Because these are closely related to pheochromocytomas in their histology and origin, it is likely that PTHrP will be incriminated as the cause of hypercalcemia in these tumors as well, but this has yet to be confirmed, PTHrP is produced by the mammary gland and appears to be associated with hypercalcemia in two benign conditions of the breast: hypercalcemia complicating Iactation" and massive mammary hypertrophy and hypercalcemia."

538 - - Parathyroid Gland unlike PTH, the humoral regulator of calcium homeostasis, PTHrP is a local regulator of growth and differentiation." Its best established role is to stimulate the proliferation of chondrocytes in the growth plate and retard the mineralization of hypertrophic cartilage. Targeted ablation of the PTHrP gene in the mouse produced an embryonic lethal disorder characterized by short-limbed dwarfism and premature mineralization of cartilage." In postnatal life, PTHrP appears to regulate the differentiation of skin and skin appendages" (its expression in keratinocytes probably explains the high incidence of hypercalcemia in squamous carcinomas that originate from this cell type). In addition, PTHrP is involved in regulation of the mammary gland" and is secreted into milk at levels 1O,OOO-fold higher than serum levels." As a product of a variety of smooth muscle beds (vascular,31 gastrointestinal, bladder.P uterine") that is released in response to stretch 32,33 and functions as a smooth muscle relaxant,34-36 PTHrP is a candidate for short-loop, local regulation of smooth muscle tone.

1,25-Dihydroxyvitamin D

Although PTHrP was not identified until 1983 and was not purified and cloned until 1987, there is now little doubt about its primary role in the causation of hypercalcemia in solid tumor patients. Less certain, but of intense interest, is the role of this protein in normal physiology. It appears that,

Probably the most important cause of hypercalcemia in lymphoma is production of the active vitamin D metabolite 1,25-dihydroxyvitamin D(l,25-(OH)z-D) in lymphoma tissue.'? About half of lymphoma patients who present with hypercalcemia have inappropriately high serum 1,25-(OH)z-D levels. 38.39 In a few cases, lymph node tissue from such patients has been shown to produce 1,25-(OH)z-D

FIGURE 61-2. Plasma concentrations of parathyroid hormone-related protein (PTHrP) in patients with hyperparathyroidism (HPT), normocalcemic patients with malignancy (Normocalc), and patients with hypercalcemia of malignancy resulting from a solid tumor (Solid) or a hematologic malignancy (Hematol). Radioimmunoassay (RIA) was used for arninoterminal PTHrP(1-34) (left), an immunoradiometric assay for PTHrP(1-74) (middle), and an RIA for midregion PTHrP(53-84) (right). The hatched area represents the normal ranges, and the dotted line represents the limits of detection; the numbers attached to each group indicate the number of patients. In the PTHrP(1-74) assay, the group Solid includes five patients classified as having the local osteolytic type of hypercalcemia (delta) and two patients with lymphoma. Note the different scales of the y axes. (Modified from Budayr AA, Nissenson RA, Klein RF, et al. Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med 1989;111:807; Burtis WJ, Brady TJ, Orloff 11, et al. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N EngI J Med 1990;322: 1106; and Blind E, Raue F, Gotzmann J, et al, Circulating levels of midregional parathyroid hormone-related protein in hypercalcemia of malignancy. CUn Endocrinol [Oxf] 1992;37:290.)

Hypercalcemia of Malignancy and Parathyroid Hormone-Related Protein - - 539

in vitro from 25-0HD.40 Challenge of normocalcemic lymphoma patients with the precursor sterol 25-0HD resulted in increased serum 1,25-(OH)z-D levels, increased serum calcium levels, and suppression of PTH.40 In contrast, healthy individuals regulate the conversion of substrate to 1,25-(OH)z-D so precisely that virtually no abnormality of calcium homeostasis is induced by the administration of vitamin D. The abnormal responsiveness of normocalcemic lymphoma patients to vitamin D indicates that the fundamental abnormality in lymphoma, unregulated extrarenal production of 1,25-(OH)z-D, is actually more common than hypercalcemia. As would be expected from this interpretation, hypercalciuria is more common than hypercalcemia in lymphoma patients'? and presumably provides a compensatory mechanism to deal with the inappropriate synthesis of 1,25(OH)z-D. In all regards, this syndrome resembles the hypercalcemia of sarcoidosis, the first proven instance of extrarenal production of 1,25-(OH)z-D in hypercalcemia.t'v? As in sarcoidosis, hypercalcemia in lymphoma is frequently responsive to administration of corticosteroids.

Parathyroid Hormone Ectopic secretion of genuine PTH from extraparathyroid tumors, once thought to be common, is now recognized as extremely rare. Only a few authenticated cases have been reported,43.44 including a single case that fulfills the most rigorous criterion for proof of ectopic hormone production: demonstration of an arteriovenous (AV) gradient for PTH across the tumor." Most of the tumors reported to secrete PTH ectopically have had small-cell histology. The diagnosis should be considered in patients with malignant tumors (particularly small-cell tumors), hypercalcemia, and elevated PTH levels. However, most cases meeting this definition prove to have a malignant tumor with coincident primary hyperparathyroidism because this coincidence is more likely than the truly rare syndrome of ectopic PTH secretion. Thus, exploration of the parathyroid glands is indicated in patients with a malignant nonparathyroid tumor who require treatment for hypercalcemia, unless the malignant neoplasm can be shown to produce PTH by immunohistochemistry or, better, by demonstration of an AV gradient for PTH across the tumor. The diagnosis of ectopic hyperparathyroidism has been made to date by exclusion in patients with normal parathyroid glands.

Prostaglandins Once thought to be the dominant mechanism by which nonparathyroid tumors produce hypercalcemia, the production of prostaglandins is now thought to be a rare cause of hypercalcemia. It is not possible to give a precise incidence or to describe a unique clinical syndrome. Nonetheless, a few well-documented cases in which prostaglandins were high and hypercalcemia was reversed by inhibition of prostaglandin synthesis seem authentic."

Local Osteolytic Hypercalcemia Local osteolysis around osseous tumors can produce hypercalcemia. The predominant mechanism involves the activation of

osteoclasts by secretion of bone-resorbing cytokines. The list of cytokines with osteoclast-activating activity includes interleukin-I, tumor necrosis factor o, interleukin-6, and transforming growth factor c, as well as PTHrp.47 As discussed, there is accumulating evidence that PTHrP is the local osteolytic factor that produces hypercalcemia in breast carcinoma. The other classic example of local osteolytic hypercalcemia is multiple myeloma. Although this is a very common syndrome, with at least one third of myeloma patients experiencing hypercalcemia at some time during their disease, the offending cytokine has not been identified with certainty. Cultured human myeloma cell lines produce bone-resorbing factors that can be neutralized with antisera to interleukin-Ijr" or tumor necrosis factor ~ (lymphotoxin)." However, it is not clear whether either of these, or a third factor, is responsible for the syndrome observed in patients.

Differential Diagnosis The most important consideration in the differential diagnosis of hypercalcemia in a patient with a malignant neoplasm is intercurrent primary hyperparathyroidism. One clue to this possibility is the presence of chronic hypercalcemia, especially hypercalcemia that predates discovery of the malignant tumor. It is important to measure the PTH level in all patients with cancer and hypercalcemia, using a two-site assay for intact PTH (immunoradiometric or immunochemoluminescent). In such assays, the level of PTH is consistently suppressed below 20 ng/L (2 nmollL) in patients with malignancyassociated hypercalcemia. I 1,50 (Older midregion and aminoterminal assays were not able to detect suppression of PTH in patients with nonparathyroid hypercalcemia and should not be used in this setting.) The finding of a high-normal or increased level of intact PTH suggests the presence of primary hyperparathyroidism. In a 1994 study of 123 consecutive hypercalcemic patients, 6 (5%) had biochemical evidence of primary hyperparathyroidism together with a malignant neoplasm." As mentioned, true ectopic secretion of PTH is rare, which should be considered in patients with inappropriately increased PTH levels in the presence of a malignant neoplasm in whom a thorough exploration of the parathyroid glands was negative. It is probably unnecessary to measure PTHrP or 1,25(OH)z-D in all patients with malignancy-associated hypercalcemia. In the typical patient with a diffusely metastatic solid tumor and a suppressed level of PTH, determination of PTHrP is unlikely to change either the diagnosis or the management. Some studies have suggested that high PTHrP levels predict a poor response to antiresorptive therapy of hypercalcemia, but as discussed later (under "Treatment of Hypercalcemia"), it is not clear whether this effect is robust enough to mandate additional laboratory testing. However, in lymphoma patients, a determination of 1,25-(OH)z-D may guide the subsequent treatment of hypercalcemia with corticosteroids. Assays ofPTHrP and 1,25-(OH)z-D are also indicated in hypercalcemic patients with suppressed PTH levels but without an obvious malignancy. The serum or plasma level of PTHrP can be determined in aminoterminal.l-!" midregion," or carboxyterminal radioirnrnunoassays (RIAs) or in two-site immunoradiometric

540 - - Parathyroid Gland

assays (lRMAs).52.53 Both aminoterminal RIAs and IRMA assays for PTHrP are currently available commercially in the United States. Although the absolute level of PTHrP is considerably higher in midregion RIAs than in aminoterminal assays or IRMAs, all classes of assays perform similarly in the setting of malignancy-associated hypercalcemia (see Fig. 61-2). IRMA assays for PTHrP are highly sensitive and specific. However, they require collection of blood in special tubes containing protease inhibitors because proteases present in serum are capable of cleaving the PTHrP molecule at a site that disrupts the two-site assay.

Treatment of Hypercalcemia There are two points of attack on hypercalcemia.t'Y One is to inhibit osteoclastic bone resorption, thus reducing the flux of calcium into the extracellular fluid. The other is to increase the urinary excretion of calcium, potentiating the only homeostatic mechanism to clear an excess calcium load. The urinary clearance of calcium is often impaired in patients with malignancy-associated hypercalcemia. The glomerular filtration rate is reduced both by direct effects of hypercalcemia and by the dehydration and prerenal azotemia that result from impaired urinary concentrating ability. In patients with PTHrP-induced hypercalcemia, the renal tubular reabsorption of calcium is also increased. Thus, the first line of attack on hypercalcemia is usually to correct dehydration and increase the urinary clearance of calcium by inducing a saline diuresis. If necessary, the urinary clearance of calcium can be greatly enhanced with the use of loop diuretics such as furosemide together with saline infusions to induce a massive natriuresis and calciuresis. However, close monitoring of central pressures, serum potassium, and serum magnesium and replacement of urinary losses of fluids and electrolytes are necessary to carry out this mode of therapy safely. Several potent and effective inhibitors of bone resorption are available for acute treatment of hypercalcemia. The bisphosphonate agent parnidronate disodium is administered in a single intravenous infusion of 60 to 90 mg over 6 to 24 hourS.56. 57 Normocalcemia results in 80% to 90% of patients, although the nadir of the serum calcium concentration is not reached until about 5 days after administration. The efficacy and safety of pamidronate make it the agent of first choice. The mean duration of the response is I to 2 weeks, and patients can be retreated on relapse. Pamidronate is considerably more potent and more effective than the older bisphosphonate etidronate disodium, but several other new bisphosphonates will prove equally effective. Among these, alendronate disodium and clodronate have had extensive trials, but neither is yet approved. Synthetic salmon calcitonin in large doses of 200 to 800 U/day reduces the serum calcium level rapidly and is a useful adjunct to pamidronate, whose action has a delayed onset. However, refractoriness to calcitonin ensues within 2 to 4 days. In patients who are refractory to pamidronate and calcitonin, the cytotoxic antibiotic plicamycin (mithramycin) is useful. Although effective, plicamycin is no longer considered the drug of first choice because of its hepatic, renal, and bone marrow toxicity after repeated administration.

PTHrP has the same hypocalciuric effect on the kidney as PTH. For this reason, it was anticipated that patients with high levels of PTHrP might be relatively refractory to agents targeted to osteoclastic bone resorption. Several studies have shown that nonresponders to pamidronate treatment have higher serum PTHrP levels than responders. 5l ,5S,59 However, this relationship is a weak one that has not been observed consistently'"; most patients with PTHrP-induced hypercalcemia respond to pamidronate treatment. Thus, the finding of a high PTHrP level should not influence the choice of therapy. In PTHrP-induced hypercalcemia, however, it is doubly important that aggressive measures to increase the urinary calcium clearance be instituted. Definitive treatment of the underlying neoplasm is also indicated. The treatment is rarely surgical because the cancer is usually advanced and diffuse by the time hypercalcemia supervenes. Chemotherapy of breast carcinoma, multiple myeloma, lymphoma, and leukemia is usually successful in hypercalcemic patients. In solid tumors other than breast carcinoma, chemotherapy is less valuable: chemotherapy has failed in many patients before the appearance of hypercalcemia.

Summary Hypercalcemia is a common end-stage problem in patients with malignant neoplasms. Malignancy is the most common cause of hypercalcemia in hospitalized patients, whereas primary hyperparathyroidism is the most common cause of hypercalcemia in nonhospitalized patients. PTHrP is the most common cause of hypercalcemia in patients with cancer. There are now PTHrP assays to quantitate PTHrP levels. Unfortunately, there are no good means of treating patients with malignant tumors and high PTHrP levels, and most patients die within 8 weeks.

REFERENCES I. Mundy GR, Cove DH, Fisken R. Primary hyperparathyroidism: Changes in the pattern of clinical presentation. Lancet 1980;I: 1317. 2. Fisken RA, Heath DA, Bold AM. Hypercalcaemia-A hospital survey. Q J Med 1980;49:405. 3. Zondek H, Petow H, Siebert W. Die bedeutung der calciumbestirnmung im blute fur die diagnose der niereninsuffizientz. Z Klin Med 1924; 99:129. 4. Case records of the Massachusetts General Hospital. Case 27461. N Engl J Med 1941;225:789. 5. Broadus AE, Mangin M, Ikeda K, et al. Humoral hypercalcemia of cancer: Identification of a novel parathyroid hormone-like peptide. N Engl J Med 1988;319:556. 6. Strewler GJ, Nissenson RA. Hypercalcemia in malignancy. West J Med 1990;153:635. 7. Ralston SH, Gallacher SJ, Patel U, et al. Cancer-associated hypercalcemia: Morbidity and mortality. Ann Intern Med 1990;112:499. 8. Bender RA, Hansen H. Hypercalcemia in bronchogenic carcinoma. Ann Intern Med 1974;80:205. 9. Broadus A, Stewart A. Parathyroid hormone-related protein: Structure, processing, and physiological actions. In: Bilezikian J, Levine M, Marcus R (eds), The Parathyroids. New York,Raven Press, 1994, p 259. 10. Orloff JJ, Reddy D, de Papp AE, et al. Parathyroid hormone-related protein as a prohormone: Posttranslational processing and receptor interactions. Endocr Rev 1994;15:40. 11. Budayr AA, Nissenson RA, Klein RF, et al. Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med 1989;111:807.

Hypercalcemia of Malignancy and Parathyroid Hormone-Related Protein - - 541 12. Burtis WJ, Brady TG, Orloff JJ, et a1. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med 1990;322: 1106. 13. Grill V, Ho P, Body JJ, et a1. Parathyroid hormone-related protein: Elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. J Clin Endocrinol Metab 1991;73:1309. 14. Ratcliffe WA, Norbury S, Stott RA, et a1. Immunoreactivity of plasma parathyrin-related peptide: Three region-specific radioimmunoassays and a two-site immunoradiometric assay compared. Clin Chern 1991;37:1781. 15. Blind E, Raue F, Gotzmann J, et a1. Circulating levels of midregional parathyroid hormone-related protein in hypercalcaemia of malignancy. Clin Endocrinol (Oxf) 1992;37 :290. 16. Fukumoto S, Matsumoto T, Ikeda K, et a1. Clinical evaluation of calcium metabolism in adult T-cellieukemiallymphoma. Arch Intern Med 1988; 148:921. 17. Watanabe T, Yamaguchi K, Takatsuki K, et a1.Constitutive expression of parathyroid hormone-related protein gene in human T cell leukemia virus type 1 (HTLV-I) carriers and adult T cell leukemia patients that can be transactivated by HTLV-l tax gene. J Exp Med 1990;172:759. 18. Ikeda K, Ohno H, Hane M, et a1. Development of a sensitive two-site immunoradiometric assay for parathyroid hormone-related peptide: Evidence for elevated levels in plasma from patients with adult T-cell leukemia/lymphoma and B-cell lymphoma. J Clin Endocrinol Metab 1994;79: 1322. 19. Dittmer J, Gitlin SD, Reid RL, et a1.Transactivation of the P2 promoter of parathyroid hormone-related protein by human T-celllymphotropic virus type I Tax 1: Evidence for the involvement of transcription factor Etsl.J Virol 1993;67:6087. 20. Powell GJ, Southby J, Danks JA, et al. Localization of parathyroid hormone-related protein in breast cancer metastases: Increased incidence in bone compared with other sites. Cancer Res 1991;51:3059. 21. Guise TA, Taylor SD, Yoneda T, et a1. Parathyroid hormone-related protein (PTHrP) expression by breast cancer cells enhanced osteolytic bone metastases in vivo [Abstract]. J Bone Miner Res 1994;9:S128. 22. Kimura S, Nishimura Y, Yamaguchi K, et a1.A case of pheochromocytoma producing parathyroid hormone-related protein and presenting with hypercalcemia. J Clin Endocrinol Metab 1990;70:1559. 23. Mune T, Katakami H, Kato Y, et al. Production and secretion of parathyroid hormone-related protein in pheochromocytoma: Participation of an alpha-adrenergic mechanism. J Clin Endocrinol Metab 1993;76:757. 24. Lepre F, Grill V, Ho PW, et a1. Hypercalcemia in pregnancy and lactation associated with parathyroid hormone-related protein [Letter]. N Engl J Med 1993;328:666. 25. Braude S, Graham A, Mitchell D: Lymphoedemalhypercalcaemia syndrome mediated by parathyroid-hormone-related protein. Lancet 1991;337:140. 26. Strewler GJ, Nissenson RA. The parathyroid hormone-related protein as a regulator of normal tissue functions. In: Kohler PO (ed), Current Opinion in Endocrinology and Diabetes. Philadelphia, Current Science, 1994, p 286. 27. Karaplis AC, Luz A, Glowacki J, et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 1994;8:277. 28. Wysolmerski JJ, Broadus AE, Zhou J, et al. Overexpression of parathyroid hormone-related protein in the skin of transgenic mice interferes with hair follicle development. Proc Natl Acad Sci USA 1994;91: 1133. 29. Wysolmerski JJ, McCaughern-Carucci JF, Daifotis AG, et at. Overexpression of parathyroid hormone-related protein or parathyroid hormone in transgenic mice impairs branching morphogenesis during mammary gland development. Development 1995;121:3539. 30. Budayr AA, Halloran BP, King JC, et a1. High levels of a parathyroid hormone-like protein in milk. Proc Natl Acad Sci USA 1989; 86:7183. 31. Hongo T, Kupfer J, Enomoto H, et a1.Abundant expression of parathyroid hormone-related protein in primary rat aortic smooth muscle cells accompanies serum-induced proliferation. J Clin Invest 1991;88:1841. 32. Yamamoto M, Harm SC, Grasser WA, et al. Parathyroid hormonerelated protein in the rat urinary bladder: A smooth muscle relaxant produced locally in response to mechanical stretch. Proc Nat! Acad Sci USA 1992;89:5326.

33. Thiede MA, Daifotis AG, Weir EC, et al. Intrauterine occupancy controls expression of the parathyroid hormone-related peptide. Proc Natl Acad Sci USA 1990;87:6969. 34. Winquist RJ, Baskin EP, Vlasuk GP. Synthetic tumor-derived human hypercalcemic factor exhibits parathyroid hormone-like vasorelaxation in renal arteries. Biochem Biophys Res Commun 1987; 149:227. 35. Nickols GA, Nickols MA, Helwig JJ. Binding of parathyroid hormone and parathyroid hormone-related protein to vascular smooth muscle of rabbit renal microvessels. Endocrinology 1990;126:721. 36. Mok LL, Cooper CW, Thompson Je. Parathyroid hormone and parathyroid hormone-related protein inhibit phasic contraction of pig duodenal smooth muscle. Proc Soc Exp BioI Med 1989;191 :337. 37. Seymour JF, Gagel RF. Calcitriol: The major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas. Blood 1993;82: 1383. 38. Adams JS, Fernandez M, Gacad MA, et al. Vitamin D metabolitemediated hypercalcemia and hypercalciuria patients with AIDS and non-AIDS-associated lymphoma. Blood 1989;73:235. 39. Seymour JF, Gagel RF, Hagemeister FB, et al. Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma. Ann Intern Med 1994;121:633. 40. Davies M, Hayes ME, Yin JA, et a1. Abnormal synthesis of 1,25dihydroxyvitamin D in patients with malignant lymphoma. J Clin Endocrinol Metab 1994;78:1202. 41. Barbour GL, Coburn JW, Slatopolsky E, et a1. Hypercalcemia in an anephric patient with sarcoidosis: Evidence for extrarenal generation of 1,25-dihydroxyvitarnin D. N Engl J Med 1981;305:440. 42. Stern PH, De Olazabal J, Bell NH. Evidence for abnormal regulation of circulating 1 alpha, 25-dihydroxyvitamin D in patients with sarcoidosis and normal calcium metabolism. J Clin Invest 1980;66:852. 43. Strewler GJ, Budayr AA, Clark OH, et a1. Production of parathyroid hormone by a malignant nonparathyroid tumor in a hypercalcemic patient. J Clin Endocrinol Metab 1993;76: 1373. 44. Yoshimoto K, Yamasaki R, Sakai H, et al. Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia. J Clin Endocrinol Metab 1989;68:976. 45. Nussbaum SR, Gaz RD, Arnold A. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma. N Engl J Med 1990;323: 1324. 46. Brereton HD, Halushka PV, Alexander RW, et a1. Indomethacinresponsive hypercalcemia in a patient with renal-cell adenocarcinoma. N Engl J Med 1974;291:83. 47. Mundy G. Hypercalcemic factors other than parathyroid hormonerelated protein. Endocrinol Metab Clin North Am 1989;18:795. 48. Kawano M, Yamamoto I, Iwato K, et at. Interleukin-l beta rather than lymphotoxin as the major bone resorbing activity in human multiple myeloma. Blood 1989;73:1646. 49. Garrett IR, Durie BGM, Nedwin GE, et a1.Production of lymphotoxin, a bone-resorbing cytokine, by cultured human myeloma. N Engl J Med 1987;317:526. 50. Nussbaum SR, Zahradnik RJ, Lavigne JR, et al. Highly sensitive twosite immunoradiometric assay of parathyrin and its clinical utility in evaluating patients with hypercalcemia. Clin Chern 1987;33:1364. 51. Wimalawansa SJ. Significance of plasma PTHrP in patients with hypercalcemia of malignancy treated with bisphosphonate, Cancer 1994;73:2223. 52. Burtis WJ, Brady TG, Orloff JJ, et al. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med 1990;322: 1106. 53. Fraser WD, Robinson J, Lawton R, et a1. Clinical and laboratory studies of a new immunoradiometric assay of parathyroid hormone-related protein. Clin Chern 1993;39:414. 54. Bilezikian JP. Management of acute hypercalcemia. N Engl J Med 1992;326: 1196. 55. Nussbaum SR. Pathophysiology and management of severe hypercalcemia. Endocrinol Metab Clin North Am 1993;22:343. 56. Gucalp R, Ritch P, Wiernik PH, et a1. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol 1992; 10: 134. 57. Nussbaum SR, Younger J, VandePol CJ, et a1. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: Comparison of 30-,60-, and 90-mg dosages. Am J Med 1993; 95:297.

542 - - Parathyroid Gland 58. Dodwell OJ, Abbas SK, Morton AR, et al. Parathyroid hormonerelated protein (50-69) and response to pamidronate therapy for tumour-inducedhypercalcaemia. Eur I Cancer 1991;27:1629. 59. Body 11, Dumon IC, Thirion M, et al. Circulating PTHrP concentrations in tumor-induced hypercalcemia: Influence on the response to

bisphosphonate and changes after therapy. I Bone Miner Res 1993;8:701. 60. Budayr AA, Zysset E, Jenzer A, et al. Effects of treatment of malignancy-associated hypercalcemia on serum parathyroid hormone-related protein. I Bone Miner Res 1994;9:521.

Hypercalcemic Crisis Hiroshi Takami, MD

The most generally accepted criteria for the diagnosis of hypercalcemic crisis include a statement about the severity of the hypercalcemia (usually Ca >14.5 mg/dl.)! and that it is associated with acute symptoms and signs that can be reversed by correcting the hypercalcemia. I Primary hyperparathyroidism (PHPT) and malignancy are the main causes of hypercalcemic crisis. Hypercalcemic crisis secondary to PHPT has been referred to in the literature as acute HPT, parathyroid crisis, parathyroid poisoning, parathyroid intoxication, parathyrotoxicosis, and parathyroid storm.r'' The manifestations include weakness, nausea and vomiting, drowsiness, stupor, coma, constipation, and tachycardia.Y Severe lifethreatening symptoms and signs of hypercalcemia constitute a "crisis," and rapid diagnosis and treatment are essential to avoid significant morbidity or mortality? The emergency treatment of hypercalcemic crisis is the same regardless of the cause, and an emergency diagnostic algorithm must be followed to demonstrate or rule out PHPT. Serum calcium should be lowered during the etiologic work-up for hypercalcemia. Earlier fluid replenishment and optimized strategies for the intensive care of critically ill hypercalcemic patients have made hypercalcemic crisis a rare event. to

Incidence and Etiology of Hypercalcemic Crisis The incidence of hypercalcemic crisis has never been determined. Bondeson and colleagues 11 reported a 10% incidence of hypercalcemic crisis as a complication in 514 cases of PHPT presenting between 1961 and 1988. Hypercalcemic crisis secondary to PHPT is commonly caused by a large parathyroid mass but may also be caused by carcinoma or hyperplasia.>' Bondeson and colleagues, II however, reported that the distribution of parathyroid pathology (adenoma, hyperplasia, and carcinoma) causing hypercalcemic crisis was the same as that of PHPT not complicated by hypercalcemic crisis. Parathyroid carcinoma is usually associated with much higher parathyroid hormone (PTH) and calcium levels than nonmalignant PHPT, and the incidence of hypercalcemic crisis complicating it may be as high as 14%.12 Maselly and coworkers" reported that 10 of 325 consecutive PHPT patients went on to develop hypercalcemic crisis and that 9 of

the 10 patients had a single adenoma. The risk of developing hypercalcemic crisis in untreated PHPT is low. Only 1 of a group of 47 patients observed over a 5-year interval developed hypercalcemic crisis,'? and only 1 of 142 patients, or 0.7%, of the patients in a prospective series at the Mayo Clinic observed for 10 years developed hypercalcemic crisis related to PHPT. 15 Fitzpatrick- reported that age at the time of clinical presentation of hypercalcemic crisis is the same as or lightly lower than the average age of PHPT patients at the time of presentation.v'v-" Other authors have reported a wide age distribution but that most cases develop in the sixth decade of life. 2,4 The male/female ratio (1.0:1.1) was found to be similar to the distribution of parathyroid carcinoma"?" but markedly different from the gender ratios in series of PHPT. 16 •17 The principal causes of hypercalcemia in inpatient and outpatient settings differ? The two most common causes of hypercalcemia, malignancy and PHPT, are also the most common causes of hypercalcemic crisis in hospitalized and ambulatory patients, respectively, accounting for more than 90% of patients (Table 62-1). However, there are many other causes of hypercalcemic crisis. In granulomatous diseases, macrophages activated by the granuloma can metabolize 25-hydroxyvitarnin D (25-0H vitamin D, calcidiol) to the more active 1,25-dihydroxyvitarnin D 3 (l,25(OHh vitamin D, calcitriol) and produce endogenous hypervitaminosis D, and on rare occasions the resultant increase in intestinal calcium absorption leads to hypercalcemic crisis," Less commonly, some lymphomas have been associated with excess endogenous 1,25(OHh vitamin D production and sometimes cause hypercalcemic crisis." The mechanism of the hypercalcemia in hyperthyroidism is a direct stimulatory effect of thyroxine on osteoclastic bone resorption,' and hypercalcemia caused by this mechanism may occur when young patients with hyperthyroidism are immobilized. Hypercalcemia may mask the usual hypermetabolic signs of thyrotoxicosis and make the hyperthyroidism more difficult to diagnose. The most common cause of hypercalcemia in inpatient settings is malignancy.P There are three separate syndromes in which malignant tumors can result in life-threatening hypercalcemic crisis: a syndrome of humoral hypercalcemia caused by endocrine and paracrine mediators, a syndrome of

543

544 - - Parathyroid Gland

hypercalcemia associated with localized osteolytic disease, and a syndrome of hypercalcemia associated with multiple myeloma and related hematologic malignancies. Humoral hypercalcemia of malignancy (HHM) results from elaboration of a bone-resorbing substance by the tumor, most often PTHrelated polypeptide (PTHrP). This 146-amino acid polypeptide is homologous to PTH in 8 of its first 13 aminoterminal residues, and it binds to the PTH receptor and produces the same hypercalcemic effects as PTH on end-organs: bone, gut, and kidney." Because PTHrP is secreted by solid malignancies in a manner that is not subject to the feedback regulation by serum calcium that occurs with PHPT, PTHrP secretion may cause an unrelenting hypercalcemic state. Humoral mediators of hypercalcemia in malignancy lead to increases in bone resorption by increasing osteolytic activity, and they probably also lead to complex disturbances in calcium homeostasis in the kidney and gut. Solid tumors of the lung, head, neck, kidney, pancreas, and ovary are often associated with humorally mediated hypercalcemia and produce factors, including PTHrP, that are potent activators of osteoclastic bone resorption and cause hypercalcemia in vivo.? Hematologic malignancies, most notably multiple myeloma, secrete a number of cytokines, which act locally in the bone marrow to stimulate osteoclastic bone resorption.'

Clinical Features of Hypercalcemic Crisis A serum calcium level of 14.5 mg/dL or higher must generally be considered a medical emergency, and most patients are symptomatic." Nevertheless, because relatively asymptomatic patients with a serum calcium of 20 mg/dL, and

even patients with levels below 14.5 mg/dL, have presented in hypercalcemic crisis," the serum calcium level should not be the sole marker used to define hypercalcemic crisis. 1 The severity of the hypercalcemia is usually proportional to the increase in PTH level. 9 The serum PTH level of patients in hypercalcemic crisis is almost always at least twice the normal level, and as many as 40% to 50% have a palpable mass on physical exarnination.s-" Mild to moderate hypercalcemia may be manifested only by anorexia, malaise, weakness, osteoporosis, and kidney stones. When these manifestations develop slowly, as they do in many mildly hyperparathyroid patients, their presence may be recognized only retrospectively, after parathyroidectomy,?·26 Hypercalcemia causes anorexia, polyuria, nausea, and vomiting, and the resultant dehydration may be profound." Isolated components of the syndrome are often nonspecific and observed in many other diseases,'? but the simultaneous presence of several of these components strongly suggests hypercalcemia. The renal symptoms of hypercalcemic crisis are polyuria and polydipsia. The neurologic symptoms are less characteristic and include depression, anxiety, and psychosis. Gastrointestinal symptoms are nausea, vomiting, constipation, peptic ulcer, and pancreatitis. Gastric acid secretion and pancreatic enzyme secretion are increased.!" Cardiac symptoms also are nonspecific. A shortened QT interval and tachycardias may be observed. The mechanism of hypertension attributable to PHPT is unclear,'? Hypercalcemic crisis is a constellation of the preceding signs and symptoms, including psychological disturbances (ranging from drowsiness to stupor to coma), renal insufficiency, and cardiac dysrhythmias (bradyarrhythmias, bundle branch blocks, complete heart blocks, and cardiac arrest)." (The preceding signs and symptoms are mild and usual, but the signs with italic letters are severe and not common.) Hypercalcemia of malignancy must be considered in cases with a history of, for example, breast cancer, in women, and lung cancer or myeloma, in both sexes.'?

Diagnosis A complete history and physical examination and a review of the medical records are the most important elements in the emergency diagnosis of hypercalcemic crisis." Patients with PHPT rarely experience hypercalcemic crisis, and those who do usually have a long-standing history of progressive symptoms of hypercalcemia. Most patients presenting with hypercalcemia secondary to malignancy have an antecedent diagnosis of malignancy, and many are already hospitalized when severe hypercalcemia develops. A serum calcium assay should be performed in all patients who present with psychological disturbances, renal insufficiency, cardiac dysrhythmias, and neurologic abnormalities," The most accurate and useful laboratory test for ruling out hypercalcemia is the ionized calcium assay," but most hospitals measure total serum calcium (ionized plus proteinbound calcium) unless the ionized calcium level is requested. If an ionized calcium assay is not available, total serum calcium may be measured and the value corrected for the measured albumin level.

Hypercalcemic Crisis - -

The most specific laboratory test in the differential diagnosis of hypercalcemia is the serum intact PTH assay?" An increased intact PTH level and calcium level are almost pathognomonic of HPT. Before the radioimmunoassay for intact PTH became available, the PTH assays in common use measured the PTH C-terminal or midregional fragment." Although detection of an elevated intact PTH level is a useful means of diagnosing PHT, the test usually takes a few days to complete and is of no immediate use in the management of hypercalcemic crisis. The quick intact PTH assay developed by Irvin and colleagues," however, has allowed rapid differential diagnosis of hypercalcemic crisis. It is an immunochemiluminometric assay and has a turnaround time of only 10 minutes." Conditions besides PHPT in which the intact PTH level is increased include hypocalcemia, secondary HPT (with low to low-normal serum calcium), and tertiary HPT (with normal to increased serum calcium) after a history of long-standing renal insufficiency? The intact PTH levels in patients with secondary HPT are characteristic of the patientto-patient variability of the half-life of intact PTH and its molecular heterogeneity and biphasic metabolism.P-" Hypercalcemia secondary to malignancy occurs in patients whose diagnosis of malignancy is already established.' Most patients who present with nonparathyroid hypercalcemia have malignant disease. It is important to establish whether the patient has HHM or skeletal metastases. Hypercalcemia develops before death from the malignancy in 30% of patients with carcinoma of the breast, 10% of patients with squamous cell carcinoma of the lung, and smaller percentages of patients with carcinoma of the esophagus, skin, kidney, pancreas, liver, colon, and ovary.v'" Reliable assays for PTHrP are now available, but it takes several days to obtain the results, and they cannot be relied on as an adjunct to the emergency management of hypercalcemia.? If the PTHrP levels are low, other osteolytic factors may be produced by the tumor, and other cases are associated with the production of interleukin-l, -6, or -11; transforming growth factor a or ~; interferon; or granulocyte-macrophage colony-stimulating factor. 10 Paraneoplastic production of ectopic PTH is extremely rare.32 If familial hypocalciuric hypercalcemia (FHH) is suspected, an above-normal 24-hour urine calcium or a calcium clearance-to-creatinine ratio greater than 0.01 in patients who have never been documented to be normocalcemic rules out FHH. I The serum 25-0H vitamin D level may be checked if excessive vitamin D intake is suspected. The serum 1,25(OHh vitamin D level is high normal or mildly elevated in patients with PHPT. A cost-effective and accurate diagnosis of HPT can be made by documenting increased calcium and intact PTH levels in patients who are not hypocalciuric.

545

Maternal PTH levels increase to enhance gastrointestinal absorption of calcium during pregnancy," thereby facilitating placental transport of calcium to the fetus. The degree of hypercalcemia, however, may be blunted by the physiologic hypoalbuminemia of pregnancy. Some of the criteria used to make the diagnosis of hyperparathyroidism in nonpregnant patients should be adjusted (i.e., lower calcium and higher PTH levels should be used) because of the physiologic increase in maternal PTH levels associated with pregnancy and the normally depressed maternal calcium levels. The maternal hypercalcemia accompanying maternal HPT depresses fetal parathyroid function." After birth, the neonate no longer has access to maternal serum calcium and is unable to mobilize calcium adequately from bone because of depressed parathyroid function, resulting in a risk of neonatal tetany. The pregnant woman, in tum, is at risk for hypercalcemic crisis. Placental delivery of calcium to the fetus is greatest during the third trimester and is protective for the mother.P:" Because this protection is lost with the delivery of the child, the neonate is at greatest risk for tetany several hours after delivery, and the mother is at greatest risk for hypercalcemic crisis during the same period.F'" The incidence of fetal complications has been reported to be 53% for treated mothers 35 ,40 and 80% for untreated mothers.f 27% to 31% of whose infants die in the neonatal period. 35,40 Other complications include intrauterine growth restriction, low birth weight, preterm delivery, and intrauterine fetal demise. 33•35,40-42 Postpartum neonatal hypocalcemic tetany has been reported to occur in 50% of infants born to untreated mothers," The diagnosis of HPT in pregnant patients is most commonly made postpartum when the infant develops neonatal tetany.'? If hypercalcemia is not controlled medically, parathyroidectomy by an experienced surgeon should be recommended despite advanced gestation.'? Urgent parathyroidectomy using improved technology is the best option, even in late gestation. Developments in surgical technology have greatly improved the safety of parathyroidectomy.P'P Innovations such as the intraoperative quick PTH assay," sestamibi scintigraphy/<" and radioguided parathyroidectomy'" have allowed the development of minimally invasive parathyroidectomy, and several investigators have reported high success rates using these techniques, with reductions in incision length, operation time, and length of hospital stay in nonpregnant patients with PHPT.43-45,49 These methods may not be used in pregnant women, but they offer the theoretical advantage of maximizing surgical efficacy while minimizing invasiveness and operation time. 50,5 1 An alternative option is medical control, such as with bisphosphonates and calcitonin. The diagnosis and management of this condition are imperative because it poses a significant risk to the mother as well as the fetus.

Hypercalcemic Crisis in Pregnancy

Treatment

PHPT associated with pregnancy is a rare condition.Pr" Although the exact incidence of PHPT during pregnancy is unknown, the incidence of PHPT in women of childbearing age is estimated to be approximately 8 cases per 100,000 population per year."

The first step in the management of hypercalcemic crisis is to lower the serum calcium level and then identify its etiology. Therapy must be directed toward increasing the urinary excretion of calcium and decreasing bone resorption.l" Increasing renal calcium excretion in hypercalcemic crisis

546 - - Parathyroid Gland by means of hydration and loop diuretics (furosemide) is quicker and easier than decreasing bone resorption (Table 62-2).1 Immediate therapy must achieve as rapid and complete volume reexpansion as practicable.' Intravenous infusion of normal saline is indicated to promote renal calcium excretion and restore cardiovascular function. 52 A 500-mL intravenous bolus of normal saline should be administered initially," and the patient's volume status should be monitored for adequate replenishment and to avoid fluid over10ad.1 Usually the goal should be 2 to 8 L per day, and when the kidneys have begun to respond to rehydration, a loop diuretic may be administered to accelerate calciuresis.P Loop diuretics have a profound effect on sodium and water excretion.> Lower doses stimulate natriuresis, which is accompanied by calciuresis,'? but if sodium excretion exceeds the rate of replacement with intravenous normal saline, renal sodium-conserving mechanisms are activated, limiting calcium excretion and exacerbating the hypercalcemia." A direct calciuretic effect of loop diuretics can be expected at high doses of 100 mg/hour.S' and aggressive fluid hydration in combination with loop diuretics is effective in lowering serum calcium by 1.5 to 2.0 mg/dL in 24 to 48 hours.' Many patients with hypercalcemic crisis and patients with hypercalcemic crisis with intercurrent cardiac or other illnesses require admission to the intensive care unit for cautious monitoring of vital signs, central venous pressure, urine output, and serum and urine electrolyte levels. It is reasonable to administer moderate doses of loop diuretics to older patients with mildly impaired cardiovascular function when there is concern about volume overload.>' Thiazide diuretics should not be used because they increase distal tubular reabsorption of calcium and may exacerbate the hypercalcemia." The routine approach, saline solution administration, is ineffective in patients with severely impaired renal function, and hemodialysis against a zero or a low calcium dialysate concentration may be necessary." Some cases of hypercalcemia caused by HPT are refractory to hydration and diuresis, and inhibitors of osteoclastic bone resorption are indicated when a 24- to 48-hour period of treatment has failed. However, in most patients with HPT, administration of normal saline and loop diuretics may be the only treatment necessary before parathyroidectomy." Parathyroidectomy is the definitive treatment for PHPT and should not be delayed when a patient in hypercalcemic crisis has recovered in response to treatment. Ultrasonography is

essential as a preoperative localization test and is generally positive in patients with hypercalcemic crisis because the parathyroid masses of such patients are usually large. However, sestamibi scintigraphy is available if localization of the parathyroid mass is not definitive. Computed tomography and magnetic resonance imaging are more expensive and less accurate. The intraoperative quick PTH assay biochemically confirms that adenomas have been completely excised.P-" Radioguided parathyroidectomy, which can be quickly performed by a significantly less invasive procedure, has been developed.f When initial therapy has been instituted, administration of inhibitors of osteoclastic bone resorption should be considered.' The agents available to inhibit bone resorption include bisphosphonates, calcitonin, plicamycin (mithramycin), glucocorticoids, and gallium nitrate.' The choice of agent should be based on the etiology of the hypercalcemia, the pharmacodynamics of the agent, its onset and duration of action, the route of metabolism, and potential side effects.l-' Administration of bisphosphonates should be considered early in patients with HHM. Bisphosphonates are chemical analogs of pyrophosphate and directly inhibit osteoclast function. Available agents are etidronate, clodronate, pamidronate, and ibandronate.!? and each member of the bisphosphonate family appears to have its own mechanism of osteoclast inhibition.r' The advantage of the more potent bisphosphonates is the ability to use smaller doses, which means a shorter infusion time. 54 Ibandronate can even be administered as a bolus to patients with normal renal function. Bisphosphonates provide a slower onset of action and longer duration of effectiveness, and because they are poorly absorbed when administered orally, intravenous administration is necessary. Multiple infusions of the second-generation bisphosphonate pamidronate (Aredia) in conjunction with volume replenishment may decrease the serum calcium level to the normal range within 7 days in about 75% of patients with hypercalcemia of malignancy.-S" Pamidronate therapy may be complicated by mild hyperthermia, gastrointestinal symptoms, hypophosphatemia, hypokalemia, and hypomagnesemia. Pamidronate is a more potent and possibly less toxic bisphosphonate than etidronate, a first-generation bisphosphonate that is often used in the treatment of Paget's disease of bone. Calcitonin (salmon, human) is a polypeptide secreted by the C cells of the thyroid and is a potent inhibitor of

Hypercalcemic Crisis - -

osteoclastic bone resorption. In pharmacologic doses, it promotes calciuresis." and its hypocalcemic effect is the most rapid among the agents, occurring within 2 hours of dosing in most patients, and is sustained for up to a week." This early loss of effectiveness has been termed the "escape phenomenon" and may be overcome by concomitant use of glucocorticoids.V'" The escape phenomenon during continued treatment with calcitonin is thought to result from downregulation of calcitonin receptors on the surface of osteoclasts.?' Calcitonin is best used as adjunctive therapy with other antiresorption agents or calciuric agents. 1,3,54 Combining the rapid hypocalcemic effects of calcitonin with the more delayed effect of a bisphosphonate is a reasonable approach to patients in severe hypercalcemic crisis. 62-6s The onset of the antihypercalcemic effect is observed within 2 hours after combination therapy consisting of a single intravenous injection of pamidronate and serial intramuscular injections of calcitonin, and the effect is of sufficient duration (Fig. 62_1).64,65 Pamidronate and calcitonin do not interfere with each other, and their combined use to treat hypercalcemia is rapid, effective, and safe. It is an aid to the safe performance of surgery in PHPT patients, appears to be useful in improving quality of life, and is therapeutically effective in patients with malignancy-associated hypercalcemia. Plicamycin (mithramycin), a compound produced by Streptomyces microorganisms, inhibits osteoclast RNA synthesis." It was of great utility in the prebisphosphonate period but is hardly ever needed today because of the availability of the highly potent bisphosphonates.'? It has a spectrum of severe side effects (hepatotoxicity, nephrotoxicity, and thrombocytopenia).

547

Glucocorticoids are effective in the treatment of hypercalcemia secondary to vitamin D or A intoxication, hyperthyroidism, and granulomatous diseases, but they function by decreasing calcium absorption from the gut, and several days may be required before their full therapeutic effect is realized." Gallium nitrate appears to act by inhibiting osteoclast function, but its exact mechanism of action is unknown, S4 Few clinicians are familiar with the drug, and because it is nephrotoxic, gallium is generally reserved for cases of hypercalcemia that have not responded to one of the other available

agents."

Intravenous phosphate lowers serum calcium by promoting its deposition in bone and soft tissues but may have serious adverse effects, including extraskeletal calcium deposition?

Summary Hypercalcemic crisis is a reversible, curable, life-threatening disorder. If proper treatment is not initiated promptly, rapid progression to death may occur. The most common cause of hypercalcemia in hospitalized patients is malignancy, whereas PHPT is the most common cause in ambulatory patients. Emergency treatment is the same regardless of the cause of the hypercalcemia and consists of fluid administration and promotion of calciuresis with normal saline and loop diuretics. Other agents, such as bisphosphonates and calcitonin, may be added later. Parathyroidectomy by an experienced surgeon after fluid replenishment and initial lowering of the serum calcium level is the only effective treatment of PHPT. Patients in hypercalcemic crisis should be treated in intensive care units.

REFERENCES 1. Kebebew E, Clark OH. Parathyroid adenoma, hyperplasia. and carci-

2. 3. 4. 5. 6.

Days after initial injection

FIGURE 62-1. Changes in corrected serum calcium levels after administration of parnidronate and calcitonin. Each patient was hydrated with normal saline before treatment. Each patient received 60 to 90 mg of parnidronate over 6 hours as a single intravenous dose and 100 IV of salmon calcitonin subcutaneously every 12 hours for 3 days. The serum calcium levels of the five patients with primary hyperparathyroidism reached the normal range on day 2 or 3 after the initial dose and remained within the normal range, whereas those of the three patients with humoral hypercalcemia of malignancy (HHM) reached the normal range on days 2 to 4 after the initial dose but rose again on days 13 to 21.

7. 8. 9. 10. 11. 12.

noma. Localization, technical details of primary neck exploration, and treatment of hypercalcemic crisis. Surg Oncol Clin North Am 1998;7:721. Bayat-Mokhtari F, Palmieri GMA, Moinuddin M, et al. Parathyroid storm. Arch Intern Med 1980;140:1092. Edelson GW, Kleerekoper M. Hypercalcemic crisis. Med Clin North Am 1995;79:79. Fitzpatrick LA, Bilezikian JP. Acute primary hyperparathyroidism. Am J Med 1987;82:275. Fitzpatrick LA. Acute primary hyperparathyroidism. In: Bilezikian JP, Levine MA, Marcus R (eds), The Parathyroid. New York, Raven Press, 1994, p 583. Wang CA, Guyton sw. Hyperparathyroid crisis: Clinical and pathologic studies of 14 patients. Ann Surg 1979;190:6. Clark 0, Siperstein AE. The hypercalcemic syndrome: Hyperparathyroidism. In: Friesen SR, Thompson NW (eds), Surgical Endocrinology: Clinical Syndromes. Philadelphia, JB Lippincott, 1990, p 311. Lemann J Jr, Donatelli AA. Calcium intoxication due to primary hyperparathyroidism. Ann Intern Med 1964;60:447. Grossman RF, Jossart GH. Hypercalcemic crisis. In: Clark OH, Duh Q-Y (eds), Textbook of Endocrine Surgery. Philadelphia, WB Saunders, 1997, p 432. Ziegler R. Hypercalcemic crisis. J Am Soc NephroI2001;12:S3. Bondeson AG, Bondeson L, Thompson NW. Clinicopathological peculiarities in parathyroid disease with hypercalcaemic crisis. Eur J Surg 1993;159:613. Wang CA, Gaz RD. Natural history of parathyroid carcinoma: Diagnosis, treatment, and results. Am J Surg 1985;149:522.

548 - - Parathyroid Gland 13. Maselly MJ, Lawrence AM, Brooks M, et al. Hyperparathyroid crisis. Successful treatment of ten comatose patients. Surgery 1981;90:741. 14. Corlew DS, Bryda SL, Bradley EL, et al. Observations on the course of untreated primary hyperparathyroidism. Surgery 1985;98:1064. 15. Scholz DA, Purnell DC. Asymptomatic primary hyperparathyroidism: IO-year prospective study. Mayo Clin Proc 1981;56:473. 16. Bilezikian JP, Silverberg SJ, Shane E, et al. Characterization and evaluation of asymptomatic primary hyperparathyroidism. J Bone Mineral Res 1991;6(SuppI2):S85. 17. Fitzpatrick LA. Is surgery necessary for the asymptomatic patient with primary hyperparathyroidism? In: Gitnick F, Barnes HV, Duffy TP, et al (eds), Debates in Medicine. Chicago, Mosby-Year Book, 1991, p 114. 18. Shane E, Bilezikian JP. Parathyroid carcinoma: A review of 62 patients. Endocr Rev 1982;3:218. 19. Wang C, Gaz RD. Natural history of parathyroid carcinoma: Diagnosis, treatment and results. Am J Surg 1979;149:522. 20. Wynne AG, Van Heerden J, Carney JA, et al. Parathyroid carcinoma: Clinical and pathologic features in 43 patients. Medicine (Baltimore) 1992;71: 197. 21. Breslau NA, McGuire JL, Zerwekh JE, et al. Lymphoma, hypercalcemia, and serum calcitriollevels. Ann Intern Med 1985;103: 152. 22. Pimentel L. Medical complications of oncologic disease. Emerg Med Clin North Am 1993;11:407. 23. Frame B, Jackson GM, Kleerekoper M, et al. Acute severe hypercalcemia in a la Munchausen. Am J Med 1981;70:316. 24. Clark OH. Presidential address. "Asymptomatic" primary hyperparathyroidism: Is parathyroidectomy indicated? Surgery 1994;116:6. 25. Duh QY, Uden P, Clark OH. Unilateral neck exploration for hyperparathyroidism: Analysis of a controversy using a mathematical model. World J Surg 1992;16:654. 26. Chan AK, Duh QY, Katz MH, et al. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: A casecontrol study. Ann Surg 1995;222:3. 27. Nussbaum SR, Potts JT Jr. Immunoassays for parathyroid hormone 1-84 in the diagnosis of hyperparathyroidism. J Bone Miner Res 1991;6(SuppI2):S43. 28. Irvin GL 3rd, Prudhomme DL, Deriso GT, et al. A new approach to parathyroidectomy. Ann Surg 1994;219:574. 29. Irvin GL 3rd. American Association of Endocrine Surgeons. Presidential address: Chasin' hormones. Surgery 1999;126:993. 30. Brossard JH, Cloutier M, Roy L. Accumulation of a non-(l-84)molecular form of parathyroid hormone (PTH) detected by intact PTH assay in renal failure: Importance in the interpretation of PTH values. J Clin Endocrinol Metab 1996;81:3923. 31. Lokey J, Pattou F, Mondragon-Sanchez A, et al. Intraoperative decay profile of intact (1-84) parathyroid hormone in surgery for renal hyperparathyroidism-A consecutive series of 80 patients. Surgery 2000;128:1029. 32. Iguchi H, Miyagi C, Tomita K, et al. Hypercalcemia caused by ectopic production of parathyroid hormone in a patient with papillary adenocarcinoma of the thyroid gland. J Clin Endocrinol Metab 1998; 83:2653. 33. Carella MJ, Gossain VV. Hyperparathyroidism and pregnancy. Case report and review. J Gen Intern Med 1992;7:448. 34. Haenel LC, Mayfield RK. Primary hyperparathyroidism in a twin pregnancy and review of fetal/maternal calcium homeostasis. Am J Med Sci 2000;319: 191. 35. Kelly TR. Primary hyperparathyroidism during pregnancy. Surgery 1991;110:1028. 36. Heath H, Hodgson SF, Kennedy MA. Primary hyperparathyroidism: Incidence, morbidity, and potential economic impact in a community. N Engl J Med 1980;302:189. 37. Kort KC, Schiller HJ, Numann P1. Hyperparathyroidism and pregnancy. Am J Surg 1999;177:66. 38. Krisoffersson A, Dahlgren S, Lithner F, et al. Primary hyperparathyroidism in pregnancy. Surgery 1984;97:326. 39. Schnatz PF, Curry SL. Primary hyperparathyroidism in pregnancy: Evidence-based management. Obstet Gynecol Surv 2002;57:365.

40. Delmonico FL, Neer RM, Cosimi AB, et al. Hyperparathyroidism and pregnancy. Am J Surg 1976;145:611. 41. Graham EM, Freedman U, Forouzan I. Intrauterine growth retardation in a woman with primary hyperparathyroidism. A case report. J Reprod Med 1998;43:451. 42. Shanghold MN, Dor N, Welt S, et al. Hyperparathyroidism and pregnancy: A review. Obstet Gynecol Surv 1982;37:217. 43. Ikeda Y, Takarni H, Sasaki Y, et al. Endoscopic neck surgery by the axillary approach. J Am Coli Surg 2000;191:336. 44. Ikeda Y, Takami H. Endoscopic parathyroidectomy. Biomed Pharmacother 2000;54:S52. 45. Takami H, Ikeda Y, Wada N. Surgical management of primary hyperparathyroidism. Biomed Pharmacother 2000;54:S17. 46. Takami H, Oshima M, Sugawara I, et al. Pre-operative localization and tissue uptake study in parathyroid imaging with technetium-99msestamibi. Aust N Z J Surg 1999;69:629. 47. Wei JP, Burke GJ. Analysis of savings in operative time for primary hyperparathyroidism using localization with technetium 99m sestamibi scan. Am J Surg 1995;170:188. 48. Norman J, Denham D. Minimally invasive radioguided parathyroidectomy in the reoperative neck. Surgery 1998;124:1088. 49. Miccoli P, Berti P, Conte M, et al. Minimally invasive video-assisted parathyroidectomy: Lesson learned from 137 cases. JAm Coll Surg 2000;191:613. 50. Doherty GM, Wells SA Jr. Parathyroid gland. In: Townsend CM (ed), Sabiston Textbook of Surgery. Philadelphia, WB Saunders, 2001, p 633. 51. Howe JR. Minimally invasive parathyroid surgery. Surg Clin North Am 2000;80: 1399. 52. Hosking DJ, Cowley A, Bucknall CA. Rehydration in the treatment of severe hypercalcaemia. Q J Med 1981;50:473. 53. Suki WN, Yium n, Von Minden M, et al. Acute treatment of severe hypercalcemia with furosemide. N Engl J Med 1970;283:836. 54. Chan FKW, Koberle LMC, Jacobs ST, et al. Differential diagnosis, causes, and management of hypercalcemia. Curr Probl Surg 1997;34:449. 55. Gucalp R, Ritch P, Wiernik PH, et al. Comparative study ofpamidronate disodium and etidronate disodium in the treatment of cancer related hypercalcemia. J Clin OncoI1992;10:134. 56. Sleeboom HP, Bijvoet OL, Van Oosterom AT, et al. Comparison of intravenous (3-amino-I-hydroxypropylidene)-I,I-bisphosphonate and volume repletion in tumour-induced hypercalcaemia. Lancet 1983;2:239. 57. Wisneski LA. Salomon calcitonin in the acute management of hypercalcemia. Calcif Tissue Int 1990;46(Suppl):S26. 58. Wisneski LA, Croom WP, Silva OL, et al. Salmon calcitonin in hypercalcemia. Clin Pharmacol Ther 1978;24:219. 59. Binshock ML, Mundy GR. Effect of calcitonin and glucocorticoids in combination on the hypercalcemia of malignancy. Ann Intern Med 1980;93:269. 60. Ralston SH, Gardner MD, Dryburgh FJ, et al. Comparison of aminohydroxypropylidene diphosphate, mithramycin and corticosteroids/ calcitonin in treatment of cancer-associated hypercalcaemia. Lancet 1985;2:907. 61. Watters J, Gerrard G, Dodwell D. The management of malignant hypercalcaemia. Drugs 1996;52:837. 62. Fatemi S, Singer FR, Reide RK. Effect of salmon calcitonin and etidronate on hypercalcemia of malignancy. Calcif Tissue Int 1992;50:107. 63. Ralston SH, Alzaid AA, Gardner MD, Boyle IT. Treatment of cancer associated hypercalcaemia with combined aminohydroxypropylidene diphosphate and calcitonin. Br Med J (Clin Res Ed) 1986;292:1549. 64. Sekine M, Takarni H, Satake S, et al. Treatment of skeletal and pulmonary metastases of differentiated thyroid carcinoma. Thyroidol Clin Exp 1997;9:89. 65. Takami H, Ogino Y, Tanaka K, et al. Somatostatin-receptor-negative carcinoid tumor responsible for Cushing's syndrome. Eur J Surg Oncol 1998;24:337.

Parathyroid Carcinoma Kerstin Sandelin, MD, PhD

Malignant transformation of a parathyroid gland is a truly rare phenomenon, and in most reported series of patients with primary hyperparathyroidism (PHPT) the incidence of carcinoma is less than I %. The inability to distinguish between some benign and malignant neoplasms still remains an important problem. Furthermore, the clinical course of malignant parathyroid tumors is quite variable. It is not uncommon to ascertain the diagnosis only after the tumor recurs locally or distant metastases develop. There are a few collective reviews and series from major cancer and endocrine surgical centers in which both clinicians and pathologists have presented data. I -5 Still, our knowledge about this unusual tumor has not increased much, and the treatment modalities are limited. Surgical excision remains the only potential method of curing this tumor, providing it is locally resectable. With the introduction of bisphosphonates, symptomatic, nontoxic, short-term palliation became available. In this chapter, the characteristic features of parathyroid carcinoma are emphasized, including its mode of presentation, clinical course, histopathologic findings, and biologic characteristics. Treatment options are discussed.

Incidence and Prevalence The incidence figures have not actually been affected since the introduction of autoanalyzers. As PHPT is no longer rare and is frequently diagnosed biochemically, the relative incidence of carcinomas has fallen because the majority of malignant cases present with symptomatic hypercalcemia (Table 63-1). Centers that have reported a higher incidence in the past may have had a selection bias as a result of being referral centers. The current exceptions are the Japanese centers that report a 10-fold higher incidence rate," for which epidemiologic factors may be responsible as well as infrequent screening for hypercalcemia. Familial segregation of parathyroid carcinoma is described in isolated familial hyperparathyroidism (HPT) and in association with multiple endocrine neoplasia (MEN) type 1.7-12 In two such independent families, no MEN I genetic deletions were found.l-'? The hyperparathyroidism-jaw tumor syndrome (HPT-JT), an autosomal dominant disorder, encompasses fibro-osseous lesions of the mandible and maxilla including uniglandular benign and malignant parathyroid neoplasms.

Previous radiation to the neck region associated with parathyroid carcinoma has been reported, although the association of radiation-induced benign tumor formation is more common.P Concomitant benign and malignant parathyroid tumors can occur." Gender and age have not proved to have predictive value because parathyroid carcinoma equally affects both genders and the peak age of diagnosis in the fifth decade of life is only slightly younger than that for patients with benign HPT.4,15-17

Clinical Presentation The differential diagnosis between severe benign HPT and parathyroid carcinoma is difficult. Therefore, every case involving the rapid onset of symptoms of HPT should be considered suspect for carcinoma. The target organs for HPT-induced hypercalcemia are the skeleton (40% to 70%), the kidneys (30% to 60%), and to a lesser extent the digestive system (i.e., pancreas and stomach-duodenum) (15%). In addition, general symptoms such as nausea, anorexia, constipation, polydipsia and polyuria, muscle weakness, fatigue, and depression are common findings. A palpable cervical mass is encountered in approximately 5%.10,15.17-20 Marked hypercalcemia, low serum phosphorus if renal function is not impaired, and a substantial elevation of serum parathyroid hormone (PTH) are common findings. With today's assays, which measure intact PTH, the diagnosis of PHPT is quickly established, and hypercalcemia caused by other malignancies can be ruled out. Moreover, there is no evidence that PTHrelated peptide (PTHrP) regulates serum calcium levels in adults, although PTH and PTHrP have a similar sequence of amino acids near the aminoterminus." Nonfunctioning parathyroid carcinomas, with a normal serum level of PTH, do occur but only in 5% of all parathyroid carcinomas."

Localization Studies As discussed in Chapter 46, localization studies are rarely ever necessary in primary operations for PHPT, whereas they are usually considered mandatory in reoperative cases regardless of the cause of the lesion. Doppman-' and Kaplan and colleaguesf rightly argued that the best localization

549

550 - - Parathyroid Gland

procedure is to find an excellent parathyroid surgeon. Ultrasonography, computed tomography (CT), magnetic resonance imaging, and scintigraphy with thallium or sestamibi all are highly efficient in the hands of a skilled operator. An additional advantage of ultrasonography is that it can be used during the operation, when it can relate the tumor to adjacent anatomic structures. For localization of recurrences or metastatic spread, a CT scan of the mediastinum, lungs, and abdomen may be of value in detecting mediastinal, lung, and liver metastases. Selective venous sampling for PTH, including distant samplings of iliac veins, may even detect remote lesions." In combination with any of the noninvasive techniques, it regionalizes the area of maximum secretion of PTH. A previous thyroid lobectomy affects the venous drainage and should be considered in evaluating the results of the venous sampling.P

Operative Findings and Histopathologic Characteristics Some macroscopic features are valuable in the intraoperative assessment of a potentially malignant tumor. These include color and findings by palpation. A grayish white tumor that is hard and grossly adherent to adjacent structures is highly suggestive of malignancy. Nonetheless, in a series of 95 cases of parathyroid carcinoma collected from centers with much experience in endocrine surgery, there was no correlation between macroscopic and microscopic findings. Invasiveness was recorded at histopathologic re-evaluation in only half of the tumors- Twenty percent of the patients were initially operated on for a benign diagnosis. Other studies have also confirmed the discrepancies in the gross appearance of the lesions." Glandular weight is more likely to be prominent, but again size alone cannot discriminate between benign and malignant tumors. The median glandular weight, available for evaluation in 35 of 95 cases, was greater than 4 g (range, 1 to 40 g).2 A major reason for the differences in incidence among centers can be the histologic criteria used. This has probably led to overdiagnosis of carcinoma in some series. 26-28 If only variables such as invasive growth pattern and metastases are used, the incidence is lower. Of 20 patients of Smith and Coombs,' at least 5 had no evidence of local infiltration,

recurrence, or metastases. In Shane and Bilezikian's review, 10 of 62 patients did not have these findings of malignancy.t-' In the previously mentioned series of 95 cases, presence or absence of local infiltrative growth pattern and metastases were used as absolute diagnostic criteria.' Two distinct groups could be separated. Fifty-six cases fulfilled these criteria, and 39 were called equivocal because these findings were absent. In the latter group, the tumors exhibited combinations of features such as fibrous bands, trabeculae, cellular atypia, and mitotic figures. None of these recurred during a median follow-up of 7 years (range, 0 to 22 years). In a second study, a more detailed histopathologic evaluation was undertaken, and a cytometric assessment of the crude DNA content of the tumor cell nuclei was also performed." There were significant differences between the carcinomas and the equivocal tumors in that the carcinomas predominantly showed a solid growth pattern with marked fibrosis. Even acinar and follicular structures were noted in tumors that eventually recurred. Among the cytologic features, the carcinoma cells were markedly atypical with macronucleoli (Fig. 63-1). These cells showed great variations in size and shape. In one third of the tumors that metastasized, no nuclear atypia could be demonstrated. Mitotic rate as a cell cycle marker has been one of the classic features for diagnosing parathyroid carcinoma. There was a significant difference in mitotic rate between carcinomas and the equivocal cases. Also, metastasizing tumors had a significantly elevated mitotic rate compared with nonrecurrent invasive tumors. Nevertheless, in 20% of the carcinomas, no mitosis was found in available sections analyzed. Necrosis has not been frequently described previously but was found in 30% of the carcinomas. In Table 63-2, a comparison of the histologic and cytologic features for both tumor groups is given. The aggressiveness of the tumors correlated with the histocytologic appearance, whereas nuclear atypia, necrosis, and mitotic activity were more frequent in metastasizing tumors than in invasive but nonrecurrent tumors.

Biologic Markers Parathyroid cells are characterized by very low turnover. Parfitt proposed a model of tumor formation starting from a

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FIGURE 63-1. Histologic section from a parathyroid carcinoma with enlarged nuclei and macronucleoli. (From Bondeson L, Sandelin K, Grimelius L. Histopathological variables and DNA cytometry in parathyroid carcinomas. Am J Surg Pathol 1993;17:825.)

set-point mutation leading to cell proliferation. Further mutational events that occur in the cell cycle can cause tumor formation that is either benign or malignant.30 An altered DNA content (i.e., nondiploid) has been associated with a proliferative state of the tumor as a result of genetic instability. It is considered one of the earliest cellular events during malignant transformation. Numerous studies have demonstrated a relationship between the DNA content of the tumor cell nuclei and the clinical outcome. Patients with diploid tumors fare better than those whose tumors contain an aberrant crude DNA content.J!-34 The ploidy pattern remains stable during tumor progression, as has been shown in studies of primary tumors and metastases. Quantitative DNA assessments have been performed in parathyroid carcinomas, and contradictory results were obtained.2.9.27.29.35-43 In the series of 95 cases, there was a clear association between an aberrant DNA content and an infiltrative growth pattern. The clinical course, measured as freedom from disease, also correlated with the DNA content. 2 When the DNA content was related to morphologic and cytologic features, significant associations were found between aberrant DNA values and the presence of necrosis, nuclear atypia, and mitosis." The proliferative activity, measured as percentage of cells in S phase, was significantly higher in a group of 15 parathyroid carcinomas compared with 31 normal and benign tumors.t? A number of cell cycle markers such as mitotic figures have been used to assess the malignancy potential of parathyroid tumors. The cellular phosphoprotein

p53 is a cell cycle regulator, and its role is to inhibit the progression of cells from G[ to S phase. Mutations of the p53 gene are common in human malignancies. However, neither benign nor malignant parathyroid tumors have been found to have p53 mutations." The parathyroid adenomatosis 1 gene (PRADlIcyclin Dl) encodes a protein closely associated with the cyclins that are important cell cycle regulators. Approximately 5% of benign parathyroid tumors have shown rearrangements of the PTH gene and PRADJ on chromosome 11.45.46 The same group of investigators reported that the retinoblastoma tumor suppressor gene RB, also a cell cycle regulator, was inactivated in parathyroid carcinomas. This was further supported by loss of expression, as determined by immunohistochemical staining. Conversely, benign parathyroid neoplasms showed no inactivation or loss of expression of RB.47 Frequent chromosomal imbalances were found in a series of 29 carcinomas studied with comparative genomic hybridization." The gene encoding HPTJT is a tumor suppressor gene called PARAIBROMIN, and its location is mapped to lq21-q32. There is reduced penetrance in females, and only 10% to 15% of patients manifest with a parathyroid carcinoma although serum calcium is markedly elevated." Two articles have reported the presence of somatic and gerrnline mutations of the HRPT2 gene in sporadic parathyroid carcinoma.v-"

Treatment Modalities Patients with parathyroid carcinoma frequently present with symptomatic hypercalcemia. They need prompt treatment and correction of renal and cardiac dysfunction because of the metabolic consequences of the high serum calcium levels. Rehydration with saline and additional electrolytes,

552 - - Parathyroid Gland including magnesium, restores glomerular function and increases urinary excretion. Loop diuretics also increase urine calcium secretion, provided that the patient is well hydrated. Calcitonin is an osteoclast inhibitor and promotes urinary calcium excretion. Its duration is short, waning after 48 to 72 hours of use. For preoperative treatment, however, a longer acting regimen is not always necessary. Plicamycin is an effective, short-acting osteoclast inhibitor that can be administered repeatedly. Its disadvantage is potential toxicity and patients' inability to tolerate adverse reactions such as nausea and vomiting. Phosphate, as either an oral or an intravenous compound, is effective in lowering serum calcium levels but is also poorly tolerated because of gastrointestinal side effects, and it can cause severe calcification in soft tissues when used intravenously. The bisphosphonates are pyrophosphate analogs and potent osteoclast inhibitors by inhibiting bone resorption when binding to hydroxyapatite. They also act as direct inhibitors of the formation of osteoclasts. 48,50.51-53 Three bisphosphonates are available at present, pamidronate, etidronate, and clodronate. The three compounds vary slightly in their mechanisms of action with regard to the effect on bone mineralization. Pamidronate is the most potent agent and causes a reduction in serum calcium levels within 24 to 48 hours. In patients with impaired renal function, repeated doses over 2 to 4 days may be given. Etidronate and clodronate also exist as oral compounds but are poorly absorbed. For prolonged use, clodronate can be given initially as an infusion with an expected effect after 2 to 5 days and then administered orally. No series have compared the effect of the various types of bisphosphonates in parathyroid carcinoma, but Ralston and colleagues showed in a small series that pamidronate had the longest median time to relapse, 23 days, compared with 12 days for the other two in cancer-associated hypercalcemia.v-" Only anecdotal reports on treated parathyroid carcinoma patients exist. With an initial good response and few side effects, however, the bisphosphonates are the preferred antihypercalcemic drugS.25,42.52,53 Gallium nitrate is a radionuclide that also has antineoplastic properties, and it lowers serum calcium levels by inhibiting bone resorption. Its effect on parathyroid carcinoma is limited to a few cases reported in the literature. WR 2721 acts by inhibiting PTH secretion, but, as with gallium nitrate, the experience is limited. 53•55 It is highly unlikely that radiation therapy or different kinds of chemotherapy are of any benefit to patients with recurrent disease. Nonetheless, each case should be assessed individually because responders to either therapeutic modality have been described.V" In approximately 20% of all primary operations, the diagnosis of parathyroid carcinoma was not expected either preoperatively or during the procedure.s" Nevertheless, the initial neck exploration is the most crucial time for achieving adequate local excision. The tumor should be excised en bloc with any locally invaded tissue such as a contiguous ipsilateral thyroid lobe. Capsular rupture must be avoided. Under no circumstances should an open biopsy be performed on a suspicious parathyroid tumor during an operation. Even rupture of a benign parathyroid tumor may cause future problems. It may be very difficult to differentiate benign tumor seeding (parathyromatosis) from carcinoma.V'" If the tumor

looks suspicious for carcinoma, it should be regarded as such until proved otherwise. Wider excisions and prophylactic neck dissections do not improve the prognosis.F" Lymph node metastases are uncommon, but any enlarged nodes in the ipsilateral central compartment should be excised. The recurrent laryngeal nerve has only rarely been infiltrated by tumor growth. Therefore, a careful dissection of the nerve is worthwhile unless it was proved dysfunctional preoperatively.

Recurrent Parathyroid Carcinoma The cervical region is by far the most common site for implants and local metastatic disease. However, parathyroid carcinoma does metastasize distantly, predominantly to the lungs, the liver, and the skeleton. Before any reoperative procedure, a careful study of previous operative notes to determine the initial location of the tumor and that of the other glands is recommended. Also, any previous archival tumor sections should be reviewed because the initial diagnosis may be incorrect. Time to recurrent disease is variable. In a series of 40 patients with metastatic disease, the median time to recurrence was 33 months (range, 1 to 228 months ).16 An aggressive surgical approach to recurrent diseases is often beneficial to the patient, and even repeated surgical procedures such as wedge resections for lung metastases are indicated. Surgical excision of metastatic lesions has been the single most effective treatment in palliating hypercalcemia. 16,42 For the histopathologic evaluation, it is advisable to obtain multiple sections. Whenever possible, some tumor tissue should be snap frozen in liquid nitrogen and stored at -70 0 C. This allows some of the molecular studies that still require fresh frozen tumor tissue. The technical considerations for reoperative HPT are outlined in another chapter.

Prognosis Patients with parathyroid carcinoma represent a heterogenous group. Some patients are "cured" for as long as a decade or more, whereas some with aggressive tumors experience recurrence early, with both local and distant spread. Of 40 patients with metastatic disease monitored over a median period of 7 years, 20 (50%) were still alive after 5 years and 14 (35%) after 8 years." Lifetime monitoring of patients with parathyroid carcinoma, with periodic measurement of serum calcium levels, is therefore advised. On the basis of histopathologic findings and biologic markers such as DNA ploidy and S phase, additional information about the prognosis can be obtained. With the rapid developments in molecular biology and cytogenetics, there is still hope for the development of discriminating markers and specifically designed anticancer drug therapy that might reduce the need for repeated surgery, with its associated morbidity.

Summary Parathyroid carcinoma is the least common malignancy among endocrine tumors. It varies in malignant potential

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from a minimally invasive local tumor with slow progression to an aggressive tumor with hematogenous metastasis and a rapid course, often with a fatal outcome because of unremitting hypercalcemia. The histopathologic pattern of these tumors more often shows prominent nuclear atypia, frequent mitosis, and an aberrant ploidy pattern with chromosomal rearrangements compared with benign parathyroid neoplasms. Recognition by the surgeon that the parathyroid tumor is malignant and performance of an adequate en bloc removal of the primary lesion, when appropriate, offer the best chance of local cure for a patient with this unusual malignancy.

REFERENCES 1. Holmes EC, Morton DL, Ketcham AS. Parathyroid carcinoma: A collective review. Ann Surg 1969;169:631. 2. Sandelin K, Auer G, Bondeson L, et al. Prognostic factors in parathyroid cancers: A review of 95 cases. World J Surg 1992;16:724. 3. Schantz A, Castleman B. Parathyroid carcinoma: A study of 70 cases. Cancer 1973;31:600. 4. Shane E, Bilezikian JP. Parathyroid carcinoma: A review of 62 patients. Endocr Rev 1982;3:218. 5. Smith JF, Coombs RRH. Histological diagnosis of carcinoma of the parathyroid gland. J Clin PathoI1984;37:1370. 6. Fujimoto Y,Obara T, Ito Y, et al. Localization and surgical resection of metastatic parathyroid carcinoma. World J Surg 1986;10:539. 7. Dinnen JS, Greenwood RH, Jones JH, et al. Parathyroid carcinoma in familial hyperparathyroidism. J Clin Pathol 1977;30:966. 8. Frayha RA, Nassar VH, Dagher F, Salti IS. Familial parathyroid carcinoma. J Med Liban 1972;25:299. 9. Mallette LE. DNA quantitation in study of parathyroid lesions. Arn J Clin Pathol 1992;98:305. 10. McHenry CR, Rosen m, Walfish PG, Cooter N. Parathyroid crisis of unusual features in a child. Cancer 1993;71:1923. 11. Streeten E, Weinstein LS, Norton JA, et al. Studies in a kindred with parathyroid carcinoma. J Clin Endocrinol Metab 1992;75:362. 12. Wassif WS, Moniz CF, Friedman E, et al. Familial isolated hyperparathyroidism: A distinct genetic entity with increased risk of parathyroid cancer. J Clin Endocrinol Metab 1993;77:1485. 13. Christmas TJ, Chapple CR, Noble JG, et al. Hyperparathyroidism after neck irradiation. Br J Surg 1988;75:873. 14. Shapiro DM, Recant W, Hemmati M, et al. Synchronous occurrence of parathyroid carcinoma and adenoma in an elderly woman. Surgery 1989;106:929. 15. Granberg PO, Cedermark B, Farnebo La, et al. Parathyroid tumors. Curr Probl Cancer 1985;9:1. 16. Sandelin K, Tullgren 0, Farnebo L. Clinical course of metastatic parathyroid cancer. World J Surg 1994;18:594. 17. Wang C, Gaz RD. Natural history of parathyroid carcinoma: Diagnosis, treatment, and results. Arn J Surg 1985;149:522. 18. Obara T, Fujimoto Y. Diagnosis and treatment of patients with parathyroid carcinoma: An update and review. World J Surg 1991;15:738. 19. Shortell CK, Andrus CH, Phillips CE, Schwartz SI. Carcinoma of the parathyroid gland: A 30 year experience. Surgery 1991;110:704. 20. Trigonis C, Cedermark B, Willems J, et al. Parathyroid carcinomaProblems in diagnosis and treatment. Clin Oncol 1984;10:11. 21. Segre GY. Receptors for parathyroid hormone and parathyroid hormone related protein. In: Bilezikian JP (ed), The Parathyroids. New York, Raven Press, 1994, p 213. 22. Murphy MN, Glennon PG, Diocee MS, et al. Nonsecretory parathyroid carcinoma of the mediastinum: Light microscopic, immunohistochemical, and ultrastructural features of a case and review of the literature. Cancer 1986;55:2468. 23. Doppman JL. Preoperative localization of parathyroid tissue in primary hyperparathyroidism.In: Bilezikian JP (ed), The Parathyroids. New York, Raven Press, 1994, p 553. 24. Kaplan EL, Yashiro T, Salti G. Primary hyperthyroidism in the 1990s. Ann Surg 1992;215:300. 25. Sandelin K, Thompson NW, Bondeson L. Dilemmas in management of parathyroid carcinoma. Surgery 1991;110:978.

26. Vetto JT, Brennan MF, Woodruf J, Burt M. Parathyroid carcinoma: Diagnosis and clinical history. Surgery 1993;114:882. 27. Anderson BJ, Samaan NA, Vassilopoulou-Sellin R, et al. Parathyroid carcinoma: Features and difficulties in diagnosis and management. Surgery 1983;94:906. 28. McKeown PP, McGarity WC, Sewell CWO Carcinoma of the parathyroid gland: Is it overdiagnoses? Arn J Surg 1984;147:292. 29. Bondeson L, Sandelin K, Grimelius L. Histopathological variables and DNA cytometry in parathyroid carcinomas. Arn J Surg Pathol 1993; 17:820. 30. Parfitt AM. Parathyroid growth. In: Bilezikian JP (ed), The Parathyroids. New York, Raven Press, 1994, p 373. 31. Falkmer VG, Hagmar T, Auer G. Efficacy of combined image and flow cytometric DNA assessments in human breast cancer: A methodological study based on a routine histopathological material of 2024 excised tumor specimens. Anal Cell PathoI1990;2:297. 32. Moberger B. DNA content and prognosis in endometrial carcinoma [Medical dissertation]. Stockholm, Karolinska Institute, 1989. 33. Munck-Wikland E, Auer G, Kuylenstierna R, et al. Image cytometry DNA analysis of invasive squamous cell carcinoma of the esophagus. Anticancer Res 1989;93:545. 34. Tallroth Ekman E, Bergholm V, Backdahl M, et al. Nuclear DNA content and survival in medullary thyroid carcinoma. Cancer 1990;65:511. 35. August DA, Flynn SD, Jones MA, et al. Parathyroid carcinoma: The relationship of nuclear DNA content to clinical outcome. Surgery 1993; 113:290. 36. Bonjer HI, Birkenhager JC, Bruining HA, et al. Single and multiglandular disease in primary hyperparathyroidism: Long term follow up studies, histological studies and DNA analyses in 693 patients. Presented at the 34th World Congress of Surgery of the ISS/SIC and the 12th World Congress of the CICD, Stockholm, 1991. 37. Bowlby LS, DeBault LE, Abraham SR. Flow cytometric DNA analysis of parathyroid glands: Relationships between nuclear DNA and pathologic classifications. Arn J PathoI1987;128:338. 38. Harlow S, Roth SI, Bauer K, Marshall RB. Flow cytometric DNA analysis of normal and pathologic parathyroid glands. Mod Pathol 1991; 4:310. 39. Howard S, Anderson C, Diels W, et al. Nuclear DNA density of parathyroid lesions. Pathol Res Pract 1992;188:497. 40. Joensuu H, Klemi PI. DNA aneuploidy in adenomas of endocrine organs. Am J PathoI1988;132:145. 41. Obara T, Fujimoto Y, Kanaji Y, et al. Flow cytometric DNA analysis of parathyroid tumors. Cancer 1990;66: 1556. 42. Obara T, Okamoto T, Yamashita T, et al. Surgical and medical management of patients with pulmonary metastases from parathyroid carcinoma. Surgery 1993;114:1040. 43. Shenton BK, Ellis H, Johnston IDA, Farndon JR. DNA analysis and parathyroid pathology. World J Surg 1990;14:296. 44. Hakim JP, Levine MA. Absence of p53 mutations in parathyroid adenoma and carcinoma. J Clin Endocrinol Metab 1994;78:103. 45. Arnold A. Molecular basis of primary hyperparathyroidism.In: Bilezikian JP (ed), The Parathyroids. New York, Raven Press, 1994, p 407. 46. Arnold A, Kim HG, Gaz RD, et al. Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest 1989;83:2034. 47. Cryns VL, Thor A, Xy HJ, et al. Loss of the retinoblastoma tumor suppressor gene in parathyroid carcinoma. N Engl J Med 1994;330:757 48. Kytola S, Farnebo F, Obara T, et al. Patterns of chromosomal imbalances in parathyroid carcinomas. Am J Pathol 2000;157:579. 49. Chen JD, Morrison C, Zhang C, et al. Hyperparathyroidism-jaw tumour syndrome. J Intern Med 2003;253:634. 50. Shattuck TM, Valimaki S, Obara T, et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 2003;349: 1722. 51. Howell VM, Haven CJ, Kahnoski K, et al. HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. J Med Genet 2003 ;40:657. 52. Kebebew E, Clark OH. Parathyroid adenoma, hyperplasia, and carcinoma: Localization, technical details of primary neck exploration, and treatment of hypercalcemic crisis. Surg Oncol Clin N Arn 1998;7:721. 53. Rodan GA. Bisphosphonates and primary hyperparathyroidism. J Bone Miner Res 2002;17(SuppI2):NI50. 54. Ralston SH, Patel V, Fraser WD, et al. Comparison of three intravenous bisphosphonates in cancer associated hypercalcemia. Lancet 1989;2:1180.

554 - - Parathyroid Gland 55. Glover DJ, Shaw L, Glick JH, et aJ. Treatment of hypercalcemia in parathyroid cancer with WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioic acid. Ann Intern Med 1985;103:55. 56. Wynne AG, Heerden van J, Carney JA, Fitzpatrick LA. Parathyroid carcinoma: Clinical and pathologic features in 43 patients. Medicine (Baltimore) 1992;71:197.

57. Fitko R, Roth SI, Hines JR, et aJ. Parathyromatosis in hyperparathyroidism. Hum PathoI1990;21:234. 58. Fraker DL, Travis WO, Merendono 11 Jr, et aJ. Locally recurrent parathyroid neoplasms as a cause for recurrent and persistent primary hyperparathyroidism. Ann Surg 1991;213:58.

Surgical Embryology and Anatomy of the Adrenal Glands Raducu Mihai, MD, PhD, MRCS • John R. Farndon, BSc, MD, FRCS

Historical Background The adrenal glands were first described in 1552 by Bartholomaeus Eustachius in his Opuscula Anatomical as "glandulae renis incumbentes" (glands lying on the kidney). His work was printed again in 1722 by Lancisus, long after Galen, da Vinci, and Vesalius failed to recognize their existence.? In 1629, Jean Riolan of Paris introduced the term capsulae suprarenales, which persisted for many years.? Their function remained controversial for the next 300 years. In 1716, the Academie des Sciences de Bordeaux offered a prize for the answer to the question "What is the purpose of the suprarenal glands?" but no progress was achieved. In the 18th century, Edward Home thought that they "form a reservoir in which some other substance is laid up in store, till wanted.'? In 1805, Cuvier defined the anatomic division into a cortex and a medulla" without suggesting any functional role of the adrenals. In 1855, Thomas Addison of Guy's Hospitals published his clinicopathologic observations of 11 patients with destruction of both adrenal glands and described the eponymous clinical syndrome. The following year, Brown-Sequard" performed unilateral and bilateral adrenalectomy in animals and provided the first experimental confirmation of Addison's theory that the adrenal glands were essential to life. In 1895, the London physiologists George Oliver and Edward Sharpey-Schafer described the presence of a substance in the adrenal medulla that elevated the blood pressure in dogs and named it adrenaline.' Their observation was confirmed in 1897 by John Abel, professor of pharmacology at the Johns Hopkins University School of Medicine, who isolated the active compound and named it epinephrinei In 1901, epinephrine was purified from the adrenal gland; subsequently, epinephrine and norepinephrine were first synthesized by Frank Stolz in Germany in 1904.9 In the 1940s, von Euler'? and Holtz and associates I I identified norepinephrine in nerve endings and the adrenal gland, and the a-adrenergic and ~-adrenergic receptors were first described by Ahlquist in 1948. 12

Surgery of the adrenal glands emerged as part of abdominal surgery at the end of the 19th century, when abdominal masses were found at operation or autopsy to be adrenal in origin. Slowly, different adrenal syndromes and tumors were distinguished. In 1865, DeCrecchio first reported congenital adrenal hyperplasia in a female pseudohermaphrodite. In 1886, Frankel':' described a type of tumor for which the pathologist Pick in 1912 proposed the name pheochromocytoma." from the Greekphaios (dark or dusky) and chroma (color). In 1912, Harvey Cushing described the classic features of his eponymous syndrome, IS and in 1955, Conn reported the first patient with primary hyperaldosteronism. 16 In the early 1960s, Sipple'? and Werner" described patients with multiple endocrine tumors (multiple endocrine neoplasia [MEN] syndromes). Successful surgical treatment of adrenal disease evolved from 1889, when Knowsley-Thomton reported the removal of a large adrenal tumor.' In 1926, Roux in Lausanne, Switzerland, and Charles Mayo in Rochester, Minnesota, successfully removed a pheochromocytoma. Efforts to provide substitutive therapy in patients with adrenocortical insufficiency were made as early as 1856 by Brown-Sequard, and early attempts at adrenal transplantation were made by Pybus in 1924 in patients with Addison's disease.!? Introduction of cortisone replacement therapy in 1949 was preceded in the 1930s by the work of Reichtenstein and Shopper in Switzerland" and Kendall?' of the Mayo Clinic, whose biochemical studies led to the understanding of the structure and synthesis of adrenocortical steroids. Their work resulted in the award of the Nobel Prize in physiology and medicine in 1950. More recent advances have dramatically changed the understanding of adrenal physiology and pathology. The hypothalamic factor controlling the pituitary-adrenal axis (corticotropin-releasing hormone [CRH]) was characterized and synthesized by Vale and coworkers in 1981. 22 The structure of corticotropin precursor-pro-opiomelanocortin (POMC), its messenger RNA, and its gene have been described. Specific intracellular location of the steroidogenic

557

558 - - Adrenal Gland cytochrome P-450 enzymes and the genes that encode them have been identified. The elucidation of the structure of the steroid receptors and the genes that encode them provides insight into the mechanism by which the steroid-receptor complex interacts with specific DNA areas (called glucocorticoid response elements) to regulate transcription of target genes. Therapeutic possibilities have increased significantly, from the first synthesis of corticosterone in 1949, to the first inhibitors of steroidogenesis in the 1960s, to the recent development of inhibitors of steroid receptors (as mifepristone [RU-486]). Surgical intervention continues to play an important role in many diseases of the hypothalarnic-pituitary-adrenal axis. An understanding of the embryology and anatomy of the adrenal glands is an essential prerequisite to successful and effective adrenal surgery.

Embryology The adrenals have a dual origin: the cortex arises from mesoderm, whereas the medulla has a neuroectodermal origin. The cortex starts to develop in the fifth week of gestation as a proliferation of coelomic mesothelium into the underlying mesenchyme between the root of the dorsal mesogastrium (the root of the mesentery) and the urogenital ridge (the mesonephros and the developing gonad). This close proximity explains why ectopic adrenal tissue has been described to be located below the kidneys and associated with the testes or ovaries. Initially, large acidophilic cells form the fetal or primitive cortex (Fig. 64-1A).23 Shortly afterward, a second wave of cells from the mesothelium penetrates and surrounds the original acidophilic cells; these cells, smaller than those of the first wave, later form the definitive cortex of the gland. The proliferating adrenal tissue extends from the level of the thoracic segments 6 to 12 and becomes larger than the kidney at midgestation." The fetal cortex undergoes rapid

degeneration in the first 2 weeks after birth, so that it accounts for only one quarter of the cortical mass at age 2 months and has vanished by 1 year. The fascicular and reticular zones of the adult cortex proliferate from the glomerular zone after birth and are fully differentiated by about the 12th year.24 The embryogenesis of the adrenal medullary cells starts in the second month of gestation. Before this, during the fourth week of embryonic life, the neural plate develops and then infolds to form the neural tube. A portion of the neuroectoderm adjacent to the tube separates and remains between the neural tube and the definitive ectoderm as the neural crest. Cells derived from the neural crest (sympathogonia) migrate ventrally from the apex of the neural tube to the dorsal aorta (where they aggregate and differentiate into neuroblasts to form sympathetic neurons) or to the adrenal primordia (where they differentiate into pheochromoblasts to form chromaffin cells) (Fig. 64-1B).25 Some primitive adrenal medullary cells remain closely associated with the developing sympathetic nervous system and give rise to the extra-adrenal chromaffin cells and chromaffin bodies. Extra-adrenal chromaffin cells are, therefore, found in the abdominal preaortic sympathetic plexus or in the paravertebral sympathetic chain. Postnatally, most of the extra-adrenal chromaffin cells begin to degenerate, whereas those of the adrenal medulla complete maturation. In the fetus, catecholamine secretion increases in response to hypoxia and hypoglycemia.P The chromaffin reaction is positive by the fifth month of fetal life, but epinephrine is present as early as the third month. The fate of the cells migrating from the neural crest can be altered by changing their environment (for reviews, see Le Douarin's study"). Progenitors from the fetal adrenal gland have been isolated and proven to be bipotential (able to develop into either chromaffin cells, under the effect of high concentration of glucocorticoids, or sympathetic neurons). Glucocorticoids act through type II receptors to upregulate the expression of phenylethanolamine N-methyltransferase (PNMT) and the epinephrine-synthesizing

FIGURE 64-1. Embryology of human adrenals. A, Longitudinal sectionof a human embryo at 50 days postconception. Note the size of

the adrenal in relation to the kidney primordium. A =adrenal cortex; L =liver; G =gut; Gn =gonad; K =kidneyprimordium; S =spine.

B, Section of human embryoat 56 days postconception. At this stage,medullary cells (M) haveinvaded the adrenalcortex. The kidney pri-

mordium (K) has further evolved. Sections were stained with hematoxylin-eosin. (Courtesy of Professor Jeremy Berry, Department of Paediatric Pathology, St. Michael'sHospital, Bristol, England.)

Surgical Embryology and Anatomy of the Adrenal Glands - - 559

enzyme and also act negatively to inhibit the neural differentiation induced by nerve growth factor (Fig. 64-2). The plasticity characteristic of the early development of the sympathoadrenalcells is maintained later in life. For example, intracerebraltransplantationof adrenal medullary cells into the paraventricular areas in humans has been attempted as treatment for patients with Parkinson's disease; the transplanted cells produce dopamine, confirming the theory of the adrenal medullaas a catecholarninergic ganglion, and hence ameliorate the symptoms of Parkinson's disease (which is due to a degenerative loss of dopaminergic neurons in the basal ganglia).

Development of Adrenal Arteries The acquisition of a vascular supply occurs at a very early stage in development. Capillaries, which arise from the adjacent mesonephric arteries, penetrate the cortex in a radial manner. The arterial blood supply during fetal period is highly variable in both the origin and the number of adrenal arteries, as well as in the asymmetry of the blood supply between the left and right adrenal glands. Initial branches

Bipotential sympathoadrenal _ progenitor

F~~;~:

/

arise from the aorta, from the vessels to the septum transversum (later the central part of the diaphragm), and from the mesonephric arteries. The inferior phrenic artery is the main arterial supply for the fetal adrenal."

Embryology and Steroidogenesis Function in the fetal cortex begins as early as the seventh week of gestation'" and steroidogenesis in the outer layers begins toward the end of the second trimester and is maximal by the third trimester. It has generally been considered that the major role of the primate placenta is to convert biologically active cortisol to its inactive metabolite cortisone (which does not bind to the glucocorticoid receptor) and so protect the fetus from the relatively high concentrations of steroid present in the maternal circulation. The placenta plays a pivotal role in the sequence of events culminating in fetal adrenal development and function. The fetus produces large amounts of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) from circulating

SA-1+

HNK-1+

B2-

depolariZ/"

~B2+ ~

SA-1+

•

Committed neuroblast

SA-1+

Chromaffin precursor

1

NGF!

High glucocorticoid

NF+ SCG10++

Sympathetic neuron

_

PNMT+

Adrenergic chromaffin cell ~

chromaffin-specific gene expression

IlIIIIIIIlI neuron-specific gene expression FIGURE 64-2. Progressive stages in the development of sympathoadrenal (SA) lineage. Changes in marker expression that correlate with these stages are shown. Cross-hatched lines in the bipotential SA progenitor indicate that both neuron-specific and chromaffin-specific genes are coexpressed. Monoclonal antibodies (HNK-l) are used to isolate bipotential SA progenitors from rat adrenal glands. SA-l antigen is a chromaffin cell marker and B2 antigen is specific for neuronal precursors. High levels of glucocorticoids induce differentiation of chromaffin cells. SA progenitor cells initiate neuronal differentiation in response to basic fibroblast growth factor (FGF), lose competence to respond to glucocorticoids, subsequently develop a dependence on nerve growth factor (NGF) for further maturation and survival, and when mature, can be identified with the use of antineurofilament (NF+) antibodies. PNMT = phenylethanolamine N-methyitransferase. (Adapted from Anderson DJ. Molecular control of cell fate in the neural crest: The sympathoadrenal lineage. Annu Rev Neurosci 1993;16:129.)

560 - - Adrenal Gland acetate and cholesterol. The placenta then removes sulfate from DHEA-S, which is further transformed by 3~-hydroxysteroid dehydrogenase (3~-HSD) (an enzyme not present in the fetal adrenal cortex) and used in the estrogenic pathway. The availability of DHEA-S for placental estrogen production is controlled by a positive feedback loop in which estrogen enhances production of precursor DHEA-S from fetal adrenal cells. The large amounts of estrogen produced by the placenta indicate the presence of an intact and functional fetoplacental unit. The fetal adrenal does not develop the enzymatic capacity to produce cortisol de novo (i.e., from endogenous cholesterol) until very late in gestation because of a lack of key ratelimiting steroidogenic enzymes (as 3~-HSD). At midgestation, essentially 100% of cortisol in fetal serum is of maternal origin. The increased placental oxidation of cortisol to cortisone provides the stimulus for fetal hypothalamic-pituitary axis function and the timely onset of de novo cortisol production. It is postulated that because the fetal production of corticosteroids is reduced, the adrenals are stimulated continuously by high levels of corticotropin and become enlarged." At term, less than 50% of fetal cortisol originates from hormone produced by the maternal adrenal.

Clinical Aspects At birth, the gland is about one third the size of the kidney, whereas in the adult, it is only about one thirtieth. This change in proportions is due not only to renal growth but also to involution of the fetal cortex after birth, so that by the end of the second postnatal month its weight is only half that at birth. In the latter half of the second year, the gland begins to increase in size and gradually attains its birth weight at or just before puberty, after which it only increases slightly in weight in adult life. ACCESSORY TISSUE

Small accessory suprarenal glands, which may consist of cortical tissue only, often occur in the areolar tissue around the principal glands. They are sometimes present in relation to the sympathetic plexus and in relation to structures derived from the urogenital ridge: epididymis, vas deferens, broad ligament of the uterus, ovarian pedicle, or within the ovary or testis. Adrenocortical rests may occur in 50% of newborn infants but tend to atrophy and disappear after a few weeks. They persist and enlarge in the adrenogenital syndrome or any condition of continued corticotropin stimulation. Those within the scrotum may be misinterpreted as testicular tumors. Ectopic medullary tissue also occurs, occasionally in conjunction with cortical tissue but more often alone, as isolated masses along the abdominal aorta or in association with the sympathetic chain and the plexus (the retroperitoneal celiac plexus). These have been described by Zuckerkandl." whose name is associated with an especially large mass that may occur anterior to the aorta and distal to the origin of the superior mesenteric artery. Coupland characterized these masses as paraganglia or chromaffin bodies. Ten percent of pheochromocytomas develop in "accessory" sites, particularly in ganglia around the aorta at the level of the kidney, anterior to the inferior aorta (at the level of the organ of Zuckerkandl), in the mediastinum, or in

the bladder. Occasionally, they have been reported in the neck, sacrococcygeal, anal, or vaginal areas. The incidence of extraadrenal pheochromocytoma is higher in children than adults. Tumors of sympathoadrenal lineage (affecting mainly children) correspond to discrete stages of differentiation in this lineage and are derived from the neural crest cells. They can be located in the adrenal medulla and sympathetic ganglia and are often associated with excessive production of catecholamines and catecholamine metabolites. Neuroblastoma, the most immature and malignant of these tumors, can be considered derivatives of primitive sympathogonia or neuroblasts. Ganglioneuroblastomas are partially differentiated neuroblastomas, and ganglioneuroma is the benign form, derived from sympathetic ganglion cells. Tumors showing an immature (neuroblast) phenotype appear to have a latent capacity to differentiate into more mature tissue and have a much higher probability of spontaneous remission than those of chromaffin type. Potential therapy for the more malignant chromaffin-like tumors might involve in situ conversion to neuroblastic-type tumors using nerve growth factor or glucocorticoid antagonists." Chromaffin cells are included in the amine precursor uptake and decarboxylation (APUD) cell group described by Pearse" on the basis of functional characteristics and embryologic origin. Tumors of the chromaffin tissue can occur in association with tumors of other cells of the APUD system, such as medullary carcinoma of the thyroid and hyperparathyroidism (as in MEN 2 syndrome).

Anatomy The adrenals are retroperitoneal organs resting on either side on the crura of the diaphragm. They lie on each side of the vertebral column (TlI-12), against the superomedial surface of the corresponding kidney, and are surrounded by a thin layer of loose areolar connective tissue and a thick fibrous capsule. This makes them easily separated from the superior pole of the kidney. The adrenal glands are held in position by numerous fibrous bands and vascular attachments.

Macroscopic Aspect The adrenal glands are darker yellow and have a finely granular surface and firm consistency compared with the surrounding perirenal fat. Each gland in the adult measures about 50 mm vertically, 30 mm transversely, and 10 mm in the anteroposterior plane (Fig. 64-3). Each gland normally weighs about 4 to 5 g regardless of age, body weight, and gender but may weigh as much as 22 g at autopsy, apparently because of the stress of terminal illness. The glands' yellowish brown color is due to the presence of lipoid substances. Up to 3% of normal adults may have macroscopic nodules in the adrenal gland." Micronodular changes are seen in two thirds of normal adults.P

Relations The right adrenal gland is triangular or pyramidal, with the apex superior and the base embracing the kidney (see Fig. 64-3). It lies anterior to the diaphragm and the right

Surgical Embryology and Anatomy of the Adrenal Glands - -

561

FIGURE 64-3. Macroscopic appearance of the adrenal glands. The size and shape of normal adrenal glands can be seen. A, Superior view. B, Inferior view. C, Cross section of the adrenal gland; the yellowish outer cortex can be differentiated from the brown medulla. The dark staining of the innennost part of the cortex (the zona reticularis) is due to the presence of lipofuscin within its cells. The adrenal vein emerging from the medullary area is easily seen. (Courtesy of Dr. Ed Sheffield, Department of Histopathology, Bristol Royal Infirmary, Bristol, England.)

kidney and posterior to the inferior vena cava and the right lobe of the liver. Superiorly, the gland is in contact with the bare area of the liver. If the inferior layer of the right triangular or coronary ligament of the liver is especially high, the right adrenal gland may reside partially in the upper part of the right paracolic gutter (Morison's pouch), where it is immediately in contact with peritoneum. Its hilum is on its anterior surface, a little inferior to the apex, and usually a single right adrenal vein emerges from the hilum.>' The left adrenalgland is crescentic and semilunar in shape (see Fig. 64-3) and extends further inferiorly on the medial margin of the kidney. It is related anteriorly to the stomach and pancreas and posteriorly to the diaphragm. Unlike the right adrenal, the left adrenal gland is largely covered anteriorly by peritoneum of the lesser sac. If the reflection of the gastrophrenic ligament is far medially, it is also covered by the peritoneum of the greater sac in the region of the left paracolic gutter.A variable small area of the left adrenal gland may lie in immediate contact with the stomach, near the cardioesophageal junction, with no intervening peritoneum (where the left gastric artery, from its position on the left crus of the diaphragm, enters the lesser omentum to gain the lesser curvature of the stomach). 34 Each gland has an anterior and posterior surface and a medial border, and the topographic anatomic relations are

summarized in Table 64-1. These relationships are important for understanding the radiologic anatomy (Fig. 64-4). The adrenal glands have a proper capsule that invests them closely, which extends as connective tissue septa carrying vessels into the interior of the gland. In addition, they share with the kidneys a second capsule-the perirenal fascia (Gerota's fascia); a considerable amount of fat lies within the perirenal space between the perirenal fascia of Gerota and the true capsules of the adrenals and the kidneys. Superiorly, the perirenal fascia is enclosed and fades out on the inferior surface of the diaphragm; inferiorly, the perirenal fascia is open and the perirenal fat merges with that of the iliac fossa, which could explain cases of mobile or ectopic kidneys. The anterior lamina of the perirenal fascia fades out in the fascia over the aorta, inferior vena cava, and other midline structures; the perirenal space does not extend across to the other side." The inclusion of the adrenal glands within Gerota's fascia is of importance surgically because the adrenals may be dissected from within the perirenal fat without compromising the peritoneum or the midline structures. Outside Gerota's fascia lies the pararenal fat, anterior to which is the fascia of Zuckerkandl. It limits the retroperitoneum anteriorly and represents a remnant of the old mesentery of the ascending and descending colon and

562 - -

Adrenal Gland

duodenum that have become secondarily adherent to the posterior abdominal peritoneum during development. Kocher's maneuver in the mobilization of the duodenum and pancreas takes advantage of the loose adhesions in the plane of Zuckerkandl's fascia.

Arterial Supply The glands have a profuse arterial supply with three main groups of vessels that divide before entering the gland and have three distinct sources: the inferior phrenic artery, the aorta, and the renal artery. As the inferior phrenic arteries pass just above and medial to the suprarenal glands, each artery usually gives off a series of branches into the gland on its own side before it

supplies the diaphragm. These arteries constitute the superior suprarenal arteries, which enter the upper part of the gland over a considerable extent. There usually is at least one artery to each gland from the aorta, just above the origin of the renal arteries: the middle suprarenal artery. One or more arteries reach the gland from the adjacent renal artery, and these are the inferior suprarenal arteries. In addition to these three regular sources of blood supply, other vessels running close by may also supply branches to the suprarenal gland. Most constant of these are branches from the intercostal, the left ovarian, or the left internal spermatic arteries. Because any arteries approaching the gland may branch and rebranch, the number of vessels entering it may be

FIGURE 64-4. Radiologic anatomy of the adrenal glands. A, CT section in the horizontal plane. The superior relationship with the liver and diaphragm and the inferior relationship with the right kidney can be seen. B, MRI in the longitudinal (axial) plane from a patient with right adrenal tumor. (Courtesy of Dr. Julian Cabala, Department of Radiology, Bristol Royal Infirmary, Bristol, England.)

Surgical Embryology and Anatomy of the Adrenal Glands - - 563 quite numerous. There is no regular position in which these branches enter the gland. This anatomic detail is important for two reasons: (1) when approaching the adrenal glands, dissecting within the perirenal fat, encountering these small arteries and veins heralds proximity of the gland; and (2) the feeding vessels bleed in an irritating manner unless dealt with by diathermy or clip ligature. Most of the branches of the suprarenal arteries ramify over the capsule before entering the gland and dividing within to form a narrow subcapsular plexus. Short cortical arteries arising from the subcapsular plexus give rise to an extensive network of sinusoidal capillaries that occupies the interstices among clusters of cells in the zona glomerulosa and among the cell columns of the zona fasciculata, and then form a deep plexus located in the zona reticularis. These capillaries are fenestrated; pores range in size from 100 nm in the outer cortex to 250 nm in the inner fasciculata and reticularis. There is no direct arterial blood supply to the zonae fasciculata and reticularis (Fig. 64_5).36,37 From the deep plexus, small venules pass between chromaffin cells of the medulla to the medullary veins, which they enter by passing between prominent bundles of longitudinally arranged muscle fibers. It appears that these bundles of fibers regulate blood flow at the corticomedullary junction (at the deep aspect of the zona reticularis). Because this would, in turn, control the rate of blood flow through the zona reticularis and zona fasciculata, it could provide part of a control mechanism for the availabilityof corticotropin to the secretory cells of these regions and hence of its possible uptake. Some major arterial branches bypass the system described previously and supply the medulla directly to provide a dual blood supply, indirect and direct. Blood coming through the indirect route (i.e., by way of the cortical sinusoids) is sufficiently rich in glucocorticoids to induce and maintain synthesis of PNMT, the enzyme needed for the

synthesis of epinephrine from norepinephrine. More than 95% of epinephrine originates from the adrenal medulla because of this anatomic-biochemical proximity. Changes in the relative blood supply may, therefore, have profound physiologic consequences. Medullary capillaries are fenestrated, which may allow free diffusion of released catecholamines. Despite the rich vascularity, the blood flow of the normal adrenal is about 10 mUmin, but the supply to both the medulla and the cortex increases under stress; corticotropin produces an immediate increase in blood flow to the adrenals.

Venous Drainage In contrast to the arteries, the main drainage of the gland is usually into a single large suprarenal (central) vein, leaving the gland through the hilum. The right one is short (0.5 em) and drains directly into the inferior vena cava. Ligature of the right adrenal vein can, therefore, be difficult, and individual peculiarities of the local anatomy sometimes oblige the surgeon to side-clamp the vena cava. On the left side, the suprarenal vein is longer (",,2 ern) and is usually joined by the inferior phrenic vein, which empties into the left renal vein. Smaller emissary veins may drain into the inferior phrenic, renal, and, rarely, hepatic portal veins." The central vein has two to four conspicuous longitudinal smooth muscle bundles, the function of which is unknown. Presumably, they constrict the outflow from the gland and may increase the exposure of cortical cells to systemic factors (corticotropin) and the exposure of medullary cells to cortisol.

Lymphatic Drainage There are two plexus: one deep to the capsule and one in the medulla. Many lymph vessels leave the suprarenal gland and end in the lateral aortic lymph nodes and in the para-aortic nodes near the crus of the diaphragm and the origin of the renal artery. Some lymphatic vessels pierce the diaphragm and drain toward the thoracic duct or the posterior mediastinum, which explains the development of distant and early metastases of cortical malignant tumors. When operating on a suspected malignant tumor of the adrenal glands, immediately adjacent, para-aortic, and paracaval nodes must be checked for evidence of local metastasis.

Nerve Supply

FIGURE 64-5. Scanning microscopy of adrenal vessels. (From Kikuta A, Mukarami T. Microcirculation of the rat adrenal gland: A scanning electron microscope study of vascular casts. Am J Anat 1982;164:22.)

The medulla is a neuroendocrine transducer, a structure that transforms the nervous signal (encoded electrically as action potentials) into an endocrine signal (chemically encoded). There is a rich nerve supply consisting of myelinated cholinergic preganglionic sympathetic fibers, which pass through the hilum and synapse on cells in the medulla. These fibers terminate in synapses with the pheochromocytes, which are, therefore, equivalent to postganglionic sympathetic neurons. The cell bodies of the neurons innervating the adrenal medulla originate in the intermediolateral cell column between T3 and L3. The greater proportion of the innervation reaches the adrenals through the ipsilateral greater thoracic splanchnic nerve (T5 to T9).

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Catecholamines are released into the systemic circulation after stimulation of the greater splanchnic nerve. Its branches end in relation to the medullary cells in a manner comparable to the synapse: acetylcholine is released on stimulation, acts on muscarinic receptors on the pheochromocytes' membranes, and alters their permeability, permitting influx of calcium, which triggers exocytosis of catecholamines. The medullary cells stand in the same relation to the preganglionic sympathetic fibers as the postganglionic cells. Relative to its size, the adrenal has a larger autonomic supply than any other organ. Spinal cord transection above T3 is usually associated with deficient epinephrine secretion. The role of sympathetic input on catecholamine release is also demonstrated by the decrease of plasma catecholamine levels in normal people after treatment with clonidine (a central (X2 agonist) or pentolinium (a ganglion-blocking agent). A pheochromocytoma, unlike the normal adrenal medulla, is not innervated, and catecholamine release is not initiated by nervous impulses. The suppression tests with clonidine and pentolinium, therefore, fail to inhibit plasma catecholamine levels in patients with pheochromocytomas. The adrenal cortex receives only a vasomotor nerve supply. Sympathetic axons innervate the subcapsular arteriolar plexus. In addition, zona glomerulosa cells and the subcapsular plexus are innervated by axons containing vasoactive intestinal polypeptide and neuropeptide Y.These axons arise and radiate outward from the adrenomedullary cells; their function is unknown, but they may be involved in the paracrine control of steroidogenesis.

Microscopic Anatomy On section, each gland consists of a thick outer cortical layer and a thin, inner medullary portion (see Fig. 64-3C). The external cortical zone is rich in lipids and so is yellowish and has a firmer consistency than the reddish brown and well-vascularized medulla. The adrenal is enveloped in a thin capsule from which septa carrying blood vessels penetrate the cortex in a radial fashion, converging on the medulla. There is a concentration of connective tissue at the boundary between the cortex and the medulla, the so-called medullary capsule. The medulla does not extend throughout the full length of the gland but is concentrated in the central part and is absent from the attenuated edges (see Fig. 64-3C). The cortex makes up to 80% to 90% of the volume of a normal gland, whereas the medulla constitutes 10% to 20%. Hyperplasia may occur in the cortex or medulla'? and disturb the normal corticomedullary ratio, and each is usually associated with hyperfunction syndromes. The classic description of the adrenal cortex comprising three concentric layers-zona glomerulosa, zona fasciculata, and zona reticularis (Fig. 64-6A)-dates from the earliest studies.t? The outermost layer, or zona glomerulosa, is so termed from the arrangement of the columnar epithelial cells in clusters or short anastomosing cords (see Fig. 64-6A). It constitutes about 15% of the cortex. The cells are smaller than in the deeper cortex and have relatively little cytoplasm in proportion to the nucleus. They have a heavily stained

heterochromatic nucleus with one or two nucleoli. The cytoplasm is less acidophilic than elsewhere and has an intermediate number of lipid inclusions (as viewed under electron microscopy and in sections stained for lipids, as with Sudan black B fat stain)." The Golgi system appears polarized toward the nearest blood vessel. In electron micrographs, cells of the zona glomerulosa are joined by occasional desmosomes and a few small gap junctions." The zona glomerulosa cells produce the mineralocorticoid aldosterone. The zona fasciculata constitutes about 75% of the cortex and is made up of pale-stained, polyhedral, vacuolated cells arranged in a parallel array (see Fig. 64-6A) at right angles to the capsule (a disposition imposed by the radial arrangement of the sinusoidal vessels)." The cells have a large amount of cytoplasm relative to the nucleus. The cytoplasm contains large vacuoles that are birefringent, sudanophilic, and osmiophilic; these lipid droplets probably represent sites of cytoplasmic storage of the steroids and their precursors. Hyperplasia of focal areas and the production of adenomas or cortical nodules are common in this metabolically active zone. On electronic microscopy, cells from the zona fasciculata present with features typical of steroid-secreting cells: large vacuoles, rounded mitochondria with particular tubular cristae, and very extensive smooth endoplasmic reticulum, which occupies 40% to 45% of the cell volume. The Golgi system is well developed and has many areas of continuity with the endoplasmic reticulum. The inner zone of the adrenal cortex-the zona reticularis-has cells arranged in large clusters (see Fig. 64-6A). This zone is sharply demarcated from both the fasciculata and the medulla. It is highly variable in thickness and in degree of vacuolation and lipid content of the cells and can be a reserve from which new cells are added to the fasciculata. In electron micrographs, the cells appear less active than those of the fasciculata; the endoplasmic reticulum is far less extensive, the Golgi complex is small, and lipid droplets are relatively few.36 The zonae fasciculata and reticularis secrete the glucocorticoid cortisol and the weak adrenal androgen DHEA. The significance of zonation in the adrenals is not clear, but it occurs slowly after birth parallel with regression of the fetal cortex and is not completed until late in the first year. Functional differences do not provide an adequate explanation for the different arrangements and morphology of the cells. It has been proposed that maintenance of normal adrenal size and function may involve cell division in the zona glomerulosa, subsequent centripetal cell migration and differentiation in the fasciculata, and eventual senescence and death in the reticularis. Although the adrenal zonae fasciculata and reticularis clearly have the ability to regenerate from subcapsular remnants, even in ectopic locations." it is less clear whether this capability is used in the maintenance of normal adrenal anatomy. Not all of the labeling experiments with 3H-thymidine provide evidence for centripetal cell movement.f It is likely that, once formed, the cells of the three zones do not move appreciably and are replaced by local mitotic activity." From a functional point of view, chronic corticotropin stimulation and the consequent exposure to an increased glucocorticoid concentration change the phenotype, structure, and responsiveness of glomerulosa cells to that of fasciculata cells.f After continuous stimulation,

Surgical Embryology and Anatomy of the Adrenal Glands - - 565

FIGURE 64-6. Histologic appearance of the adrenal glands (hematoxylin-eosin stain, medium power). The three layers of the cortex can be identified. A, The outer zona glomerulosa (G). B, The well-represented zona fasciculata (F). C, The innermost zona reticularis (R). The prominent zona fasciculata and reticularis are also shown at higher power. D. Electron microscopy of a chromaffin cell. The numerous catecholamine granules (G) with a dense core can be observed. The nuclei (N) and mitochondria can be identified. (Courtesy of Dr. Ed Sheffield, Department of Histopathology, Bristol Royal Infirmary, Bristol, England.)

corticotropin converts the innermost fasciculata cells to the reticularis phenotype, a process that extends outward until the reticularis may completely replace the zona fasciculata.f After removal of one adrenal gland, the remaining gland undergoes compensatory hypertrophy, dependent mainly on the presence of corticotropin but also influenced by other hormones such as the NHrterminal fragment of POMC. Similarly, the presence of an autonomous adenoma in one gland produces severe atrophy in the other because of the lack of trophic corticotropin effects (autonomous secretion of cortisol by the adenoma blocks by feedback the secretion and synthesis of CRH and hence of corticotropin). The recovery of an intact adrenal-pituitary axis and a normalsized remaining gland may take up to 2 years.

The medulla is made up almost entirely of rounded clusters or short cords of chromaffin cells that are in intimate relation to capillaries and venules. These cells are large, irregularly shaped polyhedrons, with acidophilic cytoplasm and pale vesicular nuclei; they are surrounded by nerves, connective tissue, and blood vessels." Cells from the adrenal medulla give characteristic color reactions determined by their content of catecholamines. With dichromate salts, they give the brown chromaffin reaction (brown staining of the granules resulting from oxidation and polymerization of the catecholamines in the granules); with ferric chloride, a green Vulpian reaction; and with silver salts, an argentaffin reaction. With histochemical staining reactions, two kinds of chromaffin cells can be distinguished between (1) those storing norepinephrine, which have a low

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Adrenal Gland

affinity for the dye azocarmine, are autofluorescent, give argentaffin and potassium iodide reactions, and are free for acid phosphatase; and (2) those storing epinephrine, which have a strong affinity for azocarmine, are not fluorescent or reactive with silver and iodate, and exhibit a positive phosphatase reaction." Electron microscopy reveals that chromaffin cells contain very large numbers (up to 30,000 granules per cell) of membrane-bound electron-dense granules, 1()() to 300 urn in diameter, similar to those in synaptic nerve endings (see Fig. 64-6B). These granules are important in the storage and secretion of catecholamines; they contain catecholamines, adenosine triphosphate, chromogranins, enkephalins, and the enzyme dopa hydroxylase (a major protein of the granule membrane)." Individual chromaffin cells contain large amounts of either norepinephrine or epinephrine; in humans, the normal adrenal medulla has cells in which epinephrine is predominant (85%) because of the high activity of PNMT induced locally by the high level of glucocorticoids. In contrast with these "traditional" data, in a recent study of 15 patients with pheochromocytomas, we found no correlation between noradrenaline output and the number or percentage of noradrenaline-type granules. In a tumor secreting only adrenaline, adrenaline-type granules were predominant (77%) but the proportion of adrenaline-type granules in tumors with normal adrenaline output varied widely (7% to 89%). These data suggest that other factors determine the secretory patterns in pheochromocytomas.f

Imaging Consequences Because of the central location within the abdominal cavity and the vicinity of numerous viscera, plain films are rarely informative. Occasionally, a large adrenal mass may be suggested by the downward displacement of the kidney, but this appearance is rarely seen, and differentiation from renal, splenic, pancreatic, gastric, and retroperitoneal tumors requires further investigation. Calcification may be seen in the adrenal glands and can be idiopathic or result from neonatal causes (infarction, hemorrhage, infection), maternal diabetes mellitus, tuberculosis, histoplasmosis, cyst, tumor, and Addison's disease." Retroperitoneal pneumography is now obsolete. Ultrasonographic visualization of the adrenal is not an easy technique and may produce false-positive results, but an accuracy of 70% has been described. Ultrasonography is considered to be the investigation of choice in the neonate and young child, when the relatively small amount of retroperitoneal fat makes computed tomography (CT) scanning a less satisfactory technique. The adult adrenal gland is slightly more echogenic than the kidney. A left adrenal mass should be distinguished from normal splenic vessels, splenic lobulation, and masses arising from the kidney, spleen, and pancreas. A mass within the right adrenal gland must be differentiated from the right crus of the diaphragm, retrocavallymphadenopathy, and masses arising from the liver and kidney. Ultrasonography is useful in assessing the development of the fetal adrenals. They appear as disklike structures medial to the kidney in transverse scanning through the fetus and as heart-shaped structures of low echogenicity superiorly and

medially to the kidney in the longitudinal plane. It is possible to monitor a linear increase of the adrenal area, circumference, and length during the 20th to 40th weeks of gestation." CT scans identifies the adrenals in nearly all patients and has a reported accuracy of more than 90% in the diagnosis of adrenal masses. The normal glands have a variable appearance on the CT scan. Usually, the right gland is linear or V shaped, with the medial and lateral limbs posteriorly; the medial limb is more caudal and is larger, measuring up to 4 em in length. The left adrenal gland is V shaped, is triangular, or has a Y configuration, with its apex anteromedial and its limbs posterior (see Fig. 64-4A).46 Absolute criteria for enlargement of the adrenals on the CT scan do not exist. Convexity of the adrenal outline is significant and should be considered abnormal. By comparison with the right crus of the diaphragm, a normal adrenal gland should not be thicker than the crus. Fine-needle biopsy under CT or ultrasonographic control can be performed in the diagnosis of incidentaloma (nonfunctioning adrenal tumor identified on a routine scan) after a pheochromocytoma has been ruled out.

Magnetic Resonance Imaging The normal adrenals are best seen on Tl-weighted sequences, in which cortex may be differentiated from medulla. The T2-weighted images appear to be suitable to help differentiate benign from malignant adrenal neoplasms (see Fig. 64-4B).46

Radionuclide Imaging Iodine 131-metaiodobenzylguanidine (MIBG) and iodine 123-MIBG) concentrate in the adrenergic neurotransmitter vesicles, and this is used for demonstrating pheochromocytomas. Selenium 6-selenomethylnorcholesterol and 1311_6~_ iodomethylnorcholesterol are used for steroidogenesis and allow imaging for adrenal hyperplasia and adenomas; suppression of the normal tissue with dexamethasone enhances uptake into the adenomas and provides a better image."

Surgical Applications Because of their fairly central position in the abdominal cavity, the adrenal glands cannot be felt, and few tumors grow large enough to be palpated. Approaches to the gland can be made through the posterior, lateral, and anterior surfaces. Laparoscopic adrenalectomy has become in recent years the technique of choice for most adrenal tumors. Surgical techniques are described in greater detail in other chapters of this book. The anatomic landmarks are mentioned here as an introduction.

Open Adrenalectomy POSTERIOR APPROACH

The posterior approach, originally described by Young," offers the technical advantage of being extraperitoneal, extrapleural, and subdiaphragmatic and the clinical advantage of being

Surgical Embryology and Anatomy of the Adrenal Glands - -

associated with a low postoperative morbidity. The incision is usually over the 11th rib. Structural stratification of the posterior thoracic wall in this region'? is summarized in Table 64-2. During right adrenalectomy, the dissection plane encounters the costopleural sinus, which can be reflected superiorly; rarely, it might be necessary to incise the pleura and diaphragm. After incision of Gerota's fascia, dissection between the right kidney and the vena cava allows identification of the adrenal gland. Posteriorly and laterally, dissection can proceed quickly because few major vessels cross

567

this space. When dissecting on the medial aspect, it must be remembered that there is usually only one adrenal vein and that this is often only I em wide and only 2 to 3 mm long. The vein is sometimes found at the upper pole of the adrenal gland, and its point of entrance into the cava lies immediately beneath the liver. Once the adrenal vein has been divided, the tumor usually becomes much more mobile, and remaining connections can be divided safely. Left adrenalectomy has fewer pitfalls. It is important to recognize and protect the spleen and to differentiate the inferior surface of the pancreas, which may look similar to an

568 - - Adrenal Gland

edge of the adrenal gland. Definitive pedicles may not be identified so clearly, but important tethering feeding vessels that fix the gland medially inferiorly and superiorly must be divided. The left adrenal vein may be identified as a discrete vessel entering the renal vein, and its length and width allow control and safe ligature division. ANTERIOR APPROACH

The anteriorapproach was initially advocated by Cahill, one of the pioneers of adrenal surgery," because of the advantage of simultaneous bilateral exploration, but it is more difficult, more time consuming, and associated with a greater morbidity (especially in the obese patient with Cushing's syndrome). It is advantageous especially when the adrenal disease is bilateral, when the tumor is large (> 10 em), or when there are preoperative indications that the tumor has invaded surrounding anatomic structures. Because of the progress in preoperative diagnosis and localization, the use of the anterior approach is decreasing. A long, curved transverse incision ("reversed smile") is used, with the center point situated halfway between the umbilicus and the xiphisternum. A vertical (midline or paramedian) incision has also been advocated. The anatomic stratification in the incision line is outlined in Table 64-2.

Left Adrenalectomy. There are three ways of accessing the adrenal region." 1. Incision of the posterior parietal peritoneum lateral to the left colon, continued upward, dividing the splenorenalligament (important relations are with the spleen, the splenic vessels, and the pancreas, which are enveloped by the splenorenal ligament, and caution should be used to avoid injury) 2. Opening of the lesser sac through the gastrocolic omentum (incision should be longitudinal, outside of the gastroepiploic arcade) 3. Through the left mesocolon, with the problem of maintaining the main branches of the middle and left colic arteries forming the vascular arcade and yet allowing enough space. Anterior access to the adrenal gland allows easy recognition of the hilum and isolation of the adrenal vein from the elements of the renal pedicle. Right Adrenalectomy. After mobilization of the hepatic flexure of the colon, the liver is carefully retracted upward; to provide maximum exposure of the adrenal gland, the falciform and the right triangular ligaments are carefully divided. The duodenum is mobilized in its second portion (Kocher's maneuver) by incision on its lateral aspect (the avascular peritoneal

SurgicalEmbryology and Anatomy of the Adrenal Glands - - 569 reflection), allowing exposure of the vena cava, the right adrenal gland, and the upper pole of the right kidney. In this area, there are important relations to remember with the common bile duct and the gastroduodenal artery. The critical step is the clamping of the right adrenal vein because it is short, leaves the gland on its anterior aspect, and enters the vena cava on its posterior surface. Early control and ligation of the adrenal vein in surgery for pheochromocytomas have been advocated in an attempt to control the amount of catecholamines released in circulation during tumor handling. Whichever technique of adrenalectomy is chosen, however, it is clear to any operator that this ideal is not easily achieved, and in some approaches the adrenal vein might be the last connection to be divided, allowing severance of the tumor from the patient.

completed upward. For adrenals greater than 5 em, the lateral and superior dissections are completed first; dissection is then carried caudally to identify the adrenal vein, which is clipped and divided. RETROPERITONEAL LAPAROSCOPIC ADRENALECTOMIES

Laparoscopic surgery of the adrenal glands is described in detail in Chapter 74. The largest experience has been with nonfunctioning adrenal masses (incidentalomas) and with aldosteronomas. The laparoscopic dissection of Cushing's adenoma has been described as moderately difficult due to the relatively higher retroperitoneal fat content present in these patients. Bilateral adrenalectomies for Cushing's disease have been described in patients who failed transsphenoidal pituitary ablation. Laparoscopic removal of pheochromocytoma has proved to be a safe alternative in skilled hands. The role of laparoscopic adrenalectomy for isolated adrenal metastases is still controversial. Contraindications to laparoscopic adrenalectomy include adrenal carcinoma and adrenal masses greater than 10 em.

One approach used by some surgeons is to create a space around the adrenal gland with an air-filled balloon inserted retroperitoneally. This allows for minimal trauma to organs within the peritoneal cavity. The patient is placed in prone jackknife position and a balloon trocar is placed in the retroperitoneal space, insufflated, and then removed. Operative and retracting ports are placed. Left Adrenalectomy. Laparoscopic ports to insert a camera and instruments (usually three or four ports) are positioned below the left rib cage. The left adrenal gland is exposed after the spleen is freed up from attachments over the adrenal, the colon is moved down, and the tissue over the upper pole of the kidney opened to reveal the adrenal gland. The inferomedial border of the gland is identified and dissected, exposing the left renal vein. The vein is divided along with remaining vascular twigs. Right Adrenalectomy. Laparoscopic ports (four or five) are inserted along the right rib cage for camera, instruments, and a liver retractor. Mobilizing the right lobe of the liver from the tissues of the back of the abdomen is critical. Once the retroperitoneum is exposed and the liver retracted, the vena cava is exposed and, by following it, the adrenal vein is identified. Depending on the anatomy of the region and the reason for the adrenalectomy procedure, the adrenal vein or veins may be divided early. Alternatively, arterial branches into the gland may be divided at this point before the vein is clipped, stapled, or oversewn.

TRANSABDOMINAL LAPAROSCOPIC ADRENALECTOMY

Summary

Left Adrenalectomy. The splenic flexure is mobilized medially to expose the lienorenal ligament . The ligament is then incised to demonstrate the short gastric vessels posteriorly behind the stomach. This allows the spleen to fall medially, exposing the retroperitoneal space. The adrenal gland, the adrenal mass, and the adrenal vein are identified. Grasping the perinephric fat, the lateral and anterior parts of the adrenal gland are dissected avoiding to grasp the adrenal gland or tumor directly, because the tissue may tear. For smaller adrenals «5 em), the gland is dissected inferomedially. This allows for early identification and clipping of the adrenal vein. As dissection is continued upward, adrenal branches of the inferior phrenic vessels are clipped. For larger glands, dissection proceeds superiorly, clipping the adrenal branches of the inferior phrenic vessels. Right Adrenalectomy. A retractor is placed through the most anterior port and the right hepatic lobe is retracted anteriorly. The lateral right hepatic attachments are divided along with the right triangular ligament. The adrenal and its mass are identified. The inferolateral edge of the right adrenal gland is identified and dissected inferiorly. For glands less than 5 em, the right adrenal vein is visualized early and taken. The adrenal branches of the inferior phrenic vein are clipped and divided as the dissection is

Understanding the embryology, anatomic relationships, and neurovascular supply of the adrenal glands helps the clinician interpret localization studies and choose the appropriate adrenal operation for individual patients.

Laparoscopic Adrenalectomy

REFERENCES 1. Eustachius B. In: Lancisius B (ed), Tabulae Anatomicae Clarissimi Viri Bartholomeai Eustachii. Amsterdam, 1722. 2. Welbourn RB. The History of Endocrine Surgery. New York, Praeger, 1990, p 147. 3. Home E. Lectures on Comparative Anatomy, Vol 5. London, Longman, Ress, Home, Brown & Green, 1828, p 259. 4. Cuvier GLC. Lecons D' Anatomie Comparee. Paris, Baudonin, 1800-1805. 5. Addison T. On the Constitutional and Local Effects of Disease of the Suprarenal Capsules. London, Samuel Highley, 1855. 6. Brown-Sequard CEoRecherches experimentales sur la physiologie et al pathologie des capsules surrenales. Arch Gen Med 1856;8:385. 7. Oliver G, Sharpey-Schafer EA. The physiological effects of extracts of the suprarenal capsules. J Physiol (Lond) 1895;18:230. 8. Abel 11, Crawford AC. On the blood pressure raising constituent of the suprarenal capsule. Johns Hopkins Hosp Bull 1897;8:151. 9. Stolz F. Ueber adrenalin und alkylaminoacetobenzcatechin. Dtsche Chern Ges 1904;37:4149. 10. Von Euler US. Specific sympathomimetic ergone in adrenergic nerve fibres (sympathin) and its relation to adrenalin and noradrenaline. Acta Physiol Scand 1946;12:73.

570 - - Adrenal Gland II. Holtz P, Credner K, Kroneberg G. Uber das sympathomimetishe pressoriche Prinzip des Hams ("urosympathin"). Arch Exp Pathol Pharmakol 1947;204:224. 12. Alquist RP. A study of adrenotropic receptors. Am J Physiol 1948; 153:586. 13. Frankel F. Ein Fall von doppelseitigen vollig latent verlaufenen Nebennierntumor und gleichseitigen Nephritis mit Veranderungen am Circulations-Apparat und Retinitis. Arch Pathol Anat 1886:103. 14. Pick L. Das gangliona embrionale sympathicum. Klin Wochenschr 1912; 19:16. 15. Cushing H. The Pituitary Body and its Disorders: Clinical States Produced by Disorders of the Hypophysis Cerebri. Philadelphia, JB Lippincott, 1912. 16. Conn JW. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 1955;45:6. 17. Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961;31:163. 18. Werner P. Endocrine adenomatosis and peptic ulcer in a large kindred: Inherited multiple tumours and mosaic pleiotropism in man. Am J Med 1963;35:205. 19. Pybus Fe. Notes on suprarenal and pancreatic grafting. Lancet 1924;1:550. 20. Reichtenstein T, Shopper CWO The hormones of the adrenal cortex. Vitam Horm 1943;1:345. 21. Kendall Ee. The chemistry and partial synthesis of adrenal steroids. Ann NY Acad Sci 1949;50:540. 22. Vale W, Spiess J, Rivier J, et al. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981;213:1394. 23. Sadler TW. Langman's Medical Embryology, 6th ed. Baltimore, Williams & Wilkins, 1990, p 382. 24. Orth DN, Kovacs WJ, DeBold CR. The adrenal cortex. In: Wilson JD, Foster DW (eds), Williams Textbook of Endocrinology, 8th ed. Philadelphia, WB Saunders, 1992, p 489. 25. Anderson DJ. Molecular control of cell fate in the neural crest: The sympathoadrenal lineage. Ann Rev Neurosci 1993; 16:129. 26. Phillippe M. Fetal catecholamines. Am J Obstet Gynecol 1983; 146:840. 27. Le Douarin NM. The Neural Crest. Cambridge, England, Cambridge University Press, 1982. 28. Pitynski K, Skawina A, Polakiewicz J, Walocha 1. Extraorganic vascular system of adrenal glands in human fetuses. Anat Anz 1998; 180:361. 29. Pepe GJ, Albrecht ED. Actions of placental and foetal adrenal steroid hormones in primate pregnancy. Endocr Rev 1995;16:608. 30. Zuckerkandl E. The development of the chromaffin organs and the suprarenal glands. In: Manual of Human Embryology, Vol 2. Philadelphia, JB Lippincott, 1912, p 157. 31. Pearse AGE. The neuroendocrine division of the nervous system: APUD cells as neurones or paraneurones. In: Osborne NN (ed), Dale's Principles and Communication Between Neurones. Oxford, Pergamon Press, 1983.

32. Russel RP, Masi AT, Richter ED. Adrenal cortical adenomas and hypertension: A clinical and pathologic analysis of 690 case-matched controls and a review of the literature. Medicine 1972;51 :211. 33. Neville AM, O'Hare MJ. Histopathology of the human adrenal cortex. Clin Endocrinol Metab 1985;14:791. 34. Williams PL, Warwick RW, Dyson M, Bannister LH (eds). Gray's Anatomy, 36th ed. New York, Churchill Livingstone, 1989, p 1468. 35. Davies J. Anatomy, microscopic structure and development of the human adrenal gland. In: Scott HW (ed), Surgery of the Adrenal Glands. Philadelphia, 18 Lippincott, 1990, p 17. 36. Fawcett DW, Raviola E. The adrenal glands. In: Fawcett DW (ed), Bloom and Fawcett: A Textbook of Histology, 12th ed. New York, Chapman & Hall, 1994, P 503. 37. Kikuta A, Mukarami T. Microcirculation of the rat adrenal gland: A scanning electron microscope study of vascular casts. Am J Anat 1982; 164:22. 38. Monkhouse WS, Khalique A. The adrenal and renal veins of man and their connections with azygos veins. J Anat 1986;146:105. 39. Camey JA, Sizemore GW, Tyce GM. Bilateral adrenal medullary hyperplasia in multiple endocrine neoplasia type 2: The precursor of bilateral pheochromocytoma. Mayo Clin Proc 1975;50:3. 40. Arnold 1. Ein Beitrag zu feineren und dem Chemismus der Nebennieren. Arch Pathol Anat Physiol Klin Med 1866;35:64. 41. Belloni AS, Neri G, Musajo FG, et al. Investigations on the morphology and function of adrenocortical tissue regenerated from the capsular fragments autotransplanted in the musculus gracilis of the rat. Endocrinology 1990;126:3251. 42. Zajicek G, Ariel I, Arber N. The streaming adrenal cortex: Direct evidence of centripetal migration of adrenocytes by estimation of cell turnover rate. J Endocrinol 1986; 111:477. 43. Hornsby PJ. Physiological and pathological effects of steroids on the function of the adrenal cortex. J Steroid Biochem 1987;27: 1161. 44. Gill GN. ACTH regulation of the adrenal cortex. In: Gill GN (ed), Pharmacology of Adrenal Cortical Hormones. New York, Pergamon Press, 1979, p 35. 45. Mihai R, Wong NACS, Luckett M, et al. No correlation between phaechromocytoma catecholamine secretion and granule ultrastructure. Br J Surg 1998;85:1681. 46. Murfitt J. The adrenal glands. In: Sutton D, Young Jw.R (eds), A Short Textbook of Clinical Imaging. New York, Springer-Verlag, 1990, p 498. 47. Hata T, Deter RL. A review of fetal organ measurements obtained with ultrasound: Normal growth. J Clin Ultrasound 1992;20:155. 48. Young HH. Genital abnormalities: Hermaphroditism and related adrenal disease. Baltimore, Williams & Wilkins, 1937. 49. Snell RS. Clinical Anatomy for Medical Students, 5th ed. Boston, Little, Brown, 1995, p 135. 50. Cahill GF. Hormonal tumours of the adrenals. Surgery 1944;16:233. 51. Skandalakis JE, Skandalakis PN, Skandalakis LJ. Surgical Anatomy and Technique. New York, Springer-Verlag, 1995, p 557.

Adrenal Physiology Staffan Grondal, MD, PhD • Bertil Hamberger, MD, PhD

The normal adrenal gland in humans weights 5 to 7 g and is 4 to 5 em long, 2 to 3 em wide, and I em thick. The paired adrenal glands are situated on the anteromedial aspect of the kidneys. The adrenal has two functional entities, the adrenal cortex and the adrenal medulla. Although there are some developmental and functional relationships between the cortex and the medulla, they are discussed separately.

Adrenal Cortex Functional Morphology The adrenal cortex constitutes about 85% of the whole gland. The cortex surrounds the medulla and is arranged in three zones: zona glomerulosa, fasciculata, and reticularis (Fig. 65-1). The zona glomerulosa lies just under the capsule and is thin. It constitutes about 15% of the cortex or may present focally with small round cells with a small cytoplasmic volume. The zona fasciculata is broad. It constitutes about 70% of the cortex, with larger cells with abundant cytoplasm ("clear" cells). Closest to the adrenal medulla lies the zona reticularis, with cells of intermediate size ("compact" cells). The adrenal gland is highly vascularized. Three major arteries from the aorta, inferior phrenic artery, and renal arteries as well as up to 50 arterioles course through the cortex and via capillaries anastomose to veins that pass the medulla and enter a central vein. The blood supply of the cortex is thereby mainly separated from that of the medulla, but the outer part of the medulla is reached by cortisol-rich blood. The right adrenal vein is 2 to 5 mm long and drains directly into the inferior vena cava, whereas the left adrenal vein is longer and drains into the left renal vein.

Functional Zonation Aldosterone is synthesized and released only from the zona glomerulosa, whereas the zona fasciculata synthesizes mainly cortisol, dehydroepiandrosterone (DHEA); other androgens and estrogen are synthesized in both the zona reticularis and zona fasciculata (see Fig. 65-1). DHEA sulfate (DHEA-S) is the quantitatively dominating steroid from the adrenal cortex and is released primarily from the zona reticularis.'

Biosynthesis of Corticosteroids Plasma cholesterol is the major source of substrate used for steroid synthesis by the adrenal cortex." Pregnenolone, the origin of all steroid hormones (C21, C19, CI8), is formed from cholesterol after hydroxylation and enzymatic cleavage of the side chain within the mitochondria. The synthesis of steroid hormones from pregnenolone is dependent on several metabolizing enzymes localized in the mitochondrion and microsomes (Fig. 65-2). Steroid hormones are metabolized by the liver and excreted in the urine as more water-soluble conjugates with glucuronic acid or sulfates.

Aldosterone Pregnenolone is 21-hydroxylated in the endoplasmic reticulum and, after 11- and 18-hydroxylation, aldosterone is formed, It is secreted in its free form and is also bound with low affinity to albumin. The main effects of aldosterone and other mineralocorticoids are to maintain normal Na" and K+ concentrations and extracellular fluid volume. Synthesis and secretion of aldosterone are regulated mainly by angiotensin II and changes of the plasma levels of potassium and sodium.' A decrease of the intravascular volume is registered in the renal juxtaglomerular cells, located in the wall of the afferent glomerular arteriole, and leads to a release of renin. These cells also respond to ~-adrenergic stimuli and prostaglandins. Renin cleaves angiotensinogen to angiotensin I, which is converted to angiotensin II by angiotensin-converting enzyme. Angiotensin II, in itself a potent vasoconstrictor, binds to membrane receptors on the zona glomerulosa cell surface. Aldosterone biosynthetic enzymes are activated through phospholipase C inositol triphosphate diacylglycerol, which increases the intracellular calcium concentration." Increments of serum potassium significantly increase serum aldosterone. Sodium depletion stimulates the conversion of corticosterone to aldosterone, but large changes of plasma sodium are necessary.' Adrenocorticotropic hormone (ACTH, corticotropin) has only a permissive role in the synthesis of aldosterone. Consequently, a prompt control of sodium and potassium intake as well as pharmacologic

571

572 - -

Adrenal Gland

The layers of the adrenal gland and their hormone production

FIGURE 65-1. Schematic of the adrenal glands with the zones and the corresponding hormones produced.

agents affecting the renin-angiotensin system, ~-adrenergic receptors, and prostaglandins are necessary when investigating aldosterone secretion.'

Cortisol In the endoplasmic reticulum, pregnenolone is converted to progesterone and 17a-progesterone is 21-hydroxylated to l l-deoxycortisol, and in the mitochondrion, II-deoxycortisol is hydroxylated to cortisol. After secretion, most of the cortisol (80%) that circulates in plasma is bound with high

affinity to a corticosteroid-binding globulin, transcortin, whereas an additional 15% is bound to albumin and less than 10% is free.' Synthesis of cortisol is completely regulated by ACTH, which binds to receptors of the adrenal cell surface. The action of ACTH is mediated by the adenylate cyclase-cyclic adenosine monophosphate-protein kinase A system." Initially, the conversion rate of cholesterol to pregnenolone increases; more chronic ACTH stimulation increases the corticosteroid enzyme activity, and hypertrophy of the adrenocortical cells occurs.' Serum levels of cortisol show a specific diurnal rhythm, with highest levels in the

Dehydroepiandrosterone

Androstenedione

Estradiol

Estrone

FIGURE 65-2. Steroid biosynthesis in the adrenal cortex and the major urinary metabolites. Mitochondrial and microsomal cytochrome PA50 enzymes catalyze the conversion of steroids.

Adrenal Physiology - - 573 early morning and low levels at night. 1 The serum cortisol level is continuously regulated by a feedback mechanism on the hypothalamus and pituitary. Patients treated with replacement or pharmacologic doses of exogenous glucocorticoids usually have low or absent measurable corticotropin in the serum. Patients receiving pharmacologic doses of steroids are unable to respond with increased endogenous cortisol secretion in response to surgical stress. Accordingly, these patients need to receive a stress dose of steroids when in a physiologically stressful state.

Sex Steroids The adrenocortical sex steroids DHEA and andostenedione are formed after 17a-hydroxylation of pregnenolone or progesterone and side chain removal from carbon 17. They are secreted mainly as sulfates and are converted in peripheral tissues from relatively weak adrenal androgens to testosterone and estrogens. ACTH stimulates the synthesis and secretion of adrenal androgens, but there is no diurnal variation of DHEA-S in serum'?

Physiologic Effects of Corticosteroids Aldosterone Aldosterone regulates electrolyte excretion and the intravascular volume through its effects on the distal tubules and cortical collecting tubes of the kidney. It binds to a mineralocorticoid receptor in the cytosol and moves into the nucleus to increase transcription." The early effect is to increase the Na absorption through the Na channels. Via changes in electrical potential across the renal tubule, K and H secretion are increased. This leads to an expanded intravascular volume and suppresses renin secretion. Chronically increased aldosterone secretion is characterized by increased peripheral vascular resistance and persistent high blood pressure.

Cortisol Cortisol exerts its effect by regulating gene transcription after binding to glucocorticoid receptors within the cell." Cortisol has a large number of metabolic effects on several tissues. However, many of the effects of glucocorticoids are based on studies of patients, animals, and cells with nonphysiologically high or low levels of glucocorticoids. Glucocorticoids are necessary for maintaining hepatic glycogen stores. They stimulate protein catabolism and lipolysis and cause hyperinsulinemia.' Cortisol is required for maintenance of normal blood pressure. The effect on immunologic function of glucocorticoids in physiologic levels is not clear, but glucocorticoid excess suppresses both immunologic and anti-inflammatory responses. Glucocorticoids have a weak mineralocorticoid effect and influence calcium homeostasis by decreasing intestinal calcium absorption and increasing urinary calcium excretion. I In pharmacologic doses, cortisol causes osteoporosis. The effects of cortisol on the central nervous system manifest as changes in excitability, behavior, and mood. 1

Adrenal Androgens The physiologic effects of DHEA-S, DHEA, and androstenedione are relatively weak, and they undergo conversion to testosterone in peripheral tissue. In females, androgens produced by the adrenal glands sustain normal pubic and axillary hair growth, and after menopause the adrenal glands are a major source of estradiol. However, in males, the high amount of androgens produced by the testis exceeds that produced by the adrenal glands. 1

Adrenal Medulla Chromaffin Cells The adrenal medulla constitutes about 15% of the adrenal and is surrounded by the cortex. The major constituent of the medulla, the catecholamine-containing cells, are of two types: the norepinephrine and the epinephrine cells. These cells are often called chromaffin cells because they stain with chromium salts, and this was an early method used to detect these cella.' Chromaffin cells in adults are primarily confined to the adrenal medulla, although they also occur in extra-adrenal locations. They may give rise to extra-adrenal paraganglioma in the organ of Zuckerkandl (distal aorta), in the bladder, in the neck and, more rarely, at other sites.'? In addition, the adrenal medulla contains sympathetic ganglion cells, connective tissue, and blood vessels. The adrenal medulla has an arterial supply via several small arteries and a venous outflow to the central adrenal vein. The epinephrine cells in the medulla are localized close to the cortex, where they are exposed to high cortisol levels of portal venous effluent. Cortisol is required for the induction of phenylethanolamine N-methyltransferase (PNMT), the methylating enzyme that converts norepinephrine to epinephrine (Fig. 65-3). Chromaffin cells in extra-adrenal locations usually do not produce epinephrine, probably because of a lack of cortisol to activate PNMT.11 The preganglionic cell bodies are located in the intermediolateral cell column in the spinal cord. Their axons pass the sympathetic ganglia and reach the adrenal gland via the splanchnic nerves and innervate the chromaffin cells.

Transmitter Mechanisms SYNTHESIS

The catecholamines are synthesized from tyrosine, which is converted to dihydroxyphenylalaline by the cytosolic enzyme tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis (see Fig. 65-3),12 and further converted to dopamine by dopa decarboxylase. Dopamine is taken up into granular vesicles and converted to norepinephrine via dopamine ~-hydroxylase (DBH). This uptake is an adenosine triphosphate (ATP)-requiring process, in which the uptake of dopamine prevents its degradation by cytoplasmic monoamine oxidase. Norepinephrine is stored in the granular vesicles in a complex where one catecholamine molecule is coupled to four ATP molecules. Certain chromaffin cells contain the enzyme PNMT, which converts norepinephrine to epinephrine. Neuropeptide Y (NPY), enkephalins, somatostatin, and chromogranins are also stored in the granular vesicles.

574 - - Adrenal Gland

I

Norepinephrine

I

I

Epinephrine MAO

MAO

~ COMT

/

I

Dihydroxymandelic acid

COMT

~

MAO

When the adrenal medulla is stimulated, the chromaffin cell membrane depolarizes, secretory vesicles fuse with the cell membrane, and the vesicular content is released via exocytosis.P All components of the granular vesicles are released: catecholamines, DBH, NPY, enkephalins, and chromogranins. Because of a rich vascular supply, most released substances are transported away from the medulla and direct reuptake back into the chromaffin cells only plays a minor role compared to sympathetic nerves. The physiologic importance of the released substances in addition to catecholamines is not clear. NPY has been shown to have vasoconstrictive effects, although it is much weaker than the catecholamines.!" Enkephalins may function as analgesics during stress. 15 The chromogranins may be of importance for storage of neurotransmitters and may also serve as peptide precursors. 16 DEGRADATION

The degradation of norepinephrine and epinephrine is shown in Figure 65-4. Monoamine oxidase is present in mitochondria of most cells and catalyzes the deamination of catecholamines. Catechol O-methyltransferase induces methylation of catecholamines or their deaminated metabolites to the major final product, vanillylmandelic acid. In the liver and gut, conjugation with sulfuric or glucuronic acid takes place, and these substancesare then excreted in the urine. Only a small amount is excreted as free dopamine, norepinephrine, and epinephrine in the urine.

Determination of Release from the Adrenal Medulla Free urinary catecholamines most likely reflect an estimation of the sympathoadrenal activity during the sampling period. In urine, vanillylmandelic acid and metanephrine levels also give a good indication of adrenal medulla catecholamine secretion. Plasma catecholamines are usually determined as unconjugated free and protein-bound levels. Under basal conditions, only a small amount of plasma norepinephrine

COMT

IMetanephrine I

INormetanephrine I

SECRETION

I

~

~

FIGURE 65-3. Synthesis of catecholamines in the adrenal medulla. DOPA = dihydroxyphenylalaline.

I

I

MAO

/

Vanillylmandelic acid

I

FIGURE 65-4. Degradation of norepinephrine and epinephrine. MAO = monoamine oxidase; COMT = catechol O-methyltransferase.

(normal, 0.6 to 2 nmol/L) originates from the adrenal medulla, because the major part of the norepinephrine is secreted from the sympathetic nerves. In contrast, plasma epinephrine (normal, 0.1 to 0.3 nmol/L) is secreted only by the adrenal medulla. The half-life of plasma epinephrine and norepinephrine is very short (l to 2 minutes), and the variations in plasma norepinephrine are a reflection of variations in sympathetic tone. Because of the effective mechanism for reuptake into sympathetic nerves, venous plasma catecholamines show variations related to the sampling site. More recently, measurement of plasma normetanephrine and metanephrine has been shown to be more reliable for evaluating hypersecretion of catecholamines from the adrenal medulla because their half-life in plasma is much longer than norepinephrine and epinephrine. I?

Physiologic Effects Catecholamines exert their effect on specific adrenergic receptors. These receptors are transmembrane proteins known to be encoded by separate genes. Initially a- and ~-adrenergic receptors were identified and their subtypes have been characterized. The at receptors mediate vascular stimulation smooth muscle contraction. ~l-receptor increases heart rate and myocardial contractility, whereas ~2 receptors are involved in smooth muscle relaxation. The ~3 receptors regulate lipolysis and energy expenditure. Catecholamines influence almost all tissues and organs in the body. Catecholamines have profound cardiovascular and metabolic effects and also influence the secretion of many hormones.t The major effects are cardiovascular, with contraction of blood vessels and increasing heart rate and force. Catecholamines also exert effects on extravascular smooth muscle, causing both contraction and relaxation. In addition, catecholamines affect metabolism by increasing oxygen consumption and heat production, and they also regulate the mobilization of glucose and fat stores.

Adrenal Physiology - -

Basal secretion of catecholamines from the adrenal medulla is low. Substantial stimulatory conditions such as trauma and surgical stress are required to increase catecholamine secretion from the adrenal medulla. The release of epinephrine is of interest in special conditions. IS Epinephrine is released from the adrenal medulla during an operation at the time of intubation and skin incision. High levels of epinephrine are also found during traumatic events, such as myocardial infarction and pain or fear. During severe hypoglycemia, epinephrine levels may be up to 50 times the basal level, owing to stimulation of glucose-sensitive neurons in the central nervous system.

Summary The adrenal gland has two functioning endocrine units, the cortex and the medulla. The cortex secretes corticosteroids, including the major glucocorticoid, cortisol, and the major mineralocorticoid, aldosterone. The cortex also secretes DHEA-S and, to a lesser extent, androgens and estrogens. Glucocorticoids are necessary for life, and their secretion is regulated by the hypothalamic-pituitary-adrenal axis. The medulla primarily secretes the catecholarnines epinephrine, norepinephrine, and dopamine.

REFERENCES I. Genuth SM. The adrenal gland. In: Levy NM, Berne RM (eds), Physiology. SI. Louis, Mosby 1998, p 930. 2. Brown M, Korvanen P, Goldstein J. Receptor-mediated uptake of lipoprotein-cholesterol and its utilisation for steroid synthesis in the adrenal cortex. Rec Progr Horm Res 1979;35:215.

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3. Quinn S, Williams G. Regulation of aldosterone secretion. Annu Rev PhysioI1988;50:409. 4. Berridge M. Inositol triphosphate and calcium signalling. Nature 1993;361:315. 5. Greenspan FS, Gardner DG. Basic and Clinical Endocrinology. New York, McGraw-Hill, 2001. 6. Gill G. ACTH regulation of the adrenal cortex. Pharmacol Ther 1976;2:313. 7. Simpson E, Waterman M. Regulation of the steroidogenic enzymes in the adrenal cortical cell by ACTH. Annu Rev PhysioI1988;50:427. 8. Horisberger J, Rossier B. Aldosterone regulation of gene transcription leading to control of ion transport. Hypertension 1992; 19:211. 9. Gustafsson J-A, Carlstedt-Duke J, Poellinger L, et al. Biochemistry, molecular biology of the glucocorticoid receptor. Endocr Rev 1987;8:185. 10. Manger WM, Gifford RWJ. Pheochromocytoma. New York, SpringerVerlag, 1977. II. Wurtman R, Axelrod J. Control of enzymatic synthesis of adrenaline in the adrenal medulla by adrenal cortical steroids. J Bioi Chern 1966;241:2301. 12. Kopin I. Catecholamine metabolism and the biochemical assessment of sympathetic activity. Clin Endocrinol Metab 1977;6:525. 13. Dahlstrom A, Belmaker S, Sandler M (eds). Part A: Basic aspects and peripheral mechanisms. In: Progress in Catecholamine Research. New York, Wiley, 1988, p 279. 14. Lundberg 1M, Torssell L, Sollevi A, et al. Neuropeptide Y and sympathetic vascular control in man. Regul Pep 1985;13:41. 15. Lewis JW, Tordoff MG, Sherman IE, et al. Adrenal medullary enkephalin-like peptides may mediate opioid stress analgesia. Science 1982;217:557. 16. Winkler H. The adrenal chromaffin granule: A model for large dense core vesicles of endocrine and nervous tissue. J Anat 1993;183:237. 17. Eisenhofer G, Lenders JW, Linehan WM, et al. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med 1999;340:1872. 18. Halter J, Pfug A, Porte OJ. Mechanism of plasma catecholamine increases during surgical stress in man. J Clin Endodrinol Metab 1977;45:936.

Adrenal Imaging Procedures Andreas Zielke, MD • Matthias Rothmund, MD

Modalities for Imaging the Adrenal Gland Evaluation of a patient with an adrenal gland mass is founded on a thorough history and physical examination, followed by appropriate biochemical tests. After the diagnosis has been established, imaging procedures are used for localization and presurgical planning. Improvements of functional and anatomic imaging procedures allow reliable preoperative evaluation of virtually all adrenal masses. Computed tomography (CT) and magnetic resonance imaging (MRI) are the main modalities used to localize adrenal tumors. The best radiologic imaging test is CT scanning, and it is usually the only imaging study required. In this chapter, we review adrenal imaging techniques and discuss their indications and limitations. We also present flowcharts showing how the most prevalent adrenal diseases, including incidentaloma of the adrenal gland, should be approached.

Computed Tomography CT is the modality most commonly used to evaluate a patient suspected of having an adrenal mass.' CT accurately delineates the location, size, and configuration of the mass; local invasion; and affected adjacent lymph nodes or distant metastases.' For routine applications, l-cm contiguous scans in the adrenal area are usually obtained. For smaller masses (e.g., in primary hyperaldosteronism) thinner scans, such as 0.5-cm slices, are necessary. The normal right adrenal gland is a comma-shaped gland of roughly I x 2 x 0.5 cm, and the left adrenal is a lambda-shaped gland of roughly similar size. The normal adrenal gland is approximately the same size as the diaphragmatic stripe seen on CT (Fig. 66-1). The right adrenal gland is usually directly posterior to the inferior vena cava, and the left adrenal is anterior to the upper portion of the kidney and adjacent to the aorta. Although intravenous contrast material is not routinely used, it is useful for differentiating vascular structures from the adrenal or for enhancement characterization of adrenal tumors. Oral contrast media to opacify bowel may be required for extra-adrenal pheochromocytomas and for delineation of adrenal carcinomas. Despite the merits of CT scanning, it lacks specificity. For example, adrenal

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adenomas, carcinomas, and pheochromocytomas cannot be differentiated by plain CT scanning. Cysts and myelolipomas are the only conditions that are reliably diagnosed by CT. In cases of Addison's disease, CT scanning may reveal atrophy;' but as exemplified in this condition, much of its capacity to differentiate one lesion from another is based on size rather than specific tissue characteristics.' False-negative examinations result largely from trying to image tumors smaller than 1 em in diameter.

Magnetic Resonance Imaging MRI is increasingly used because it can reveal tissue-specific characteristics, which allows the examiner to differentiate metastases, adrenocortical carcinoma, and pheochromocytoma from adenoma, lipoma, myelolipoma, and cysts." Because MRI does not use ionizing radiation, it is an attractive modality for evaluating children and pregnant women." Tl-weighted images allow relatively fast data acquisition, which may be accelerated by using paramagnetic contrast media such as gadolinium-diethylenetriaminepenta-acetic acid (DTPA), resulting in a reduction of motion artifact and increasing the sensitivity for identifying adrenal lesions. T2-weighted sequences reveal characteristic signal intensities in certain conditions and help with the differential diagnosis." Some studies have suggested that MRI can differentiate nonfunctioning from malignant adrenal lesions," but because of similar characteristics of some tumors, the results are not reliable enough to use in selecting therapy.S?

Adrenal Scintigraphy Adrenal scintigraphy provides localization and functional information and is therefore helpful for differentiating certain adrenal neoplasms. Scintigraphy is often used in conjunction with CT or MRI because it offers much less anatomic information than other modalities. Numerous radiolabeled pharmaceuticals are being investigated to provide improved localization tests for the adrenal cortex and medulla. Iodocholesterol-labeled analogs such as l31I-6~-iodomethyl 19-norcholesterol (NP-59) and 75Se-6~-selenomethyl cholesterol are used to scan the adrenal cortex.V' Studies using NP-59 make use of the fact that adrenal lesions can be distinguished on the basis of intact steroidogenesis pathways and

Adrenal Imaging Procedures - - 577

noninvasive, and involving no ionizing irradiation, which makes it attractive for evaluating children and pregnant women. For children, ultrasonography has been very effective, whereas in adults, visualization of the right adrenal is successful in approximately 90% of cases and for the left the success rate is only 75%.14 Ultrasonography delineates lesions of 2 em or larger and is helpful in differentiating cysts from solid masses and in evaluating involvement of large vessels and liver metastases. 15 Ultrasonography is an ideal screening modality for adrenal neoplasms and for following the progression of adrenal masses. Ultrasonography is not as accurate as CT. It requires an experienced interpreter and is notoriously operator dependent.'

Arteriography and Adrenal Venography

FIGURE 66-1. CT images of normal adrenal glands. A, The medial limb of the right adrenal gland (arrow) is dorsal to the inferior vena cava and ventral to the upper pole of the kidney. B. The left adrenal gland (arrow) has an inverted V appearance. (From Davidson AJ, Hartman DS. Radiology of the Kidney and Urinary Tract, 2nd ed. Philadelphia, WE Saunders, 1994, p 716.)

the presence of abundant intracellular cholesterol. However, imaging requires several days, which is unacceptable in some cases. Moreover, in several comparative studies, CT required less time to perform and interpret, cost less, used less ionizing radiation, and provided similar diagnostic accuracy. to Metaiodobenzylguanidine (MIBG) is the most frequently used radionuclide for imaging the adrenal medulla. MIBG is an analog of guanethidine. It is taken up by adrenergic granules and adrenal medulla cells because of its structural similarity to norepinephrine. However, it has essentially no pharmacologic effect. II Because MIBG is concentrated in catecholamine storage vesicles, it allows functional assessment of adrenal medullary tissue and is diagnostic for pheochromocytomas." Iodine 131 MIBG is the most commonly used isotope, but 123I_MIBG has resulted in more accurate delineation of pathologic tissues than 13II_MIBG and provides superior dosimetry. 13 MIBG studies take 3 days to complete, and their spatial resolution is poorer than that provided by CT scans.

Ultrasonography Controversy exists regarding the efficacy of ultrasonography in the evaluation of adrenal tumors. Ultrasonography offers the particular advantages of being less expensive, being

Considered invaluable tools in differentiating hyperplasia from carcinoma in the 1980s, arteriography and adrenal venography have almost completely been replaced by CT and MR!. In general, these invasive methods should be reserved for the rare instance in which CT or MRI provides insufficient information. Arteriography in patients with pheochromocytoma may be hazardous, and venography may be dangerously invasive, especially in children; it has been associated with significant morbidity in pediatric cases. 15 Selective arteriography, however, may be helpful if it is difficult to determine whether a mass on CT is suprarenal or renal in origin. 16 Venography, often used in combination with selective venous sampling, is employed more often than arteriography. I? Although the method successfully approaches the left adrenal gland in virtually all cases, this cannot always be accomplished for the right gland and demands an experienced radiologist. Venography with selective adrenal sampling is useful in examining patients with hyperaldosteronism or Cushing's syndrome when the clinician cannot discriminate by CT or MRI between hyperplasia and adenoma, and it is occasionally useful for determining the source of ectopic corticotropin (ACTH) production. Complications occur in about 5% of patients and consist mainly of contrast extravasation and hematoma and rarely of adrenal vein thrombosis and adrenocortical insufficiency. I?

Hyperadrenocorticism The most common cause of Cushing's syndrome is exogenous administration of corticosteroids. Regarding the remaining organic causes, approximately 70% of patients with Cushing's syndrome have pituitary Cushing's, resulting in bilateral adrenocortical hyperplasia and cortisol excess. Ten percent have adrenal adenomas, 10% have adrenal carcinomas, and 8% to 10% have ectopic Cushing's or extrapituitary ACTHproducing tumors, including small cell lung cancers, cancers of the pancreas, carcinoid tumors, medullary thyroid cancers, and other neoplasms.

Computed Tomography Studies The initial localizing procedure of choice for patients with adrenal Cushing's syndrome is a contrast-enhanced CT scan

578 - - Adrenal Gland gland, and only few adenomas show contrast enhancement. Large or heterogeneous tumors with areas of low density caused by necrosis or hemorrhage and calcifications should raise the suspicion of carcinoma and prompt a search for local invasion or distant metastases. CT may also be helpful in evaluating hyperplasia (Fig. 66-3). In fewer than half of cases with ACTH-dependent Cushing's syndrome, CT reveals bilaterally enlarged adrenal glands with uniform thickening of both limbs. Careful examination of the entire gland is mandatory for differentiating adenoma from the rare incidence of a dominating nodule in macronodular hyperplasia. The absence of an adrenal tumor and an apparently normal adrenal morphologic pattern on CT in biochemically proven Cushing's disease suggests adrenal hyperplasia.

Other Imaging Modalities FIGURE 66-2. CT scan of an adrenocortical adenoma causing

Perinephric fat provides excellent contrast for MR!. Fast, gadolinium-enhanced MRI can detect lesions less than I em in diameter, but it provides little additional information if a CT examination has already been performed. Ultrasonography may be difficult to perform in cases of Cushing's syndrome because of the truncal obesity of the patients. Ultrasonography can identify large tumors, but it is of limited value as a routine adrenal imaging modality for these patients. Adrenal venography with selective venous sampling for cortisol allows differentiation of adrenal tumors (i.e., unilateral peak cortisol concentrations) from hyperplasia (i.e., bilateral increased cortisol concentration). Selective venous sampling, however, is unable to differentiate malignant from benign adrenal lesions, although malignant tumors are more likely to secrete multiple hormones.'?

Cushing's syndrome. Contrast-enhanced CT depicts a 2.5-cm, solid, homogeneous, well-delineated left adrenal tumor. The diagnosis of adrenocorticism was established biochemically.

of 10-mm collimation, with even narrower collimation in equivocal cases. CT can detect virtually all adrenal masses that are large enough to cause Cushing's syndrome. The abundant perinephric fat in most patients with corticoid excess allows the adrenal gland to be displayed clearly, and tumors at least I em in diameter are identified routinely (Fig. 66-2). Adrenal adenomas causing Cushing's syndrome are usually 2 to 5 em in diameter, and CT detection approaches 98%.18 The density, although variable, is mostly similar to the soft tissue density of the adjacent adrenal

Clinical Suspicion of Cushing's Syndrome Biochemistry

I

I

ACTH dependent

I

ACTH independent

I

I

No further adrenal imaging

CT

FIGURE 66-3. The flowchart

I

Typical adenoma or typical carcinoma

shows the procedures used in imaging the adrenal glands for a possible case of Cushing's syndrome. ACTH = corticotropin; 19NP-59 = l3lI-6~-iodomethyl norcholesterol.

I

Equivocal or suspected hyperplasia

I

I

Scintigraphy-NP-59 uptake

I

Surgery None (cancer)

I

Surgery

Bilateral (hyperplasia)

I

Observe/treat

Unilateral (adenoma)

I

Surgery

Adrenal Imaging Procedures - -

579

Because abdominal CT provides excellent results, adrenocortical scintigraphy using NP-59 is recommended only for selected patients. NP-59 scintigraphy has been recommended in cases of adrenal hyperplasia, for which it has an overall accuracy of 90% to 95% in experienced hands. Scintigraphy is performed without dexamethasone suppression, and images are obtained 5 to 7 days after administration of the tracer. Bilateral uptake suggests adrenal hyperplasia, and unilateral uptake, secondary to contralateral adrenal suppression, indicates an adrenal adenoma. Bilateral nonvisualization of the adrenals has been associated with carcinoma because of the lack of tracer uptake by malignant tumors.v" However, other factors resulting in bilateral nonvisualization, such as hypercholesterolemia and glucocorticoid administration, should be excluded. NP-59 scintigraphy has failed to gain popularity in many institutions because of limited experience with the isotope, the time required to complete the study, high costs, and the need for an investigational new drug approval for its use. FIGURE 66-4. Contrast-enhanced CT scan of a patient with primary hyperaldosteronism identifies a 1.5-cm-diameter, wellmarginated, rounded adenoma adjacent to the right adrenal gland. The aldosteronoma is isodense with adjacent adrenal tissue. Notice the normal size and appearance (lambda shape) of the left adrenal gland.

Primary Hyperaldosteronism Seventy-five percent of patients with primary hyperaldosteronism have benign adrenal adenomas, and 25% have idiopathic hyperplasia of the zona glomerulosa. Fewer than 1% have adrenocortical cancer. In patients with primary hyperaldosteronism, it is essential to determine whether it is caused by an adrenal adenoma or by hyperplasia because virtually all patients with adenomas benefit from surgical treatment (i.e., abatement of hypokalemia and lower blood pressure), but most patients with hyperplasia do not. 20

Because of their small size, these tumors may be missed during CT scanning, resulting in a sensitivity of 85% with a positive predictive value of up to 100%.21,22 Five percent to 15% are not identified, leaving a sizable group of patients for whom scintigraphy and venous sampling playa major role (Fig. 66-5). Isodense small lesions close to the apex of the adrenal are the ones most likely to be missed. If CT reveals a unilateral mass in a patient with biochemically proven primary aldosteronism, no further studies are usually required. If CT findings are negative or equivocal, adrenal venous sampling should be performed, Selective adrenal venous sampling has identified a hypersecreting abnormality in almost 100% of cases in selected series.' Combined CT and selective adrenal venous sampling approaches a sensitivity of 100% in identifying the cause of primary aldosteronism.P In the case of an aldosteronoma,

Localization Studies Aldosteronomas are usually small lesions, averaging 0.6 to 1.8 em in diameter. CT scanning, therefore, requires 0.3- to O.5-mmcontiguous slices in the adrenal area, and the patient's cooperation is necessary for achieving adequate sensitivity.P" Aldosteronomas often appear as well-marginated, rounded tumors that are isodense or, less frequently, hypodense compared with adjacent adrenal tissue (Fig. 66-4). They typically are not enhanced after administration of a contrast agent.

Biochemically Confirmed Primary Hyperaldosteronism

I

CT

FIGURE 66-5. The flowchart shows the diagnostic modalities used in imaging the adrenal glands for a suspected case of hyperaldosteronism. NP-59 = 1311-6~-iodomethyl 19-norcholesterol.

I Typical adenoma or typical carcinoma

I

Surgery

I

I

Equivocal or symmetric enlargement

I

I Scintigraphy-NP-59 uptake I - - - IJ'-------

Early unilateral adenoma

Early bilateral hyperplasia

Surgery

Observe

I

I

I

NP-59 not available

\ Late bilateral or none

I

Nond/agnostic

I

Venous sampling

580 - - Adrenal Gland unilateral peak levels are found on the side of the tumor. In bilateral adrenal hyperplasia, venous sampling yields symmetrically elevated levels. When performing selective venous sampling, the clinician must obtain blood samples for aldosterone and for cortisol.P Simultaneous measurement of cortisol permits verification of the source of the sample and correction for a dislodged catheter or dilution. Venous sampling is considered the "gold standard" for localizing aldosteronomas by several researchers, although most clinicians use it only selectively for patients with equivocal studies.s'

Other Imaging Modalities Immunoiodocholesterol-labeled analogs (e.g., NP-59) have been successfully used to image aldosteronomas.P The sensitivity varies greatly among series (50% to 90%), indicating problems inherent in the technique." Pretreatment with dexamethasone enhances accuracy, and discontinuation of diuretics and antihypertensive agents is required. Unfortunately, the test is time consuming, requiring 2 to 7 days. An asymmetric pattern identifies an aldosteronoma taking up the radionuelide. Idiopathic hyperplasia is functionally depicted as bilateral foci of moderate NP-59 uptake within 72 to 120 hours after administration. Bilateral uptake seen after more than 120 hours during constant dexamethasone suppression is considered nondiagnostic.F Sensitivity depends primarily on the adenoma's size, and the results of NP-59 scans are less accurate for patients with very small adrenal neoplasms and negative CT scans. Small and hypovascular aldosteronomas are also difficult to identify by ultrasonography, MRI, or arteriography.

Pheochromocytoma

normal-appearing adrenal gland, contiguous thin sectioning (0.5- to 1.0-cm slices) is recommended" Pheochromocytomas show a wide range of morphologic patterns; most pheochromocytomas are rounded masses with homogeneous densities similar to or less than that of liver tissue, and they may occasionally show a hemorrhagic, cystic ("Swiss cheese") appearance or calcified lesions (Fig. 66-6). Despite this heterogeneity, diagnosis of malignancy is unreliable unless local invasion or metastases are apparent. The diagnostic capability of CT scanning may be increased with contrast enhancement, but there is a small and unpredictable risk of precipitating a hypertensive crisis, making a-adrenergic blockade before invasive localization studies essential.28 Contrast enhancement of the tumors is irregular; the periphery of these tumors is often more intensely enhanced. Plain CT is highly accurate (-95%) for intraglandular lesions, but it is less useful in identifying extra-adrenal lesions and lesions in MEN patients, for which it is only 60% to 80% sensitive. CT scanning is even less accurate in evaluating patients with metastatic or recurrent disease (sensitivity of about 60%).8.26.28 Contrast enhancement is essential to provide acceptable sensitivity for detecting extra-adrenal pheochromocytomas, especially those in the neck and mediastinum.P CT scanning in combination with MIBG (MIBG-CT) appears to be the procedure of choice for identifying extraadrenal, ectopic tumor locations. MIBG is selectively taken up by the adrenal medulla and by pheochromocytomas and has been especially useful in evaluating ectopic disease and malignant pheochromocytomas (Fig. 66-7). It is the recommended procedure for patients with recurrent or metastatic disease." Some experts recommend MIBG scanning as the initial diagnostic procedure for every patient suspected of

In planning the localization of a pheochromocytoma, one should consider whether the tumor is sporadic or familial and whether the patient is an adult or child. Most pheochromocytomas are sporadic (85%), and 15% are familial and occur in patients with multiple endocrine neoplasia (MEN) type 2, neurofibromatosis, or Sturge-Weber syndrome. Although 85% of the tumors are unilateral, bilateral pheochromocytomas are found in 50% of familial cases. About 15% of pheochromocytomas are malignant and are usually distinguishable clinically only by the absence or presence of local invasion and metastases. Tumors in extraadrenal locations, which are more likely to be malignant, are found in only 15% of adults, but in children the incidence rises to about 25%. Fewer than 2% of tumors are found in the mediastinum, neck, or head.

Localization Studies Because pheochromocytomas have usually attained a considerable size before being discovered, CT28.29 and Tl- and T2-weighted MRI scans reliably detect pheochromocytomas, with an accuracy of almost 100%.8.26 After peroral contrast preparation of the bowel, an abdominal CT scan from the diaphragm distal to the aortic bifurcation is performed as the initial imaging procedure. Because tumors may extend superiorly and inferiorly from an otherwise

FIGURE 66-6. Contrast-enhanced CT scan of a patient with pheochromocytoma manifesting as a rounded mass with density similar to or slightly less than that of liver tissue. The tumor has several cystic lesions, giving it a "Swiss cheese" appearance. Despite this heterogeneity, a diagnosis of malignancy is unlikely.

Adrenal Imaging Procedures - - 581 sequences using gadolinium-DTPA enhancement enable determination of vascular invasion by these tumors." However, because the spatial resolution of MRI is inferior to that of CT, routine scanning should be done with CT. Moreover, CT has greater sensitivity in detecting liver metastases than MRI.

Other Imaging Modalities

FIGURE 66-7. Metaiodobenzylguanidine scanning confirms a left adrenal pheochromocytoma, identified as a mark on top of the left of the two symmetrically depicted kidneys, together with an ectopically located second tumor at the level of the aortic bifurcation (marker).

having pheochromocytoma because this modality detects most

tumors.P:" For diagnostic use, a tracer dose of 0.5 mCi is given, imaging the adrenals in only a few normal control subjects. For localizing primary, metastatic, and recurrent disease, this approach has a false-negative rate of 11.4% and a false-positive rate of 1.8%.35 MIBG has been used for radioablative treatment of unresectable or metastatic pheochromocytomas. Although there have been some good responses, overall, it has been disappointing." Positron emission tomography has been used after administration of 2-fluorine-18-fluoro-2-deoxY-D-glucose (FDG). The method was found promising for localization of pheochromocytomas in the 10% of patients with falsenegative MIBG scintigrams." Pheochromocytomas are localized and characterized by MRI. The approach is at least equivalent to CT for localization of adrenal pheochromocytomas that are larger than 2 em.' Tumors tend to be hyperintense on T2-weighted pulse sequences." Because of the consistency of hyperintensity, recurrent tumor, metastatic disease, and extra-adrenal pheochromocytomas are readily identified, and in this instance MRI is more accurate and sensitive than CT. Moreover, owing to the marked hyperintensity of functioning pheochromocytomas on T2-weighted pulse sequences, MRI permits differentiation of pheochromocytomas from nonfunctioning adrenal neoplasms. Tumors of the urinary bladder or the paracardiac region, which are difficult to evaluate by CT, are clearly recognized by MRI. In one study, T2-weighted MRI and MlBG-CT scans were nearly equivalent for localizing and staging adrenal pheochromocytomas.w" T'l-weighted MRI

In the rare event that these noninvasive techniques fail, arteriography may be useful. However, patients must be treated with a-adrenergic blockade (e.g., phenoxybenzarnine) to should be used in a avoid hypertensive crisis. ~-Blockade patient with tachyarrhythmias whose tumor secretes epinephrine rather than norepinephrine. Arteriography should include the superior, middle, and inferior adrenal arteries and may be enhanced by subtraction techniques, especially in the 15% of tumors displaying no or only moderate hypervascularization. Selective venography and selective venous sampling of veins in the abdomen, pelvis, and chest may very occasionally be useful for diagnosing small lesions, especially intraglandular lesions or tumors at ectopic sites. A positive result allows the physician to narrow the specific region for further anatomic imaging. However, these techniques require great care and may be dangerous (Fig. 66-8).

Incidentalomas of the Adrenal Gland and Adrenocortical Carcinoma The frequent use of imaging procedures, especially ultrasonography and CT, results in the discovery of unsuspected adrenal masses. So-called incidentalomas or adrenalomas are the most common reason the clinician becomes concerned about the adrenal gland. Incidentalomas have been found in 0.6% to 4.3% of patients or at autopsy.42,43 The major concern when evaluating a patient with an incidentaloma is whether the tumor is functioning and whether it is benign or malignant (Fig. 66-9). Certain information helps determine management of patients with incidentalomas. Tumors that are homogeneous, have a smooth contour with well-delineated margins, and are smaller than 4 em on ultrasonography or CT are usually benign. Two thirds of adrenal carcinomas are functioning tumors." Most patients with adrenocortical carcinomas present with tumors larger than 6 em in their greatest diameter at the time of diagnosis.s When metastatic disease to the adrenal is suspected, percutaneous biopsy is useful; however, it is unable to distinguish between an adrenocortical adenoma and carcinoma. Most patients with CT-confirmed diagnoses of simple adrenal cysts or adenomyelolipomas do not require adrenalectomies. The masses should be monitored for growth. The most common cause of nonfunctioning adrenal masses is cortical adenomas, followed by metastases to the adrenals, myelolipomas, ganglioneuromas, adrenal cysts, and a multitude of other rare findings, some of which have specific CT and MRI characteristics. Of all incidentally discovered masses, 6.5% are pheochromocytomas'? and

582 - - Adrenal Gland Biochemically Confirmed Pheochromocytoma Abdominal CT

I

I

I

Negative (adrenal)

Positive (adrenal)

I

I

I

Surgery

I

MIBG Scintigraphy-131I uptake

1--1- - 1

Negative

I

I

Negative

I

PET (FOG) scan

I

I

Positive

MRI (abdomen/chest/pelvis)

Surgery

I

I

Repeat using 1231-MIBG or perform MRI

MIBG not available

I

Negative

I

I

Refer for MIBG

I

Positive

FIGURE 66-8. The flowchart shows the diagnostic procedures used in imaging the adrenal glands for a suspected pheochromocytoma. FDG = 2-fluorine-18-fluoro-2deoxy-n-glucose; MIBG = metaiodobenzylguanidine; PET positron emission tomography.

I

Surgery

Positive

I

Surgery

7% are aldosteronomas." The probability of an incidentaloma being an adrenal adenoma producing excess glucocorticoids is estimated at 0.035%; this number falls to 0.01 % in the absence of hypertension and obesity. Primary adrenal carcinomas, overall, are rare tumors, with an estimated annual incidence of 0.06 to 0.27 per 100,000 persons, resulting in an estimated prevalence of less than 0.06% of all incidentalomas.v

FIGURE 66-9. Contrast-enhanced CT scan shows a right adrenal carcinoma of considerable size (13 x 10 ern). In this carcinoma, areas of low attenuation, suggesting tumor necrosis, are not appreciable, but the tumor is heterogeneous.

Adrenal Adenomas Typically, a nonhyperfunctioning adenoma is a welldelineated, rounded, homogeneous mass. Calcification may occur but is uncommon, as is central necrosis or hemorrhage. The sizes of incidentally detected adenomas range from 0.5 to 6 cm.? However, CT does not reliably differentiate benign adenomas from malignant lesions." Densities range from approximately 0 to 30 HU.47 One study suggested that CT attenuation values may enable one to differentiate nonhyperfunctioning adenomas (:::;5 HU) and metastases from hyperfunctioning adenomas (~16.5 HU); values in excess of 20 HU were indicative of malignancy?" If available, NP59 scintigraphy should be performed because increased tracer uptake by a nonhyperfunctioning lesion detected by ultrasonography or CT (i.e., concordant uptake) indicates that the lesion is benign. Discordant uptake indicates that the lesion is a complex adenoma with hemorrhage or calcification (i.e., decreased, absent, or distorted uptake) or not an adenoma at all, requiring further assessment.48 Adrenal adenomas larger than 1.5 em are reliably detected by MRI, and MRI may be used to characterize an adrenal mass. For example, a decrease in the tumor's signal intensity compared with the liver or fat signal intensity on Tl- and T2-weighted MRI images occurs with adrenal adenomas, but relative increases in signal density occur for carcinomas and functioning adenomas. However, at present, the data are insufficient for directing therapy.'"

Metastases The adrenal gland is a common site of metastatic disease. In a series of 1000 consecutive postmortem examinations of patients with epithelial malignancies, adrenal metastases

Adrenal Imaging Procedures - - 583 were found in 27%.50 Despite the impressive figure, even in patients with a predisposition for metastatic disease, such as those with lung cancer, the most likely cause of an incidentally discovered adrenal mass is adrenal adenoma." However, bilateral, nonfunctioning masses in a patient with known cancer are likely to be metastatic disease. Overall, the radiologic appearance of metastases is not specific. During CT scanning, a metastasis usually appears as a solid mass, and if less than 3 em in diameter, it is often homogeneous. Adrenal metastases may be impossible to differentiate from adenomas, pseudocysts, or inflammatory masses. Features suggesting metastases include larger sizes (>3 em), poor definition of margins or invasion of adjacent tissue, inhomogeneous attenuation (i.e., hemorrhage or necrosis), and a thick, perifocal, irregularly enhancing rim. 52 MRI has been used in differentiating metastatic disease from primary adrenal neoplasms with some success, but indeterminate findings occur for about one third of these patients.P Several studies have suggested that there are intensity cutoff points below which all lesions are adenomas and above which all lesions are carcinomas.s-'! However, the accuracy of MRI as a single modality for determination of the nature of these lesions remains to be proved. It appears that percutaneous fine-needle aspiration biopsy is still the most effective and definitive method for confirming metastatic disease. With experienced cytopathologists, the method gains a positive predictive value of approximately 100% and an overall diagnostic accuracy of 80% to 100%. Adrenal biopsy is an invasive method, and complications may occur, including pneumothorax or bleeding. Pheochromocytoma must be ruled out before needle biopsy is done.

Adrenocortical Carcinoma If adrenocortical carcinoma is suspected on clinical grounds, CT scanning should be performed. Characteristics of adrenocortical cancer, such as poorly defined, irregular, or lobulated margins; large, central areas or multiple, scattered areas of decreased attenuation; irregular contrast

enhancement; and signs of local invasion, are helpful in establishing the diagnosis. 54.55 CT scanning also provides information about local tumor extension, liver metastases, and resectability. Differentiating adrenocortical carcinoma from other lesions is usually not a problem because most carcinomas have attained considerable size at the time of diagnosis (Fig. 66-10).8 MRI may be helpful in evaluating a suspected adrenal carcinoma because a high signal intensity on T2-weighted or gadolinium-DTPA Tl-weighted images supports the diagnosis of malignancy and allows the assessment of vascular extension and venous invasion.v-" This finding may eliminate the need for venography or arteriography.

Summary For patients with Cushing's syndrome and adrenal neoplasms, abdominal CT scanning is almost 100% accurate, and falsenegative results in cases of biochemically proven Cushing's syndrome are rare. For these patients, normal adrenal morphologic patterns seen on CT scans suggest adrenal hyperplasia. When CT and MRI findings are nondiagnostic, adrenocortical scintigraphy using iodocholesterols is helpful. For patients with biochemically proven primary hyperaldosteronism, abdominal CT scanning with contiguous 0.3- to 0.5-cm collimation of the adrenal is the localization procedure of choice. When a unilateral adrenal lesion is identified, no further imaging is necessary. When CT scanning is normal, equivocal, or depicts bilateral adrenal masses, adrenal venous sampling with aldosterone and cortisone testing should be done. For patients with biochemically proven pheochromocytomas, abdominal CT scanning has nearly 100% accuracy. When intravenous contrast enhancement is required, patients must be prepared with (l- and ~-adrenergic blockade. For patients with negative studies or for patients with recurrent or metastatic disease, MIBG or MRI scanning is helpful. MIBG scanning is also the modality of choice for patients with MEN syndromes.

Incidentaloma discovered by US or CT History, physical examination, and biochemical test to assess function

I

FIGURE 66-10. The flowchart shows the diagnostic procedures used in imaging incidentalomas. FNAC = fine-needle aspiration cytology; US = ultrasonography.

I

Hormone-secreting tumor

Hormonally silent tumor

Forfurtherimaging referto other algorithms

Repeat or review CT

I

I

I

I

Cyst Adenolipoma Myelolipoma

Carcinoma

Observe

Surgery

I

I

I

Known malignancy

I

FNAC

I

~

<3.5 em

I Observe

>3.5 em

I

Surgery

584 - - Adrenal Gland

Incidentalomas are the most common adrenal tumors requiring evaluation by the clinician. Most masses are benign. When CT scanning fails to show a cyst, adenomyelolipoma, or carcinoma, biochemical studies are necessary to determine whether the tumor is functioning. All functioning adrenal tumors and most nonfunctioning adrenal tumors larger than 4 em in the maximal diameter should be removed, especially if the tumor is heterogeneous and has an irregular contour.

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24. Shapiro B, Grekin R, Gross MD, Freitas JE. Interference by spironolactone on adrenocortical scintigraphy and other pitfalls in the location of adrenal abnormalities in primary aldosteronism. Clin Nucl Med 1994;19:441. 25. Gross MD, Shapiro B, Gerkin RJ, et al. Scintigraphic localization of adrenal lesions in primary aldosteronism. Am J Med 1984;77:839. 26. Herd GW, Semple PF, Parker D, et al. False localization of aldosteronoma by dexamethasone-suppressed adrenal scintigraphy. Clin Endocrinol (Ox±) 1987;26:699. 27. van Erkel AR, van Gils APG, Lequin M, et al. CT and MR distinction of adenomas and nonadenomas of the adrenal gland. J Comput Assist Tomogr 1994;18:432. 28. Radin DR, Ralls PW, Boswell WD Jr, et al. Pheochromocytoma: Detection by unenhanced CT. AJR Am J Roentgenol 1986;146:741. 29. Raisanen J, Shapiro B, Glazer GM, et al. Plasma catecholamines in pheochromocytoma: Effect of urographic contrast media. AJR Am J Roentgenol 1984;143:43. 30. Shin MS, Gupta KL, Ho KJ, et al. Thoracic pheochromocytoma: Computerized tomographic characteristics. South Med J 1986;79:244. 31. Quint LE, Glazer GM, Francis IR, et al. Pheochromocytoma and paraganglioma: Comparison of MR and CT with MIBG scintigraphy. Radiology 1987;165:89. 32. Francis IR, Gross MD, Shapiro B, et al. Integrated imaging of adrenal disease. Radiology 1992; 184: I. 33. Mazley PD, Kim CK, Mahsin J, et al. The efficacy of iodine 123 MIBG as a screening test for pheochromocytoma. J Nucl Med 1994;35: 1138. 34. Dunn GD, Brown MJ, Sapsford RN, et al. Functioning middle mediastinal paraganglioma (phaeochromocytoma) associated with intercarotid paragangliomas. Lancet 1986; 1:1061. 35. Shapiro B, Sisson JC, Eyre P, et al. 1311_MIBG_A new agent in diagnosis and treatment of pheochromocytoma. Cardiology 1985;72(Suppl I): 13. 36. Beierwaltes WHo Update on basic research and clinical experience with MIBG. Med Pediatr OncoI1987;15:163. 37. Shulkin BL, Koeppe RA, Francis lA, et al. Pheochromocytomas that do not accumulate MIBG: Localization with PET and administration of FDG. Radiology 1993; 186:711. 38. Falke THM, vanGils APG, vanSeters AP, Sandler MP. Magnetic resonance imaging of functioning paragangliomas. Magn Reson Q 1990;6:35. 39. Velchnik MG, Alavi A, Kressel HY, Engelman K. Localization of pheochromocytoma: MIBG, CT, MRI correlation. J Nucl Med 1990;30:328. 40. van Gils APG, Falke THM, van Erkel AR, et al. MR imaging and MIBG scintigraphy of pheochromocytomas and extraadrenal functioning paragangliomas. Radiographies 1991; II :37. 41. Smith SK, Turner DA, Matalon DAS. Magnetic resonance imaging of adrenal cortical carcinoma. Urol Radiol 1989; II: I. 42. Abecassis M, McLoughlin MJ, Langer B, et al. Serendipitous adrenal masses: Prevalence, significance, and management. Am J Surg 1985; 149:783. 43. Glazer HS, Weymann PJ, Sagel SS, et al. Nonfunctioning adrenal masses: Incidental discovery on computed tomography. AJR Am J Roentgenol 1982; 139:81. 44. Copeland PM. The incidentally discovered adrenal mass. Ann Intern Med 1983;98:940. 45. Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma: Review of a 50-year autopsy series. Mayo Clin Proc 1981;56:354. 46. Ross NS, Aron DC. Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 1990;323:1401. 47. Dunnik NR. Adrenal imaging: Current status. AJR Am J Roentgenol 1990;154:927. 48. Gross MD, Shapiro B, Francis IR, et al. Scintigraphic evaluation of clinically silent adrenal masses. J Nucl Med 1994;34:1145. 49. Mezrich R, Banner MP, Pollack HM, et al. Magnetic resonance imaging of adrenal glands. Urol Radiol 1986;8: 127. 50. Abrams HL, Spiro R, Goldstein N, et al. Metastases in carcinoma: Analysis of 1000 autopsied cases. Cancer 1950;3:74. 51. Oliver TW, Bernardino ME, Miller JL, et al. Isolated adrenal masses in non-small cell bronchogenic carcinoma. Radiology 1984;153:217. 52. Berland LL, Koslin DB, Kenney PJ, et al. Differentiation between small benign and malignant adrenal masses with dynamic increment CT. AJR Am J Roentgenol 1988; 151:95.

Adrenal Imaging Procedures - - 585 53. Chezmar JL, Rabbins SM, Nelson RC, et al. Adrenal masses: Characterization with Tl weighted MR imaging. Radiology 1988; 166:357. 54. Dunnick NR, Heaston D, Halvorsen R, et al. CT appearance of adrenal cortical carcinoma. J Comput Assist Tomogr 1982; 6:978.

55. Hussain S, Belldegrumn A, Seltzer SE, et al. Differentiation of malignant from benign adrenal masses: Predictive indices on computed tomography. AJR Am J Roentgenol 1985;144:61. 56. Falke TH, Peetoom JJ, deRoos A, et al. Gadolinium DTPA enhanced MR imaging of intravenous extension of adrenocortical carcinoma. J Comput Assist Tomogr 1988;12:331.

Clinically Inapparent Adrenal Mass (Incidentaloma or Adrenaloma) Dimitrios A. Linos, MD, FACS

Historically, the adrenal tumor that was discovered incidentally, usually during an imaging procedure such as computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography for symptoms unrelated to adrenal disease, (e.g., back pain) was called an incidentaloma:' As more physicians (and patients on their own) ordered these easily available imaging studies for common diseases potentially related to adrenal pathology (and not the known syndromes), such as mild and nonparoxysmal hypertension, diffuse obesity, and diabetes, an increasingly number of unsuspected (but hardly incidental) adrenal tumors were found. I have proposed that these tumors be included with the true incidentalomas under the broader term adrenaloma because they share the same diagnostic and therapeutic dilemmas.? The term adrenaloma implied that the discovered tumor (incidentally or not) derives from the adrenal but is not obviously an aldosteronoma, a Cushing's syndrome adenoma, a pheochromocytoma, a virilizing or feminizing tumor, or a functioning adrenal carcinoma. Recently, at a State of the Science Conference at the National Institutes of Health Conference, the term clinically inapparent adrenal mass was coined.' The widespread teaching is that most adrenalomas are indolent tumors, nonfunctioning and asymptomatic, causing no harm to the patient.t-' Recent studies, however, have shown that a high percentage of these tumors can be subclinically functioning, causing symptoms milder than those encountered in the well-known adrenal-hyperfunctioning syndromes but still harmful to the patient.v!" Thus, the screening tests of serum potassium, urinary vanillylmandelic acid (VMA), and serum cortisol do not suffice and more detailed and in-depth laboratory investigation is necessary. The fear of adrenal carcinoma that dictated the approach to these tumors in the past (with the main emphasis on the size of the tumor) should be changed to the fear of the subtle function of these usually benign adrenal cortical adenomas with coexistent metabolic pathology (e.g., hypertension, obesity, diabetes).

586

Frequency The overall frequency of adrenal adenomas in 87,065 autopsies in 25 studies was 5.9% (range 1.1% to 32%).15 The frequency of adrenal masses discovered by CT, MRI, or ultrasonography is somewhat lower. Abecassis and associates" in a 2-year period examined 1459 patients and found 63 (4.3%) with adrenal masses. Of those, 19 patients (1.3% of examined patients and 30% of patients with adrenal masses) had adrenalomas. At the Mayo Clinic.!? in a 5-year period, 61,054 patients underwent CT scanning. In 2066 patients (3.4%), an adrenal abnormality was found; among these, 259 patients (12.5%) had an adrenaloma or adrenal lesion larger than 1 em, without biochemical evidence or symptoms suggestive of cortical or medullar hypersecretion or general constitutional symptoms suggestive of malignant disease. Similar findings have been described in more recent studies. 18-2o Thus, in the era of widespread use of highresolution ultrasonography, new-generation CT scans, and MRl, we can anticipate a 5% incidence of adrenalomas.

Pathology Most surgically removed clinically inapparent adrenal masses have been classified as nonfunctioning cortical adenomas.v" Benign masses such as nodular hyperplasia, adrenal cysts, myelolipomas, ganglioneuromas, hematomas, hamartomas, hemangiomas, leiomyomas, neurofibromas, teratomas, as well as infections (tuberculosis, fungal, echinococcosis, nocardiosis) are also included in the pathology of these resected tumors (Fig. 67-1). Potentially lethal neoplasms, however, such as pheochromocytomas and primary carcinomas are always first on the list of resected adrenalomas.P'P' Pheochromocytoma is the most frequently found hormoneproducing adrenaloma that occasionally has a normal preoperative laboratory evaluation.P<" Few cases of aldosteronomas

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FIGURE 67-1. Adrenalomas. A, Adenoma (in subclinical Cushing'S syndrome). B, Pheochromocytoma (in subclinical pheochromocytoma). C, Aldosteronoma (in subclinical aldosteronism). D, Adrenal cyst. E, Myelolipoma. F, Schwannoma. G, Primary adrenal carcinoma. H, Secondary adrenal carcinoma: a solitary metastasis from cervical cancer on which surgery was performed 10 years previously. (From Linos DA: Management approaches to adrenal incidentalomas [adrenalomas]: A view from Athens, Greece. Endocrinol Metab Clin North Am 2000;29:141.)

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Adrenal Gland

and androgen-producing adenomas have been described among cases of surgically removed adrenalomas.t'" In a large, multicenter, retrospective Italian study of 380 surgically treated adrenalomas (out of 1096 collected), 198 (52%) were cortical adenomas, 47 (12%) were cortical carcinomas, 42 (II %) were pheochromocytomas and 93 were other less frequent tumors.'

The Goal of Evaluation Although by definition the clinically inapparent adrenal masses appear "nonfunctioning," on the basis of clinical and essential laboratory findings more and more investigators have shown that a high percentage of them may be subclinically functioning and/or associated with other metabolic abnormalities. In a multicenter, retrospective evaluation of 1096 patients with adrenal incidentaloma, the work-up revealed that 9.2% had subclinical Cushing's syndrome, 4.2% had pheochromocytoma, and 1.6% had clinically unsuspected aldosteronornas.P Rossi and colleagues'? followed prospectively 50 consecutive patients with clinically inapparent adrenal masses. Detailed hormonal investigation found 12 (24%) of 50 to have subclinical Cushing's syndrome defined as abnormal response to at least two standard tests of hypothalamuspituitary-adrenal axis function in the absence of clinical signs of Cushing's syndrome. In the same study, 92% of patients had hypertension, 50% obesity, 42% type 2 diabetes mellitus, and 50% abnormal serum lipid concentration. The clinical and hormonal features improved in all patients treated by adrenalectomy but were unchanged in all those who did not undergo surgery (follow-up, 9 to 73 months). All 13 patients who had resection of truly nonfunctioning adenomas because of large size had improved clinically to such an extent that antihypertensive and antidiabetic therapy was reduced or discontinued. All the improvements persisted during the follow-up. Another multicenter study'? of 64 consecutive patients with clinically inapparent adrenal masses found a higher than expected prevalence of abnormal glucose tolerance in 39 patients (61%). The same authors," following 62 consecutive patients with clinically inapparent adrenal masses, found abnormal glucose tolerance in 66%. Midorikawa and coworkers,'! studying 15 patients with clinically inapparent adrenal masses (4 with subclinical Cushing and 11 with truly nonfunctioning tumors), found a high prevalence of altered glucose tolerance and insulin resistance. Adrenalectomy reversed insulin resistance in all patients with subclinical functioning and truly nonfunctioning adrenal adenomas. Terzolo and associates! followed 41 patients with clinically inapparent adrenal masses (12 with subclinical Cushing's syndrome) and compared them with 41 controls. They found that the 2-hour postchallenge glucose was significantly higher in patients than in controls. Similarly, both systolic and diastolic blood pressures were higher in patients. The calculated whole-body insulin sensitivity index (derived from the oral glucose tolerance test) was significantly reduced in the patients. They concluded that patients with these tumors (subclinically functioning or nonfunctioning)

display some features of the metabolic syndrome such as impaired glucose tolerance, increased blood pressure, and high triglyceride levels. Garrapa and colleagues" evaluated body composition and fat distribution, as measured by dual-energy x-ray absorptiometry (DEXA), in women with nonfunctioning clinically inapparent adrenal masses and in women with Cushing's syndrome compared with healthy controls matched for age, menopausal status, and body mass index. Women with clinically inapparent adrenal masses had larger waist circumference, reflecting intra-abdominal fat. The blood pressure was higher in patients with these tumors than controls, and 50% of patients were hypertensive. High-density lipoprotein (HDL) cholesterol levels and triglyceride mean values were also higher in patients with clinically inapparent adrenal masses than in controls. If central fat deposition, hypertension, and low HDL are important risk factors for cardiovascular disease, then patients with clinically inapparent adrenal masses, whether subclinically functioning or nonfunctioning, are at higher risk than the general population for cardiovascular disease. Chiodini and coworkers" performed a longitudinal study evaluating the rate of spinal and femoral bone loss levels in 24 women with clinically inapparent adrenal masses. They were divided into two groups on the basis of the median value of urinary cortisol excretion. The group with higher cortisol values (subclinical Cushing levels) had more lumbar trabecular bone loss than those with low cortisol secretion (not hypersecreting tumors). Therefore, the "cavalier" attitude toward clinically inapparent adrenal masses should be changed. These tumors are at an intermediate stage, between normal and pathologic. They should be screened to rule out (1) subclinical Cushing's syndrome, (2) subclinical pheochromocytoma, (3) subclinical primary aldosteronism, and (4) adrenal carcinoma (primary or solitary metastasis).

Screening for Subclinical Cushing's Syndrome Patients with subclinical Cushing's syndrome have none of the signs and symptoms of the typical Cushing's syndrome (e.g., plethora, moon face, central obesity, easy bruising, proximate muscle weakness, acne, osteoporosis). The frequency of subclinical Cushing's syndrome among patients with adrenaloma ranges from 12% to 24%.10,36 Depending on the amount of glucocorticoids secreted, the clinical significance of subclinical Cushing's syndrome ranges from slightly attenuated diurnal cortisol rhythm to atrophy of the contralateral adrenal gland, a dangerous condition after unilateral adrenalectomy if appropriate therapeutic measures are not taken early enough." The best screening test for autonomous cortisol secretion is the short dexamethasone suppression test. A 2- or 3-mg dose is better than the usual l-mg dose to reduce falsepositive results. A suppressed serum cortisol «3 ug/dl, or 80 nmollL) excludes Cushing's syndrome. A serum cortisol greater than 3 ug/dl. requires further investigation, including a confirmatory high-dose dexamethasone suppression test (8 mg), corticotropin-releasing hormone test, and analysis of diurnal cortisol rhythm. If serum cortisol concentrations are not suppressible by high-dose dexamethasone, the diagnosis

Clinically Inapparent Adrenal Mass (Incidentaloma or Adrenaloma) - -

of subclinical Cushing's syndrome is established. Another suggested test is the growth hormone response to growth hormone-releasing hormone. A blunted growth hormone release might prove a sensitive and early sign of subclinical Cushing's syndrome." As already discussed, glucose tolerance is altered in patients with clinically inapparent adrenal masses (with and without subclinical Cushing), and a glucose tolerance test is recommended in patients with clinically inapparent adrenal masses. lO,12,38 Finally, bone mineral density of the spine should be performed to detect reduced bone mass in patients with subclinical Cushing's syndrome. 14 Adrenal scintigraphy with 1311-6~-iodomethylnorcholesterol (NP-59) can reveal a "functioning" but not "hypersecretory" tumor when there is an uptake of the nucleotide in the tumor site and no uptake in the contralateral suppressed gland. Some authors 39,40 suggested a significant positive correlation between abnormal cortical secretion and NP-59 uptake, making NP-59 scanning a cost-effective diagnostic tool for evaluating clinically inapparent adrenal masses. Others" found it cumbersome because it requires several days to obtain the images and it is unable to take up NP-59 in the presence of hemorrhage or inflammation; they recommend no routine use of NP-59 scanning.

Screening for Subclinical Pheochromocytoma The typical patient with pheochromocytoma is hypertensive and may have paroxysmal hypertension and related symptoms (headache, hypertensive crisis, sweating, and cardiac arrhythmias). The proposed term subclinical pheochromocytoma refers to the totally asymptomatic clinically inapparent adrenal masses that histologically proves to be a pheochromocytoma. In several series of clinically inapparent adrenal masses, the frequency of pheochromocytomas ranges from 10% to 40%.31,33 Although the percentage of asymptomatic pheochromocytomas among patients with nonfunctioning adrenal tumors is relatively high, most test positive on hormonal evaluation, which is a measurement of 24-hour urinary metanephrines and VMA or fractionated urinary catecholamines. In the National Italian Study Group, 27 patients (3.4% of the total patients with incidentaloma) were found to have pheochromocytoma; 24-hour urinary catecholamine and VMA concentrations were elevated in 86% and 4.6% of patients, respectively.F indicating that a combination of tests is more useful clinically than an individual test. The efficacy of single-voided ("spot") urine metanephrine and normetanephrine assays for diagnosing pheochromocytoma has been documented. Such tests may avoid the inconvenience of 24-hour urine collection." There is no indication for routine use of 1311-metaiodobenzylguanidine (I-MIBG) scintigraphy in the evaluation of an adrenaloma unless catecholamine and urinary metabolites are elevated. Because there are cases of clinically inapparent adrenal masses that preoperatively had negative urinary VMA, metanephrines, and MIBG scanning but that intraoperatively behaved (with later histologic proof) as pheochromocytomas, prophylactic measures should always be taken (e.g., arterial line, immediate access to intravenous nitroprusside [Nipride]) during surgery.

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Screening for Subclinical Primary Aldosteronism The typical primary aldosteronism is characterized by hypertension with hypokalemia, elevation of plasma aldosterone, and suppressed plasma renin activity. Subclinical primary aldosteronism describes the patient with adrenaloma who is normotensive or hypertensive with normokalemia. More than 40% of patients with primary aldosteronism are normokalemic; therefore, the previously recommended measurement of potassium as the only test to rule out primary aldosteronism in the case of clinically inapparent adrenal masses should be abandoned.f Instead, a detailed, time-consuming evaluation is necessary, especially in all hypertensive patients, to rule out primary aldosteronism, which may be the cause of hypertension in up to 15% of these patients.v" In a normotensive patient with a serum potassium level greater than 3.9 nmol/L, no further hormonal evaluation is necessary. The screening for subclinical primary aldosteronism should include, in addition to serum potassium, the upright aldosterone level to plasma renin activity (PRA) ratio, since a single value of aldosterone may be normal. Patients with two or more samples with a positive aldosterone-PRA ratio (>40) should undergo the fludrocortisone suppression test (0.4 mg every day for 4 days) or the acute saline suppression test (2 L of 0.9% NaCl solution infused intravenously over 4 hours) to confirm the diagnosis. Bilateral adrenal venous sampling with measurements of aldosterone and cortisol levels is the necessary next step to lateralize and determine the subtype of primary aldosteronism to identify the patient who will be cured through surgery.

Screening for Adrenal Carcinoma The risk of a clinically inapparent adrenal mass harboring a primary carcinoma of the adrenal is very low." The annual incidence of the latter has been estimated to range from 1 case per 600,000 to 1 case per 1.6 million persons. Its prevalence is approximately 0.0012%.46 In contrast, metastatic carcinoma to the adrenal is a common finding in patients with lung, breast, colon, and other extra-adrenal malignancies. In published series of surgically resected adrenalomas, the frequency of histologically confirmed primary adrenal carcinoma ranges from 4.2% to 25%.7 The frequency of adrenal metastasis from lung cancer at autopsy ranges from 17% to 38%. In patients with adrenal mass in the setting of extra-adrenal malignancy, the probability of this mass being metastatic ranges from 32% to 73%.5,33,47 SIZE OF TUMOR

The size of a clinically inapparent adrenal mass is frequently used to predict potential malignancy and the need for surgery. Although most clinically treated adrenal malignancies are discovered when they are larger than 6 em in diameter, several reports have described very large tumors that never metastasized and small adrenal tumors that did (Fig. 67-2). In several series, adrenocortical carcinomas with a maximum diameter of 3 em or less have been described. 15,33,37,47 The size of a clinically inapparent adrenal mass as reported on a CT scan is usually smaller than the size reported on the histology report. This underestimation ranges from 16% to 47%.48 In an analysis of the CT and histology reports

590 - - Adrenal Gland one may see a irregular, blurred, heterogeneous tumor with areas of necrosis; such lesions are suggestive of malignancy, especially if enlarged lymph nodes or local invasion is also detected." On MRI studies, one should look for heterogeneously increased, early T2-weighted signal, weak and late enhancement after gadolinium injection, or an intravascular signal identical to the tumor signal. When NP-59 scintigraphy is available, the lack of (or very weak) uptake in the tumor and normal contralateral uptake is suspicious for malignancy. Positron emission tomography (PET) can be used following the administration of 2-deoxy-2[18F]-fluoro-D-glucose (lsF-FDG). The 18F_FDG PET scan is a useful tool confirming isolated metastases and selecting patients for adrenalectomy. It has been used in studies to distinguish between primary and metastatic adrenal lesions, especially in patients with other primary malignancies (Fig. 67-3).50 FINE-NEEDLE ASPIRATION

FIGURE 67-2. This larger than 6 em, clinically inapparent adrenal mass was suspicious for malignancy on CT scan (A) but histologically was proved a benign cortical tumor (8).

of 76 patients with various diseases, we found" that the mean estimated diameter of the adrenal tumor was 4.64 em on the CT report when the real size (pathology report) was 5.96 cm. Further analysis of different CT scans revealed a consistent underestimation in all groups. In the group of adrenal tumors with a maximum diameter of less than 3 em, the mean diameter reported on CT was 2.32 em in contrast to the true histologic size of 3.63 em (P < 0.001). We therefore proposed the formula Histologic size = 0.85 + (1.09 x CT size) to correct the underestimated CT size so as to use the size criterion more accurately." A recent study" showed that the above "Linos formula" turned out to be significantly more accurate than direct radiologic measurements in predicting the real pathologic size of the tumor. IMAGING

In addition to assessing distant metastasis and tumor size, imaging studies may suggest malignancy. On a CT study,

Fine-needle aspiration (FNA) biopsy of a clinically inapparent adrenal mass has a limited role. It is useful in cases of coexistent extra-adrenal carcinoma (usually lung cancer) to confirm the radiologic evidence of adrenal metastasis. In a study by Silverman and coworkers," 3 of 33 FNA specimens that contained "benign" adrenal tissue were later proved to be malignant. Each malignant lesion was smaller than 3 em in diameter. In 14 patients in whom the FNA was nondiagnostic, two masses proved to be malignant. Generally, FNA cannot differentiate cortical adenoma from carcinoma because it cannot detect invasion of the tumor into the capsule. Although it has been suggested that FNA is useful in the differential diagnosis of a cystic adrenal mass, we strongly object to such practice because cystic pheochromocytomas are prevalent. Diagnostic puncture of such a lesion (or of a rare cystic echinococcal parasitic cyst) can be harmful to the patient. The possibility of seeding a malignant adrenal neoplasm in the retroperitoneum is an additional reason that FNA should be discouraged.

Genetic and Molecular Biology Studies Currently, the only accepted criteria to determine whether a clinically inapparent adrenal mass is benign or malignant are metastasis (synchronous or metachronous) and local invasion into adjacent structures. The mapping and identification of genes responsible for hereditary syndromes (e.g., multiple endocrine neoplasia type 1, Li-Fraumeni syndrome) have increased our understanding of adrenocortical tumorigenesis. Oncogenes and tumor suppressor genes involved in adrenal carcinomas include mutations in the p53 tumor suppressor gene. Among those, the Ki-67 index (percentage of immunopositive cells), when above 5%, can be a useful indicator in the differentiation of adenomas from carcinomas.P Adrenal carcinomas are monoclonal, whereas adrenal adenomas may be polyclonal in approximately 25% to 40% of cases." Although these findings do not have direct clinical application, it is hoped that future research will facilitate the diagnosis and predict the natural course of these tumors.

Clinically Inapparent Adrenal Mass (Incidentaloma or Adrenaloma) - - 591

FIGURE 67-3. The positron emission tomography scandetected a small isolatedadrenal metastasis (arrow) (witha concurrent negative CT scan) in this 69-year-old man who had been treatedfor mesothelioma in the past. Laparoscopic adrenalectomy allowed full extirpationof this single metastasis.

Management of Clinically Inapparent Adrenal Masses: Surgery Versus Follow-Up Several recent studies that we briefly discussed demonstrated the following: 1. A relatively high percentage of clinically inapparent adrenal masses, especially adrenal cortical adenomas, are subclinically functioning. 2. A relatively high percentage of patients with a clinically inapparent adrenal mass display pathologic features such as impaired glucose tolerance, insulin resistance, increased blood pressure, high triglyceride levels, low HDL, central fat deposition and reduced trabecular bone mineral density. 3. When adrenalectomy was done in patients who either had proven subclinical hypercortisolism or even truly nonfunctioning tumors, the associated abnormalities and symptoms (e.g., hypertension, obesity, altered glucose tolerance) were normalized or significantly improved. In the era of laparoscopic adrenalectomy that carries a minimal mortality and morbidity, it appears logical to advocate surgery in patients with a clinically inapparent adrenal

mass when 1. There is laboratory evidence for a subclinically functioning tumor. 2. There are associated pathologic features such as hypertension, impaired glucose tolerance (or diabetes), pathologic triglyceride profile, central fat deposition, and reduced bone mineral density. 3. There is clinical and radiologic evidence for primary or solitary metastatic adrenal carcinoma. The age and the anxiety of the patient should also playa role in the decision to operate or not. Conservative management is recommended for those patients with clinically inapparent adrenal mass in whom 1. There is no clinical or laboratory evidence for subclinical function of the tumor. 2. There are no associated symptoms potentially related to the clinically inapparent adrenal mass. 3. There is no suspicion of adrenal carcinoma. In these patients a yearly check-up should be continued for 5 to 10 years with the main emphasis on the possibility that the silent, nonfunctioning tumor may develop hyperfunction. Limited, complete follow-up studies (with repeated radiologic and hormonal evaluation) have been performed on patients with clinically inapparent adrenal masses. Barzon and associates" followed 75 patients with clinically

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inapparent adrenal mass, for a median of 4 years, and found 9 of them to have enlargement. Overt Cushing's syndrome developed in two patients, subclinical Cushing's syndrome in three, and clinical pheochromocytoma in one. No patient had a malignancy. The estimated cumulative risks for mass enlargement and hyperfunction were 18% and 9.5%, respectively, after 5 years, and 22.8% and 9.5% after 10 years. In another study,55 53 patients with clinically inapparent adrenal masses were followed for 6 to 78 months (median, 24 months). During the follow-up, 22 lesions (41.5%) increased in size and 6 lesions (11.3%) decreased in size or disappeared. No clinically inapparent adrenal mass grew or developed hypersecretion. Thus, during follow-up of the truly nonfunctioning clinically inapparent adrenal masses, yearly hormonal evaluation should be emphasized rather than repeating imaging studies.

What is the Best Surgical Approach in the Management of Clinically Inapparent Adrenal Masses? Traditionally, surgical approaches to the adrenals have been anterior transperitoneal, posterior extraperitoneal, and thoracoabdominal (for large tumors)." The application of laparoscopic techniques in the surgery of the adrenal glands has essentially replaced all traditional open approaches in the same manner as laparoscopic cholecystectomy has replaced traditional open cholecystectomy. Because there are so many benefits associated with the laparoscopic approach, open adrenalectomy should be reserved for very large adrenal carcinomas invading the surrounding tissue. We have compared the anterior, posterior, and laparoscopic approach in 165 patients who underwent adrenalectomy between 1984 and 1994.57 Although in this study we included our early cases and learning experience, the advantages of the laparoscopic approach were clearly shown in terms of morbidity (12.2% in the anterior approach, 8.1% in the posterior approach, and 0% in the laparoscopic approach), mean operating time, mean length of postoperative hospitalization (8.1 vs. 4.5 vs. 2.7 days), and minimal postoperative pain. The lack of long incisions and their immediate and longterm complications (e.g., wound infection, hernia, esthetic dissatisfaction) and the opportunity for an early return to full activity make the laparoscopic approach the procedure of choice for nearly all clinically inapparent adrenal masses, including the laparoscopically removable primary or secondary carcinomas (see Fig. 67_3).31.58 Although the posterior open adrenalectomy has more advantages than the anterior open adrenalectomy, the advantages of anterior laparoscopic adrenalectomy outweigh the advantages of the posterior laparoscopic approach.v-" The anterior (or lateral) laparoscopic adrenalectomyenables the removal of large tumors, the performance of additional procedures (e.g. cholecystectomy), and the performance of bilateral laparoscopic adrenalectomies when indicated. 61.62 We have simplified'< the anterior laparoscopic technique, which has become easier and more "friendly" to the surgeon compared to the originally described techniques.P Thus, more and more surgeons will switch to the laparoscopic approach for the management of adrenal tumors.

Summary The adrenal tumors that are not apparently clinically functioning and often (but not always) are incidentally found (incidentalomas/adrenalomas) are becoming more prevalent and constitute a diagnostic and therapeutic problem. The purpose of the diagnostic approach is to confirm whether these tumors are (1) subclinically functioning and/or (2) suspicious for malignancy. Therefore the diagnostic process should include the following: 1. The short dexamethasone suppression test (2 mg of dexamethasone) followed by the high-dose test (8 mg of dexamethasone) if serum cortisol is greater than 3 ~g/dL to rule out subclinical Cushing's syndrome. 2. Measurement of 24-hour urine metabolites of catecholarnines (metanephrines, normetanephrines) to rule out subclinical pheochromocytoma (when the patient is normotensive). 3. Measurement of the upright aldosterone level to plasma renin activity (PRA) ratio in addition to the potassium level to rule out subclinical aldosteronism (normotensive or hypertensive with normokalemia patient) Because of the recently described association of these adrenal tumors to the metabolic syndrome, we have to add the following diagnostic tests: • Glucose tolerance test • Bone mineral density studies • Body composition and fat distribution by DEXA The suspicion for malignancy or not is mainly supported by the imaging studies (CT, MRI, PET scan, ultrasonography) as well as the size of the tumor. The role of the FNA biopsy is limited and indicated only when a primary malignancy coexists (to rule out metastasis). The clinical application of genetic and molecular biology tests for these tumors is limited. Once the diagnostic evaluation is complete, the therapeutic management dilemma of conservative versus surgical resection is addressed. All tumors that have no laboratory evidence of hypersecretion and no clinical and/or imaging suspicion for malignancy need to be treated conservatively with annual hormonal and imaging study follow-up. All tumors that have laboratory evidence of autonomy and subclinical functioning, especially in patients who belong to the metabolic syndrome (e.g., hypertension, obesity, glucose intolerance) need to be treated surgically. The anterior laparoscopic adrenalectomy offers minimal cost (e.g., less pain, less hospital stay, faster recovery, excellent cosmetic results). Other factors such as the age of the patients and their overall clinical condition and anxiety level will determine the best management of adrenalomas.

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3. Grumbach M. Biller B. Braunstein G, et a1. Management of the clinically inapparent adrenal mass ("incidentaloma"), Ann Intern Med 2003;138:424.

Clinically Inapparent Adrenal Mass (Incidentaloma or Adrenaloma) - - 593 4. Young AE, Smellie WD. The adrenal glands. In: Farndon JR (ed), Endocrine Surgery, 2nd ed. London, WB Saunders, 2001, p 123. 5. Ross NS, Aron DC. Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 1990;323:1401. 6. Barzon L, Boscaro M. Diagnosis and management of adrenal incidentalomas. J UroI2000;163:398. 7. Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. J Clin Endocrinol Metab 2000;85:637. 8. Terzolo M, Bossoni S, Ali A, et al. Growth hormone (GH) responses to GH-releasing hormone alone or combined with arginine in patients with adrenal incidentaloma: Evidence for enhanced somatostatinergic tone. J Clin Endocrinol Metab 2000;85:1310. 9. Terzolo M, Pia A, Ali A, et al. Adrenal incidentaloma: A new cause of the metabolic syndrome. J Clin Endocrinol Metab 2002;87:998. 10. Rossi R, Tauchmanova L, Luciano A, et al: Subclinical Cushing's syndrome in patients with adrenal incidentaloma: Clinical and biochemical features. J Clin Endocrinol Metab 2000;85:1440. 11. Midorikawa S, Sanada H, Hashimoto S, et al. The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection. Clin EndocrinoI2001;54:797. 12. Fernadez-Real JM, Engel WR, Simon R, et al: Study of glucose tolerance in consecutive patients harbouring incidental adrenal tumours: Study Group of Incidental Adrenal Adenoma. Clin Endocrinol (Oxf) 1998;49:53. 13. Garrapa GGM, Pantanetti P, Arnaldi G, et al. Body composition and metabolic features in women with adrenal incidentaloma or Cushing's syndrome. J Clin Endocrinol Metab 2001;86:5301. 14. Chiodini I, Torlontano M, Carnevale V, et al. Bone loss rate in adrenal incidentalomas: A longitudinal study. J Clin Endocrinol Metab 2001;86:5337. 15. Young WF: Management approaches to adrenal incidentalomas: A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 2000;29: 159. 16. Abecassis M, McLoughlin MJ, Langer B, et al: Serendipitous adrenal masses: Prevalence, significance, and management. Am J Surg 1985;149:783. 17. Herrera MF, Grant CS, van Heerden JA, et al. Incidentally discovered adrenal tumors: An institutional perspective. Surgery 1991;110:1014. 18. Caplan RH, Srutt PJ, Wickus G. Subclinical hormone secretion by incidentally discovered adrenal masses. Arch Surg 1994;129:291. 19. Prinz RA, Brooks MH, Churchill R, et al. Incidental asymptomatic adrenal masses detected by computed tomographic scanning: Is operation required? JAMA 1982;248:701. 20. Glazer HS, Weyman PJ, Sagel SS, et al. Nonfunctioning adrenal masses: Incidental discovery on computed tomography. AJR Am J Roentgenol 1982;139:81. 21. Belldegrun A, Hussain S, Seltzer SE, et al. Incidentally discovered mass of the adrenal gland. Surg Gynecol Obstet 1986;163:203. 22. Mantero F, Masini AM, Opocher G, et al: Adrenal incidentaloma: An overview of hormonal data from the National Italian Study Group. Horm Res 1997;47:284. 23. Linos DA, Stylopoulos N, Raptis SA: Adrenaloma: A call for more aggressive management. World J Surg 1996;20:788. 24. Bitter DA, Ross DS. Incidentally discovered adrenal masses. Am J Surg 1989;158:159. 25. Caplan RH, Kisken WA, Huiras CM. Incidentally discovered adrenal masses. Minn Med 1991;74:23. 26. Cajraj H, Young AE. Adrenal incidentaloma. Br J Surg 1993;80:422. 27. Geelhoed GW, Druy EM. Management ofthe adrenal "incidentalorna," Surgery 1992;92:866. 28. Didolkar MS, Bescher RA, Elias EG, et al. Natural history of adrenal cortical carcinoma: A clinicopathologic study of 42 patients. Cancer 1984;47:2153. 29. Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma: Review of a 50-year autopsy series. Mayo Clin Proc 1981;56:354. 30. Proye C, Fossati P, Fontaine P, et al. Dopamine secreting pheochromocytoma: An unrecognised entity? Classification of pheochromocytomas according to their type of secretion. Surgery 1986;100:1154. 31. Kebebew E, Siperstein AE, Clark OH, Duh QY. Results of laparoscopic adrenalectomy for suspected and unsuspected malignant adrenal neoplasms. Arch Surg 2002;137:948. 32. Aso Y, Homma Y. A survey on incidental adrenal tumors in Japan. J Urol 1992;147:1478.

33. Terzolo M, Ali A, Osella G, et al: Prevalence of adrenal carcinoma among incidentally discovered adrenal masses: A retrospective study from 1989 to 1994. Gruppo Piemontese Incidentalomi Surrenalici. Arch Surg 1997;132:8. 34. Yamakita N, Saitoh M, Mercado-Asis LB, et al. Asymptomatic adrenal tumor: 38 cases in Japan including seven of our own. Endocrinol Jpn 1990;37:671. 35. Fernadez-Real JM, Gonzalbez J, Ricart W. Metabolic abnormalities in patients with adrenal incidentaloma [Letters). J Clin Endocrinol Metab 2001;86:950. 36. Terzolo M, Osella G, Ali A, et al: Subclinical Cushing's syndrome in adrenal incidentaloma. Clin Endocrinol (Oxf) 1998;48:89. 37. Chidiac RM, Aron DC: Incidentalomas: A disease of modern technology. Endocrinol Metab Clin North Am 1997;26:233. 38. Beuschlein F, Borgemeister M, Schirra J, et al. Oral glucose tolerance testing but not intravenous glucose administration uncovers hyperresponsiveness of hypothalamo-pituitary-adrenal axis in patients with adrenal incidentalomas. Clin Endocrinol 2000;52:617. 39. Barzon L, Scaroni C, Sonino N, et al: Incidentally discovered adrenal tumors: Endocrine and scintigraphic correlates. J Clin Endocrinol Metab 1998;83:55. 40. Dwamena BA, Kloos RT, Fendrick AM, et al: Diagnostic evaluation of the adrenal incidentaloma: Decision and cost-effectiveness analysis. J Nucl Med 1998;39:707. 41. Ito Y, Obara T, Okamoto T, et al: Efficacy of single-voided urine metanephrine and normetanephrine assay for diagnosing pheochromocytoma. World J Surg 1998;22:684. 42. Linos DA: Management approaches to adrenal incidentalomas (adrenalomas): A view from Athens, Greece. Endocrinol Metab Clin North Am 2000;29:141. 43. Gordon RD, Ziesak MD, Tunny TJ, et al: Evidence that primary aldosteronism may not be uncommon: 12% incidence among antihypertensive drug trial volunteers. Clin Exp Pharmacol Physiol 1993;20:296. 44. Gordon R, Stowasser M, Rutherfort J. Primary aldosteronism: Are we diagnosing and operating on too few patients? World J Surg 200 1;25:941. 45. Proye C, Jafari Manjili M, Combemale F, et al. Experience gained from operation of 103 adrenal incidentalomas. Langenbecks Arch Surg 1998;338:330. 46. Schteingart DE. Management approaches to adrenal incidentalomas: A view from Ann Arbor, Michigan. Endocrinol Metab Clin North Am 2000;29:127. 47. Linos DA, Avlonitis VS, I1iadis K: Laparoscopic resection of solitary adrenal metastasis from lung carcinoma: A case report. J Soc Laparoendoscopic Surg 1998;2:291. 48. Linos DA, Stylopoulos N: How accurate is computed tomography in predicting the real size of adrenal tumors? Arch Surg 1997;132:740. 49. Fajardo R, Montalvo J, Velazquez D, et al. Correlation between radiologic and pathologic dimensions of adrenal masses. World J Surg 2004;28:494. 50. Yun M, Kim W, Alnafisi N, et al. 18F_FDG PET in characterizing adrenal lesions detected on CT or MR!. J Nucl Med 2001;42: 1795. 5 I. Silverman SG, Mueller PR, Pinkey LP, et al: Predictive value of imageguided adrenal biopsy: Analysis and results of 101 biopsies. Radiology 1993;187:715. 52. Wachenfeld C, Beuschlein F, Swermann 0, et al. Discerning malignancy in adrenocortical tumors: Are molecular markers useful? Eur J Endocrinology 2001; 145:335. 53. Reincke M, Beuschlein F, Slawik M, Borm K: Molecular adrenocortical tumourgenesis. Eur J Clin Invest 2000;30:63. 54. Barzon L, Scaroni C, Sonino N, et al. Risk factors and long-term follow-up of adrenal incidentalomas. J Clin Endocrinol Metab 1999;84:520. 55. Grossrubatscher E, Vignati F, Posso M, Lohi P: The natural history of incidentally discovered adrenocortical adenomas: A retrospective evaluation. J Endocrinol Invest 2001;24:846. 56. Linos DA: Surgical approach to the adrenal gland. In: van Heerden JA (ed), Common Problems in Endocrine Surgery: Recommendations of the Experts. St. Louis, Year Book, 1989, p 349. 57. Linos DA, Stylopoulos N, Boukis M, et al: Anterior, posterior or laparoscopic approach for the management of adrenal diseases? Am J Surg 1997;173:120. 58. Gagner M, Pomp A, Heniford BT, et al: Laparoscopic adrenalectomy: Lessons learned from 100 consecutive procedures. Ann Surg 1997;226:238.

594 - - Adrenal Gland 59. Thompson GB, Grant CS, van Heerden JA, et al: Laparoscopic versus open posterior adrenalectomy: A case-control study of 100 patients. Surgery 1997;122:1132. 60. Ting Ac, Lo CY, Lo CM: Posterior or laparoscopic approach for adrenalectomy. Am J Surg 1998;175:488. 61. Lanzi R, Montorsi F, Losa M, et al: Laparoscopic bilateral adrenalectomy for persistent Cushing's disease after transsphenoidal surgery. Surgery 1998;123:144.

62. Miccoli P, Raffaelli M, Berti P,et al. Adrenal surgery before and after the introduction of laparoscopic adrenalectomy. Br J Surg 2002;89:779. 63. Linos D. Laparoscopic right adrenalectomy. In: van Heerden JA, Farley DF (eds), Operative Techniques in General Surgery, Vol 4. Philadelphia, WB Saunders, 2002, p 304.

Hyperaldosteronism Takao Obara, MD • Yukio Ito, MD • Masatoshi Iihara, MD

Hyperaldosteronism occurs in primary and secondary forms. In this chapter, we describe the characteristic features of primary hyperaldosteronism and discuss the rational surgical management of this disorder. Primary hyperaldosteronism is characterized by excessive secretion of aldosterone from the adrenal gland associated with suppression of plasma renin activity (PRA), which usually results in hypertension and hypokalemia. Conn first described this syndrome in 1954. I Primary hyperaldosteronism is an uncommon but potentially curable cause of hypertension. The development of simplified testing and improvement of localization studies have allowed this condition to be diagnosed accurately and the tumor removed more precisely, Nevertheless, the most appropriate diagnostic approach for selecting surgically curable forms of primary hyperaldosteronism remains a matter of controversy. There are several subtypes of primary hyperaldosteronism. Aldosterone-producing adrenocortical adenoma and idiopathic hyperaldosteronism (bilateral adrenal hyperplasia) are the two most common subsets and account for 95% of all cases.s-' An aldosterone-producing adenoma is usually treated by unilateral adrenalectomy, whereas idiopathic hyperaldosteronism does not respond to surgical treatment and is best managed medically. Uncommon forms of primary hyperaldosteronism include primary adrenal hyperplasia.v' aldosterone-producing carcinoma.s-' and glucocorticoidsuppressible hyperaldosteronism.s-? Primary adrenal hyperplasia is morphologically similar to idiopathic hyperaldosteronism but mimics aldosterone-producing adenoma in response to biochemical tests and unilateral adrenalectomy. Glucocorticoid-suppressible aldosteronism (familial hyperaldosteronism type 1) is familially inherited in an autosomal fashion and is caused by the presence of a chimeric gene, consisting of the regulatory region of a gene coding for the enzyme ll~-hydroxylase (CYPllBl), adrenocorticotropin (ACTH), and the coding region of the gene for aldosterone synthesis (CYPllB2).8 Hence, aldosterone synthesis is primarily regulated by ACTH, resulting in excessive aldosterone production. This condition can be controlled by glucocorticoid administration. Familial hyperaldosteronism type 2 refers to the familial occurrence of

aldosterone-producing adenoma, adrenal hyperplasia, or both.IO,11 The appropriate treatment of primary hyperaldosteronism depends on the correct differential diagnosis of these subtypes.

Pathologic Features Aldosterone-producing adenomas are usually solitary tumors involving only one adrenal gland (Fig. 68-1). Most adenomas are smaller than 2 em in diameter. The mean diameter in 210 patients with surgically proven aldosteroneproducing adenomas in our series was 1.8 em, which is consistent with previous reports. 12 The cut surface usually has a characteristic golden yellow appearance. Microscopically, the typical tumor is mostly composed of large lipid-laden clear cells. In contrast, idiopathic hyperaldosteronism usually affects both adrenal glands and appears as micronodular or macronodular hyperplasia. Despite these typical pathologic features of adenoma and hyperplasia, there is a pathologic continuity between predominant unilateral adenoma and macronodular and micronodular hyperplasia. For instance, the extratumoral cortex of a solitary adenoma is not always normal: it may be hyperplastic or occasionally atrophic. Macroscopic or microscopic nodules often accompany aldosterone-producing adenoma (Fig. 68-2). Of our patients, 19% had multiple macronodules in association with distinct adenoma and an additional 43% had adenoma-associated micronodules.P Other authors have reported similar frequencies (55% and 42%) of macronodular or micronodular lesions associated with adenoma.lv" Macronodular hyperplasia and nonfunctioning cortical nodules associated with adenoma are not always distinguishable histologically. Patients with macronodules associated with adenoma are likely to have severe, prolonged hypertension. In addition, rare cases of bilateral solitary adrenal adenomas'v" and unilateral adrenal hyperplasia'> have been reported. These variable presentations thus reflect the fact that clinical primary aldosteronism is not a single pathologic entity, and they have important clinical implications with regard to therapy.

595

596 - -

Adrenal Gland

FIGURE 68-1. Cut surface of an adrenal gland showing a typical aldosterone-producing adenoma.

Clinical Characteristics The diagnosis of primary hyperaldosteronism is usually made between the ages of 30 and 60 years. The disease is more common in women than in men. The ages of the patients in our series ranged from 17 to 74, with a mean of 47.0 years. The female-to-male ratio was 1.5:1 (131:85) in our series, which corresponds to that in most other studies. 17.23 The hypertension of primary aldosteronism is moderate to severe and is indistinguishable from that seen in other disorders. The highest blood pressure recorded in our series was 3001150 mm Hg, and malignant hypertension is rare in this disorder. The duration of hypertension before recognition of hyperaldosteronism is variable. Among our patients, the duration of documented hypertension ranged from 1 to 480 months (median, 104 months), corresponding to that in other reports.17.22.23 The other characteristic symptomsmuscle weakness, cramping, intermittent paralysis, headaches, polydipsia, polyuria, and nocturia-are mainly attributable to hypokalemia. Because many patients were initially treated medically for hypertension by the referring physician without a diagnosis, the precise incidence of symptoms specific for hyperaldosteronism is not always clear. Periodic paralysis has been considered to be a common presenting symptom in Asian patients.v-" In our series, the incidence was approximately 23%. Hyperparathyroidism or prolactinoma coexistent with primary aldosteronism has been reported. Gordon and Stowasser" reported that 14 of 596 patients with primary hyperaldosteronism had hyperparathyroidism, and 4 had pituitary adenoma. In our series, two patients had primary hyperparathyroidism and another had prolactinoma. Some of these patients may have rare multiple endocrine neoplasia (MEN) type 1.26.28 Whether this combination of endocrine disorders represents a variant of MEN or two sporadic conditions is unknown. Family history and testing for gerrnline MEN I gene mutation on chromosome 11 as well as documenting hypercalcemia and hyperparathyroidism should clarify this situation.

FIGURE 68-2. Cut surfaces of adrenal glands removed from patients with primary hyperaldosteronism, showing an adenoma associated with macronodular lesions (arrows) (A) and double adenomas (B). (From Ito Y, Fujimoto Y, Obara T, et aI. Clinical significance of associated nodular lesions of the adrenal in patients with aldosteronoma. World J Surg 1990;14:331.)

Screening for and Diagnosis of Primary Aldosteronism The prevalence of primary hyperaldosteronism in an unselected hypertensive population is probably around 2%,2.29,30 although several studies have reported higher figures of 10% to 15%.31,32 The recent increase in the reported prevalence of primary hyperaldosteronism is likely to reflect improvement in screening methodologies as well as selection bias. Nevertheless, it seems a reasonable idea that primary hyperaldosteronism is more common than previously estimated, not only in white but also in Asian hypertensive patients.3.33.34 Most patients with primary hyperaldosteronism have hypokalemia (serum potassium concentration less than 3.4 mEq/L), especially on sodium loading. Although diuretic therapy itself is the most common cause of hypokalemia in patients with hypertension, these patients should have both PRA and plasma aldosterone concentration (PAC) measured to test for primary hyperaldosteronism. In 7% to 38% of patients with primary aldosteronism, the serum level of

Hyperaldosteronism - - 597

potassium is reported to be normal. 30,35,36 Therefore, normokalemia does not exclude primary hyperaldosteronism, Because of the high proportion of normokalemic patients, Gordon and colleagues'? recommended extending the screening for aldosteronism from hypertensive patients who are hypokalemic or resistant to medical therapy to all hypertensive patients, Furthermore, approximately 1% of patients with incidentally discovered adrenal masses associated with hypertension have aldosteronoma, Consequently, they need to be tested for hyperaldosteronism, Screening for primary hyperaldosteronism can be performed by measurement of both PRA and PAC. Hiramatsu and coworkers" first described the raised ratio of PAC to PRA as a useful screening tool for diagnosis of aldosteroneproducing adenoma among hypertensive patients, Its diagnostic accuracy was soon confirmed by other investigators.Pr'? The cutoff value of the ratio differs from 20: 1 to 50: 1 when expressing PAC in ng/dL and PRA in ng/ml.Zhr, The screening strategy is further improved by using not only the PAC to PRA ratio but also elevated levels of PAC, thus distinguishing primary aldosteronism from other causes of hypertension, Weinberger and Fineberg" found that the use of a PAC to PRA ratio of more than 30 and a PAC value greater than 20 ng/dL provided a sensitivity of 90% and a specificity of 91 % for identification of primary hyperaldosteronism, Young recommended using a PAC to PRA ratio of 20 and greater with a PAC of 15 ng/dL or higher to diagnose primary aldosteronism.Pv" The ratio of PAC to PRA may be a sensitive screening test even in patients still taking antihypertensive drugs." However, because many antihypertensive medications-particularly spironolactone, angiotensinconverting enzyme inhibitors, and diuretics-affect reninaldosterone regulation, they should be discontinued 4 to 6 weeks before diagnostic studies are performed. Some patients require continued use of antihypertensive medication to avoid severe hypertension. Antihypertensive agents such as prazosin, guanethidine, and guanadrel are recommended, The diagnosis of primary aldosteronism can be confirmed in almost all cases if the PAC (normal 2,2 to 15 ng/dL) is increased in conjunction with suppressed PRA (below 0,2 to 0.5 ng/mL/hr) in a hypertensive patient, specifically one who demonstrates hypokalemia. An elevated basal PAC and a PAC to PRA ratio greater than 50: 1 are also reliable criteria for diagnosis.f'-" When the results of hormonal measurements are equivocal, additional tests are helpful. The diagnosis of primary aldosteronism in a suspected case can be confirmed by demonstrating either inability to suppress aldosterone production with a high-sodium diet or inability to stimulate PRA with a low-sodium diet. Both measurement of urinary aldosterone levels during oral administration of salt and measurement of PAC with intravenous salt loading are used to evaluate the lack of suppressibility of aldosterone secretion,3,30,34,35,42 On sodium loading, primary hyperaldosteronism is confirmed if there is a failure to suppress PAC below 10 ng/dL,30 In primary hyperaldosteronism, 24-hour urinary excretion of aldosterone exceeds 12 Ilg,3,34 However, the risk of increasing the intake of sodium in patients with severe hypertension must be carefully considered, Captopril, an angiotensin-converting enzyme inhibitor, has also been used to demonstrate the lack of the suppressibility of

aldosterone.r' but its true value is limited." Fludrocortisone administration is also used as a confmnatory test for primary hyperaldosteronism.l'r" but its validity has not been fully evaluated.f Lack of stimulation of PRA can be demonstrated after diuretic administration (furosemide) and after the patient has been standing for 2 hours, 16

Biochemical Differentiation between Aldosterone-Producing Adenoma and Idiopathic Hyperaldosteronism When the diagnosis of primary hyperaldosteronism has been made, the distinction between a discrete aldosterone-secreting adrenocortical neoplasm and idiopathic hyperaldosteronism remains critical in the selection of patients who will benefit from adrenalectomy; this operation is more likely to correct hyperaldosteronism and hypertension in patients with aldosterone-producing adenoma than in those with idiopathic hyperaldosteronism, Postural response and decrease in aldosterone concentration can be used to differentiate between aldosteroneproducing adenoma and idiopathic hyperaldosteronism related to bilateral hyperplasia." In patients with idiopathic hyperaldosteronism, PAC usually increases after standing for 4 hours, whereas a postural decrease in PAC is characteristic of patients with aldosterone-producing adenoma, This phenomenon is due to the fact that aldosterone-producing adenomas are relatively unresponsive to angiotensin but still follow the corticotropin circadian rhythm, whereas in idiopathic hyperaldosteronism aldosterone production is influenced by the slight increases in PRA and cortisol levels that occur in an upright position, Unfortunately, this postural test of PAC for differentiating between aldosterone-producing adenoma and idiopathic hyperaldosteronism is not always reliable because falsenegative results for the postural response of PAC have occurred, 12.13,1 8,47,48 In a review of 16 articles, Young and Klee reported that the accuracy of the postural study was 85% in 246 patients with surgically verified aldosteroneproducing adenomas, 12 In our previous series, many patients with adenoma (43%) showed an anomalous response to the postural test." Presumably, stress during the test caused corticotropin release, which resulted in elevation of PAC. Measurement of plasma 18-hydrocorticosterone (I8-0HB) concentration has also been reported to be useful for determining whether a patient with primary hyperaldosteronism has an aldosterone-producing adenoma or idiopathic hyperaldosteronism.t? A plasma 18-0HB level greater than 100 ng/dL is usually associated with an aldosterone-producing adenoma." However, the assay of 18-0HB is not commonly available, and the cumulative diagnostic accuracy for aldosterone-producing adenoma based on four separate studies was reported to be 82%,12 It appears that none of the currently available biochemical studies can correctly distinguish between patients with idiopathic hyperaldosteronism related to bilateral adrenal hyperplasia and those with aldosterone-producing adenoma with 100% accuracy, Diagnosis of idiopathic hyperaldosteronism

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Adrenal Gland

on the basis of biochemical studies alone would exclude a considerable number of patients with aldosterone-producing adenomas from curable adrenalectomy. Moreover, the subtypes termed primary adrenal hyperplasia and aldosteroneproducing renin-responsive adenoma have been said to be correctable by unilateral adrenalectomy.50 The former exhibits the features of aldosterone-producing adenoma in terms of postural response and 18-0HB excess, and the latter responds to postural stimulation in the same way as idiopathic hyperaldosteronism.50

Localization Studies Localization studies are indicated in all patients in whom the diagnosis of primary aldosteronism has been confirmed because aldosterone-producing adenomas and idiopathic hyperaldosteronism are not always distinguishable by biochemical tests. Visualizing an adrenal tumor or detecting unilateral excessive aldosterone production by means of localization studies greatly facilitates the selection of patients for adrenalectomy. Figure 68-3 is an algorithm for selecting the patients who are most likely to benefit from unilateral adrenalectomy. At most institutions, including our own, the adrenal computed tomography (CT) scan is the initial localizing procedure. An adrenal tumor with homogeneous, negative CT attenuation before and after enhancement is likely to be an aldosterone-producing adenoma (Fig. 68-4). The procedure is noninvasive and can be performed on an outpatient basis. The sensitivity of locating adenomas with the new generation of high-resolution CT scanners ranges from 82% to 90%.12.16.18.51 Young and Klee stated that in a patient with primary hyperaldosteronism, if a solitary unilateral adrenal macroadenoma larger than I ern along with a normal contralateral adrenal

gland is found on CT scanning, no other subtype studies are necessary and unilateral adrenalectomy should be considered.F Doppman and colleagues'? also stated that patients with an obvious unilateral nodule and a normal contralateral gland on CT scanning do not require further localization study. It is also worth noting that, although aldosterone-producing adrenal tumors are rarely malignant, unilateral large (4 em and greater) adrenal tumors are likely to be adrenocortical carcinomas. Although the CT-based diagnosis of adenoma is reliable with acceptable certainty, it is worth noting that the CTbased diagnosis of hyperplasia is unreliable.F The presence of non-aldosterone-secreting nodules in the ipsilateral or contralateral adrenal gland associated with an adenoma may result in a misdiagnosis as hyperplasia. In addition, hyperplasia may be associated with a unilateral macronodule and cause an erroneous diagnosis of an adenoma. Therefore, all patients with unilateral adenomas as small as 1 em or bilateral nodules on CT and those with bilateral normal glands require further localization studies using isotope adrenal scanning or selective adrenal venous sampling for aldosterone and cortisol levels, or both. Adrenal scanning with 13II-6~-iodomethyl-19-norcholesterol (NP-59) during dexamethasone suppression is considered the next choice for locating a hyperfunctioning adrenal gland if CT scan results are not definitive.P>' Problems with adrenal scintigraphy include the requirement of 5 to 7 days for completion and the need to block the thyroid to prevent uptake of radioiodine. Furthermore, the laterality of NP-59 uptake depends primarily on the adenoma size.55 Unfortunately, this technique has insufficient diagnostic accuracy for smaller tumors. Adrenal venous catheterization with blood sampling to measure aldosterone and cortisol concentrations is still the most accurate test for the differential diagnosis of

I Confirmed primary hyperaldosteronism I

...

Unequivocal findings I

• Unilateral adrenal tumor >4-5 cm

I Adrenal CT scan I I

Equivocal findings

~

...

• Unilateral attenuated adrenal tumor >1cm

Lateralized

• No tumor found • Unilateral adrenal tumor <1 cm • Bilateral adrenal masses

~

lodochloseterol (NP-59) scan with dexamethasone suppression Ambiguous ~

I

+

Adrenal v,enous sampling

Lateralized

Open unilateral adrenalectomy

+

Laparoscopic unilateral adrenalectomy

I

I

I

~AmbigUOUS

Medical therapy (spironolactone)

I

FIGURE 68-3. An algorithm for selecting patients with primary aldosteronism for unilateral adrenalectomy. CT = computed tomography.

Hyperaldosteronism - - 599

FIGURE 68-4. A typical CT scan finding in a patient with an aldosterone-producing adenoma. Note the attenuated lesion in the left adrenal gland (arrow).

primary hyperaldosteronism.52.56-60 Some investigators claim that adrenal venous sampling is a routine part of investigations for patients with primary hyperaldosteronism.56 It, however, is invasive and is usually reserved for patients in whom both CT and isotope scanning of the adrenals are inconclusive. Complications, such as rupture and thrombosis of the adrenal veins, bleeding, or adrenal infarction, have occurred. In addition, correct catheterization in both adrenal veins is essential. Catheterization of the right adrenal vein is often difficult, and failure to do so decreases the reliability of this procedure. The study, therefore, requires an experienced angiographer. Blood samples are obtained from each adrenal vein and from the inferior vena cava for measurement of both aldosterone and cortisol concentrations, preferably with ACTH stimulation. Infusion of ACTH before and during the procedure minimizes episodic changes in aldosterone secretion caused by stress-induced endogenous ACTH release. Patients receive an intravenous bolus of 0.25 mg of cosyntropin (synthetic ACTH) 15 minutes before blood sampling, followed by an infusion of 0.25 mg of corticotropin in 250 mL of normal saline at a rate of 4 to 6 mL/min throughout the procedure." Alternatively, an infusion of cosyntropin at 0.05 mg/hr is started 30 minutes before adrenal catheterization and continued throughout the procedure.v-" Comparison of ratios of aldosterone to cortisol in the adrenal veins and the inferior vena cava below the renal veins (or a peripheral vein) allows detection of unilateral or bilateral sources of aldosterone hypersecretion (Fig. 68-5, Table 68-1). The cutoff value for lateralization is controversial. An aldosterone-to-cortisol ratio fourfold greater than that in the other adrenal vein is considered indicative of a unilateral aldosterone-producing tumor.59.60

Surgical Treatment We believe that virtually all patients who prove to have a unilateral aldosteronoma or unilateral excessive aldosterone

FIGURE 68-5. CT scans of the abdomen revealed a lO-mm nodular lesion (arrow) in the right adrenal gland (A) and thickened limb (arrowhead) of the left adrenal gland (B) in a 48-year-old patient with primary hyperaldosteronism (a ratio of plasma aldosterone concentration to plasma renin activity of 370). Adrenal venous sampling lateralized excessive secretion of aldosterone to the right gland (see Table 68-1), and this was confirmed at surgery.

production are acceptable candidates for adrenalectomy. The treatment of choice for aldosterone-producing adenoma and primary adrenal hyperplasia is unilateral adrenalectomy. To decrease the surgical risks, hypokalemia should be corrected before the operation by the administration of spironolactone, oral potassium, or both. Several studies have shown that normalization of blood pressure with spironolactone before the operation is a good predictor of the successful treatment of hypertension after unilateral adrenalectomy.14.15.19.23 We are, however, often unable to evaluate an isolated response to spironolactone because other antihypertensive medications have usually been

600 - -

Adrenal Gland

previously administered. In addition, spironolactone is equally effective in controlling arterial pressure in patients with aldosterone-producing adenoma and those with idiopathic hyperaldosteronism, irrespective of the different responses of the blood pressure in patients with these two conditions after unilateral adrenalectomy." We, therefore, do not use the response to spironolactone alone as a criterion for selection of adrenalectomy in patients with primary hyperaldosteronism. Laparoscopic adrenalectomy is currently recommended as the optimal approach for primary hyperaldosteronism, although traditionally unilateral adrenalectomy by either a flank or posterior approach was the procedure of choice. The details of the operative technique for laparoscopic adrenalectomy are given elsewhere in this text as well as in the literature. 62-64 Laparoscopic adrenalectomy has been used since 1992.65-67 Many studies have shown that this procedure has several advantages over open adrenalectomy, such as less postoperative blood loss, earlier recovery, and a smaller wound.68-73 The operative time and operative complications are not significantly different from those of open adrenalectomy. During the past 6 years, we have performed 75 laparoscopic adrenalectomies for aldosterone-producing adenomas. The average total operating time was 181 minutes, and the average blood loss was 27 mL-similar to that reported by others. Most laparoscopic adrenalectomies for aldosteroneproducing adenomas involve total removal of the adrenal gland. Several studies have reported that laparoscopic adrenal-sparing surgery is feasible and effective in the treatment of patients with primary hyperaldosteronism.r'" The idea of adrenal-sparing surgery or partial adrenalectomy was initially advocated in open surgery." The need for adrenal preservation by partial adrenalectomy for patients with aldosterone-producing adenoma is unclear because long-term adrenal problems are rare after unilateral adrenalectomy.

Outcome: Risk Factors for Postoperative Persistent Hypertension Removal of the hyperfunctioning adrenal gland normalizes the renin-aldosterone system and corrects the hypokalemia. We have had a 98% success rate with unilateral adrenalectomy

in our 216 patients with primary hyperaldosteronism. Five patients had persistent hyperaldosteronism after unilateral adrenalectomy. These included three with idiopathic hyperaldosteronism who were thought to have an adenoma before surgery, one who was thought to have primary adrenal hyperplasia without a concurrent adenoma, and another with an aldosterone-producing carcinoma. Another patient had bilateral macronodular hyperplasia and eventually underwent bilateral adrenalectomy that resulted in resolution of both the hyperaldosteronism and hypertension. The long-term cure rate of hypertension by unilateral adrenalectomy for patients with primary hyperaldosteronism averages 69% in reported series.P In our present series of 210 patients with aldosterone-producing adenoma, 60% became normotensive (defined as a blood pressure lower than 140/90 mm Hg) without medication, and 40% improved markedly but have remained hypertensive since the operation. The incidence of persistent hypertension in our series is comparable to that in previous reports, with relief of hypertension in 31% to 80% of patients. 14 •16.I 7,19-23.78-81 This variation in the rate of resolution of hypertension after adrenalectomy might be influenced by the use of different definitions of normal blood pressure (160/95 mm Hg versus 140/90 mm Hg) and unequal duration of follow-up. It is worth noting that normalization of blood pressure does not always occur immediately after surgery. It takes more than 1 year for some patients to become normotensive.F Identification of patients who are likely to have persistent hypertension after an adrenal operation is clinically important. Several authors have investigated various discriminant factors of persistent hypertension after removal of an adrenallesion. We previously reported that age, gender, and the pathologic features of the resected adrenal gland are statistically significant prognostic factors of persistent hypertension after unilateral adrenalectomy in patients with primary hyperaldosteronism.P In the present expanded series, univariate analysis showed that several variables, including age, gender, duration of known history of hypertension, and preoperative ratio of PAC to PRA, had a significant effect on postoperative hypertension (Table 68-2). However, a stepwise logistic regression analysis showed that only two factors-age and gender-remained as significantly prognostic factors (Table 68-3). There was a strong positive correlation between increasing age and duration of hypertension among our patients. Overlap effects of these

Hyperaldosteronism - -

two factors on the logistic model have diminished the significant association between duration of hypertension and postoperative blood pressure control. To propose that the older the patient who undergoes adrenalectomy, the greater the chance of postoperative hypertension, seems reasonable because the persistent hypertension is probably the result of reduced ability to reverse pathologic vascular changes, It also suggests that early diagnosis and operative intervention at a younger age result in a more favorable outcome, Similar studies have shown that a significant correlation exists between age, or duration of hypertension, and postoperative blood pressure control. 19,79,83,84 Women seem to have a better response than men, a finding that agrees with other reports,21,83 In some studies, a positive family history of hypertension is predictive for persistent hypertension after adrenalectomy.23,81 This variable probably reflects the fact that patients with persistent hypertension have concurrent refractory essential hypertension. Other investigators have shown various predictive factors, such as 24-hour urinary aldosterone excretion. We have previously reported that the presence of

601

macro- or micronodules associated with a distinct adenoma was an independent prognostic factor for a poorer outcome of hypertension. It is debatable whether macro- or micronodular hyperplasia is the cause or the result of aldosterone excess. Moreover, distinction between nonfunctioning cortical nodules associated with adenoma and macronodular hyperplasia is not always possible, either histologically or clinically. Because preoperative aldosterone excess and its metabolic consequences have been corrected in our patients following unilateral adrenalectomy, we believe that most of the nodules are not aldosterone-producing hyperplastic lesions but instead may result from severe prolonged hypertension. 13,82 Although the significance of macro- and micronodules in addition to an obvious adenomatous tumor remains to be determined, current findings indicate that their presence does not necessarily preclude the diagnosis of aldosterone-producing adenoma.

Summary Primary hyperaldosteronism accounts for about I % to 2% of patients with hypertension but appears to be the most common form of secondary hypertension, It should be suspected in patients with hypokalemia or hypertension refractory to treatment. The diagnosis of hyperaldosteronism is usually made by documenting an increased serum or urinary aldosterone level in a patient with a low PRA. However, patients with aldosterone-producing adenomas cannot be distinguished from those with idiopathic hyperplasia by biochemical studies alone. Thus, localization studies, including CT scanning, NP-59 scanning, and selective venous catheterization for aldosterone and cortisol levels, are mandatory. Unilateral adrenalectomy corrects the hypokalemia in virtually all patients and hypertension in

602 - - Adrenal Gland about 60% of patients. Laparoscopic unilateral total adrenalectomy is the standard procedure for patients with aldosterone-producing adenomas.

REFERENCES 1. Conn J. Part I. Painting background. Part II. Primary aldosteronism, a new clinical syndrome, 1954. J Lab Clin Med 1990;116:253. 2. Ganguly A. Primary aldosteronism. N Engl J Med 1998;339:1828. 3. Young WF Jr. Primary aldosteronism: A common and curable form of hypertension. Cardiol Rev 1999;7:207. 4. Ganguly A, Zager P, Luetscher J. Primary aldosteronism due to unilateral adrenal hyperplasia. J Clin Endocrinol Metab 1980;51: 1190. 5. Irony I, Kater C, Biglieri E, et al. Correctable subsets of primary aldosteronism. Am J Hypertens 1990;3:576. 6. Arteaga E, Biglieri E, Kater C, et al. Aldosterone-producing adrenocortical carcinoma. Preoperative recognition and course in three cases. Ann Intern Med 1984;101:316. 7. Yoshimoto T, Naruse M, Ito Y, et al. Adrenocortical carcinoma manifesting pure primary aldosteronism: A case report and analysis of steroidogenic enzymes. J Endocrinol Invest 2000;23: 112. 8. Lifton RP, Dluhy RG, Powers M, et al. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet 1992;2:66. 9. Sutherland DJ, Ruse JL, Laidlaw JC. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J 1966;95:1109. 10. Stowasser M, Gordon RD, Tunny TJ, et al. Familial hyperaldosteronism type II: Five families with a new variety of primary aldosteronism. Clin Exp Pharmacol PhysioI1992;19:319. II. Stowasser M, Gunasekera TG, Gordon RD. Familial varieties of primary aldosteronism. Clin Exp Pharmacol PhysioI2001;28:1087. 12. Young WJ, Klee G. Primary aldosteronism. Diagnostic evaluation. Endocrinol Metab Clin North Am 1988;14:367. 13. Obara T, Ito Y, Okamoto T, et al. Risk factors associated with postoperative persistent hypertension in patients with primary aldosteronism. Surgery 1992;112:987. 14. Ferriss J, Brown J, Fraser R, et al. Results of adrenal surgery in patients with hypertension, aldosterone excess, and low plasma renin concentration. Br Med J 1975;1:135. 15. Hunt T, Schmbelan M, Biglieri E. Selection of patients and operative approach in primary aldosteronism. Ann Surg 1975;182:353. 16. Gleason PE, Weinberger MH, Pratt JH, et al. Evaluation of diagnostic tests in the differential diagnosis of primary aldosteronism: Unilateral adenoma versus bilateral micronodular hyperplasia. J Urol 1993;150:1365. 17. Lins P, Adamson U. Primary aldosteronism. A follow-up study of 28 cases of surgically treated aldosterone-producing adenomas. Acta Med Scand 1987;221 :275. 18. Vetter H, Fischer M, Galanski M, et al. Primary aldosteronism: Diagnosis and noninvasive lateralization procedures. Cardiology 1985;72:57. 19. Celen 0, O'Brien MJ, Melby JC, et al. Factors influencing outcome of surgery for primary aldosteronism. Arch Surg 1996;131:646. 20. Favia G. Lumachi F, Scarpa V, et al. Adrenalectomy in primary aldosteronism: A long-term follow-up study in 52 patients. World J Surg 1992;16:680. 21. Lo CY, Tam PC, Kung AW, et al. Primary aldosteronism. Results of surgical treatment. Ann Surg 1996;224:125. 22. Milsom S, Espiner E, Nicholls M, et al. The blood pressure response to unilateral adrenalectomy in primary aldosteronism. Q J Med 1986; 61:1141. 23. Proye CA, Mulliez EA, Carnaille BM, et al. Essential hypertension: First reason for persistent hypertension after unilateral adrenalectomy for primary aldosteronism? Surgery 1998;124:1128. 24. Huang YY, Hsu BR, Tsai JS. Paralytic myopathy-A leading clinical presentation for primary aldosteronism in Taiwan. J Clin Endocrinol Metab 1996;81:4038. 25. Gordon RD, Stowasser M. Familial forms broaden the horizons for primary aldosteronism. Trends Endocrinol Metab 1998;9:220. 26. Beckers A, Abs R, Willems PJ, et al. Aldosterone-secreting adrenal adenoma as part of multiple endocrine neoplasia type 1 (MENI): Loss of heterozygosity for polymorphic chromosome II deoxyribonucleic acid markers, including the MENI locus. J Clin Endocrinol Metab 1992;75:564.

27. Gould E, Albores SJ, Shuman 1. Pituitary prolactinoma, pancreatic glucagonomas, and aldosterone-producing adrenal cortical adenoma: A suggested variant of multiple endocrine neoplasia type I. Hum PathoI1987;18:1290. 28. Strauch G, Vallotton MB, Touitou Y, et al. The renin-angiotensinaldosterone system in normotensive and hypertensive patients with acromegaly. N Engl J Med 1972;287:795. 29. Hiramatsu K, Yamada T, Yukimura Y, et al. A screening test to identify aldosterone-producing adenoma by measuring plasma renin activity. Arch Intern Med 1981;141:1589. 30. Streeten DH, Tomycz N, Anderson GH. Reliability of screening methods for the diagnosis of primary aldosteronism. Am J Moo 1979;67:403. 31. Gordon RD, Stowasser M, Tunny TJ, et al. High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol 1994;21:315. 32. Lim PO, Rodgers P, Cardale K, et al. Potentially high prevalence of primary aldosteronism in a primary-care population. Lancet 1999;353:40. 33. Loh KC, Koay ES, Khaw MC, et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab 2000;85:2854. 34. Young WFJ. Primary aldosteronism: Update on diagnosis and treatment. Endocrinologist 1997;7:213. 35. Bravo E. Primary aldosteronism. Issues in diagnosis and management. Endocrinol Metab Clin North Am 1994;23:271. 36. Melby rc Clinical review I: Endocrine hypertension. J Clin Endocrinol Metab 1989;69:697. 37. Gordon RD, Ziesak MD, Tunny TJ, et al. Evidence that primary aldosteronism may not be uncommon: 12% incidence among antihypertensive drug trial volunteers. Clin Exp Pharmacol Physiol 1993;20:296. 38. Hamlet SM, Tunny TJ, Woodland E, et al. Is aldosterone/renin ratio useful to screen a hypertensive population for primary aldosteronism? Clin Exp Pharmacol PhysioI1985;12:249. 39. Weinberger MH, Fineberg NS. The diagnosis of primary aldosteronism and separation of two major subtypes. Arch Intern Moo 1993;153:2125. 40. Young WF Jr. Management approaches to adrenal incidentalomas. A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 2000;29:159. 41. McKenna TJ, Sequeira SJ, Heffernan A, et al. Diagnosis under random conditions of all disorders of the renin-angiotensin-aldosterone axis, including primary hyperaldosteronism. J Clin Endocrinol Metab 1991;73:952. 42. Blumenfeld JD, Sealey JE, Schlussel Y, et al. Diagnosis and treatment of primary hyperaldosteronism. Ann Intern Med 1994;121:877. 43. Weinberger MH, Grim CE, Hollifield JW, et al. Primary aldosteronism: Diagnosis, localization, and treatment. Ann Intern Med 1979;90:386. 44. Lyons DF, Kern DC, Brown RD, et al. Single dose captopril as a diagnostic test for primary aldosteronism. J Clin Endocrinol Metab 1983;57:892. 45. Ganguly A. Prevalence of primary aldosteronism in unselected hypertensive populations: Screening and definitive diagnosis. J Clin Endocrinol Metab 2001 ;86:4002. 46. Ganguly A, Melada G, Luetscher J, et al. Control of plasma aldosterone in primary aldosteronism: Distinction between adenoma and hyperplasia. J Clin Endocrinol Metab 1973;37:765. 47. McLeod M, Thompson N, Gross M, et al. Idiopathic aldosteronism masquerading as discrete aldosterone-secreting adrenal cortical neoplasms among patients with primary aldosteronism. Surgery 1989;106:1161. 48. Nomura K, Toraya S, Horiba N, et al. Plasma aldosterone response to upright posture and angiotensin ii infusion in aldosterone-producing adenoma. J Clin Endocrinol Metab 1992;75:323. 49. Kern DC, Tang K, Hanson CS, et al. The prediction of anatomical morphology of primary aldosteronism using serum 18-hydroxycorticosterone levels. J Clin Endocrinol Metab 1985;60:67. 50. Biglieri E, Irony I, Kater C. Identification and implications of new types of mineralocorticoid hypertension. J Steroid Biochem 1989; 32:199. 51. Weigel RJ, Wells SA, Gunnells JC, et al. Surgical treatment of primary hyperaldosteronism. Ann Surg 1994;219:347. 52. Doppman JL, Gill JJ, Miller DL, et al. Distinction between hyperaldosteronism due to bilateral hyperplasia and unilateral aldosteronoma: Reliability of CT. Radiology 1992;184:677. 53. Gross M, Shapiro B. Scintigraphic studies in adrenal hypertension. Semin Nucl Med 1989;19:122.

Hyperaldosteronism - - 603 54. Hollak CE, Prummel MF, Tiel-van Buul MM. Bilateral adrenal tumours in primary aldosteronism: Localization of a unilateral aldosteronoma by dexamethasone suppression scan. J Intern Moo 1991;229:545. 55. Nomura K, Kusakabe K, Maki M, et al. Iodomethylnorcholesterol uptake in an aldosteronoma shown by dexamethasone-suppression scintigraphy: Relationship to adenoma size and functional activity. J Clin Endocrinol Metab 1990;71:825. 56. Harper R, Ferrett CG, McKnight JA, et al. Accuracy of CT scanning and adrenal vein sampling in the pre-operative localization of aldosterone-secreting adrenal adenomas. QJM 1999;92:643. 57. Magill SB, Raff H, Shaker JL, et al. Comparison of adrenal vein sampling and computed tomography in the differentiation of primary aldosteronism. J Clin Endocrinol Metab 2001;86:1066. 58. Melby Je. Diagnosis of hyperaldosteronism. Endocrinol Metab Clin NorthAm 1991;20:247. 59. Phillips JL, Walther MM, Pezzullo JC, et al. Predictive value of preoperative tests in discriminating bilateral adrenal hyperplasia from an aldosterone-producing adrenal adenoma. J Clin Endocrinol Metab 2000;85:4526. 60. Young WF Jr, Stanson AW, Grant CS, et al. Primary aldosteronism: Adrenal venous sampling. Surgery 1996;120:913. 61. Doppman JL, Gill JR Jr. Hyperaldosteronism: Sampling the adrenal veins. Radiology 1996;198:309. 62. Gagner M. Laparoscopic adrenalectomy. Surg Clin North Am 1996;76:523. 63. Kebebew E, Siperstein AE, Duh QY. Laparoscopic adrenalectomy: The optimal surgical approach. J Laparoendosc Adv Surg Tech A 2001;11:409. 64. Marescaux J, Mutter D, Wheeler MH. Laparoscopic right and left adrenalectomies. Surgical procedures. Surg Endosc 1996;10:912. 65. Gagner M, Lacroix A, Prinz RA, et al. Early experience with laparoscopic approach for adrenalectomy. Surgery 1993;114:1120. 66. Higashihara E, Tanaka Y, Horie S, et al. Laparoscopic adrenalectomy: The initial 3 cases. J VroI1993;149:973. 67. Suzuki K, Kageyama S, Veda D, et al. Laparoscopic adrenalectomy: Clinical experience with 12 cases. J VroI1993;150:1099. 68. Brunt LM, Doherty GM, Norton JA, et al. Laparoscopic adrenalectomy compared to open adrenalectomy for benign adrenal neoplasms. J Am Coli Surg 1996;183:1. 69. Guazzoni G, Montorsi F, Bocciardi A, et al. Transperitoneal laparoscopic versus open adrenalectomy for benign hyperfunctioning adrenal tumors: A comparative study. J VroI1995;153:1597.

70. Korman JE, Ho T, Hiatt JR, et al. Comparison of laparoscopic and open adrenalectomy. Am Surg 1997;63:908. 71. Linos DA, Stylopoulos N, Boukis M, et al. Anterior, posterior, or laparoscopic approach for the management of adrenal diseases? Am J Surg 1997;173:120. 72. Prinz RA. A comparison of laparoscopic and open adrenalectomies. Arch Surg 1995;130:489. 73. Shen WT, Lim RC, Siperstein AE, et al. Laparoscopic vs open adrenalectomy for the treatment of primary hyperaldosteronism. Arch Surg 1999;134:628. 74. Al-Sobhi S, Peschel R, Bartsch G, et al. Partiallaparoscopic adrenalectomy for aldosterone-producing adenoma: Short-and long-term results. J EndouroI2000;14:497. 75. Irnai T, Tanaka Y, Kikumori T, et al. Laparoscopic partial adrenalectomy. Surg Endosc 1999;13:343. 76. Kok KY, Yapp SK. Laparoscopic adrenal-sparing surgery for primary hyperaldosteronism due to aldosterone-producing adenoma. Surg Endosc 2002;16:108. 77. Nakada T, Kubota Y, Sasagawa I, et al. Therapeutic outcome of primary aldosteronism: Adrenalectomy versus enucleation of aldosteroneproducing adenoma. J VroI1995;153:1775. 78. Blumenfeld JD, Vaughan ED Jr. Diagnosis and treatment of primary aldosteronism. World J VroI1999;17:15. 79. Horky K, Widimsky JJ, Hradec E, et al. Long-term results of surgical and conservative treatment of patients with primary aldosteronism. Exp Clin Endocrinol 1987;90:337. 80. Lim RI, Nakayama D, Biglieri E, et al. Primary aldosteronism: Changing concepts in diagnosis and management. Am J Surg 1986; 152: 116. 81. Sawka AM, Young WF, Thompson GB, et al. Primary aldosteronism: Factors associated with normalization of blood pressure after surgery. Ann Intern Moo 2001;135:258. 82. Ito Y, Fujimoto Y, Obara T, et al. Clinical significance of associated nodular lesions of the adrenal in patients with aldosteronoma. World J Surg 1990;14:330. 83. Stowasser M, Klemm SA, Tunny TJ, et al. Response to unilateral adrenalectomy for aldosterone-producing adenoma: Effect of potassium levels and angiotensin responsiveness. Clin Exp Pharmacol PhysioI1994;21:319. 84. Streeten D, Anderson GJ, Wagner S. Effect of age on response of secondary hypertension to specific treatment. Am J Hypertens 1990;3:360.

Adrenocortical Carcinoma: Nonfunctioning and Functioning Charles A. G. Proye, MD • Jon Armstrong, MD • Francois N. Pattou, MD

Adrenocortical carcinomas account for 0.02% of all carcinomas and rank among the least common malignant endocrine tumors. However, after anaplastic thyroid carcinomas, they are the most malignant endocrine tumors. From 20% to 40% have metastasized at the time of presentation, and the overall 5-year survival is 19% to 35%.1.2 Early surgery with adrenalectomy is the only means of cure.

Incidence Functioning adrenocortical neoplasms with clinical manifestations of hypersecretion occur in 4 cases per million and roughly half are adenomas and the rest carcinomas. Adrenocortical carcinomas at autopsy account for 2.5 cases per million. Hence, the suggested incidence of nonfunctioning adrenocortical carcinomas should be 0.6 to 1.7 cases per million.' If these figures are matched with the prevalence of adrenal masses found incidentally (i.e., 0.6% to 1.3% of the ambulatory population), it is evident that, in the setting of the adrenal "incidentalorna," nonfunctioning adrenocortical carcinomas are an uncommon cause. Van Heerden and colleagues" reported that only 4 of 342 (1.2%) patients with incidentalomas at the Mayo Clinic had adrenocortical cancers. Our experience in Lille, France, of adrenal incidentalomas is consistent with this finding. Among 213 adrenal incidentalomas, of which 103 were operated, there were 5 (2%) adrenocortical carcinomas.t Pheochromocytomas and metastasis to the adrenal gland should be the primary concern in this setting, because they occur in 1% to 15% and 4% to 22%, respectively." The characteristics of 54 adrenocortical carcinomas, among 486 patients who underwent adrenal surgery, are listed in Table 69-1.

604

Clinical and Biochemical Tests Suggesting Malignancy Some features of a nonmetastatic adrenal tumor, regardless of the size, are highly suggestive of malignancy, especially if combined. These are as follows: Clinical Abrupt onset of disease Pyrexia Abdominal pain Abdominal mass Inferior vena caval compression or obstruction Associated breast carcinoma, osteosarcomas, or brain tumors (Li-Fraumeni syndrome) Clinical and biochemical Mixed hormone secretion Mild androgenic changes (an indication of the secretion of precursors) Feminizing syndrome Ectopic secretion syndrome Biochemical Urinary ketosteroid production in excess of 30 to 40 mg/day Elevated dehydroepiandrosterone levels observed in 80% of cases" Inactive precursor secretion, pregnenolone and aldosterone precursors, especially 18-hydroxylated compounds?

Criteria of Malignancy of Cortical Tumors The criteria determining whether an adrenal neoplasm is benign or malignant are not precise. Currently, the only accepted criteria are metastasis, either synchronous or

Adrenocortical Carcinoma: Nonfunctioningand Functioning - - 605

metachronous, and local invasion into surrounding structures. Adrenal tumors metastasize to the lung (72%), the liver (55%), the peritoneum (33%), the bone (24%), the contralateral adrenal (15%), and the brain (10%). Local recurrence at reoperation is not an absolute criterion of malignancy because intraoperative disruption of the capsule of a benign tumor may result in local seeding, with growth and apparent invasion. Large adrenal neoplasms are more likely to be malignant. Critical size and weight usually range from 6 to 10 em in diameter and from 40 to 100 g, respectively. The size suggestive of malignant tumors may be greater for androgensecreting tumors than for other tumors. Not all patients with adrenocortical carcinomas have metastatic disease at presentation, nor do all of these cancers exceed 6 em in diameter. Therefore, the clinical problem is to determine whether an adrenal mass is likely to be malignant at an early stage. In general, adrenal tumors larger than 4 em in maximal diameter should be removed for fear of malignancy. Independent of the size, some other features in nonfunctioning tumors help determine whether a patient is best treated medically or surgically. Features other than size suggesting malignancy include: 1. Heterogeneous pattern on computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography 2. Irregular surface 3. Adjacent adenopathy A method of defining malignancy histologically has been relatively simply defined by Weiss.8 This classification incorporates nine histologic features (Table 69-2). The presence of three or more of these features in a specimen correlates well with a clinically malignant outcome.

The Weiss histopathologic system is now the most commonly used method for assessing malignancy because of its simplicity, reliability, and excellent interobserver agreement. 9 Some of the criteria are, however, less reliable than others, and a statistically modified system of weighting has been proposed? (2 mitotic rate x 2 cytoplasm x abnormal mitosis x necrosis x capsular invasion) with a significant correlation with the Weiss system. Cytologic criteria are not consistent enough to predict tumor behavior; cellular atypia and abundance of mitosis are only suggestive, as is aneuploidy flow cytometry.'? Needle biopsy is not recommended for diagnosis because it cannot differentiate between an adrenocortical adenoma and an adrenocortical carcinoma. There is also concern about rupture of the tumor capsule. A high mitotic index is perhaps more of prognostic than diagnostic significance in malignant adrenocortical cancers.'! Needle biopsy is, however, useful when metastatic disease to the adrenal is suspected. Major diagnostic problems arise in the evaluation of patients with tumors between 3 and 6 em in diameter, exhibiting weak mitotic activity, with few areas of necrosis without obvious capsular invasion. In such cases, immunohistochemistry may prove helpful as benign tumors stain positively for vimentin (connective cell antigen) in 14% of cases versus 80% to 90% for malignant tumors. Synaptophysin (neuroendocrine cell antigen) is also more often expressed in malignant tumors. 12 MIB-l, another immunohistochemical marker, has also shown promise in delineating benign from malignant adrenal tumors.v"

Clinical Presentation Women are affected twice as often as men. Three clinical patterns can be encountered. 1. A mass syndrome without any clinical evidence of hypersecretion (30% of cases). The patient complains of a large and sometimes huge flank tumor discovered by himself or herself. Alternatively, the tumor may be discovered by the patient's physician when the patient presents with a flank pain or pyrexia of unknown origin (possible tumor necrosis factor [TNF] secretion), asthenia, or weight loss. The erythrocyte sedimentation rate is often elevated. Subtle signs of hormonal secretion can be discovered, for instance, glycosuria or a shadow of a mustache above a woman's lip. In addition, there may be signs of inferior vena caval compression or

606 - - Adrenal Gland

FIGURE 69-1. A, Patient with a palpable left abdominal mass. B, Adrenocortical carcinoma specimen weighing 4.6 kg. C, Neoplastic thrombi extracted during operation from the inferior vena cava.

obstruction (i.e., ankle edema) leading to MRI and intraoperative findings of neoplastic caval thrombus (Fig. 69-1). Tumor rupture or hemorrhage is rarely encountered. 2. An overt clinical syndrome of hypersecretion (60% of cases). Women younger than 40 years are more often affected. In patients with malignant adrenocortical tumors, the syndrome is of almost pure hypercortisolism in 30% of such cases, virilization in 22%, feminization in 10%, hyperaldosteronism in 2.5%, and mixed secretions in 35%.1.12 Although adrenocortical carcinomas account for 5% to 10% of cases of hypercortisolism, 80% are due to corticotropinsecreting pituitary tumors. Notably, however, 40% of patients with Cushing's syndrome and adrenal neoplasms have malignant tumors. Virilizing tumors are malignant in 30% of cases, feminizing tumors in men are virtually always malignant, and pure aldosterone-secreting tumors are malignant in less than 1% of cases.!" Mixed secretion is highly suspicious of malignancy. Ectopic hyperinsulinism with hypoglycemia (Anderson's syndrome) or ectopic

hyperparathyroidism with hypercalcemia has been reported, occasionally occurring synchronously in the same patient (Fig 69-2).15 3. The adrenal incidentaloma (10% of cases?). The smallest reported metastasizing adrenocortical carcinoma was 3 em in diameter and weighed 25 g.16 Metastases occurred postoperatively. There is no evidence in the literature that solid, nonsecreting adrenal incidentalomas smaller than 3 em in diameter are malignant (i.e., metastatic at presentation). Nevertheless, the referring physician may question whether benign adrenocortical adenomas could tum into malignant tumors. Current genetic and biochemical studies do not support this possibility. Most adrenocortical carcinomas are monoclonal, whereas the majority of adrenal adenomas are polyclonal.'? Conversely, genetic changes in locus llp15 are common in adrenocortical carcinomas and very rarely seen in adrenal adenomas." Point mutations of ras genes are equally encountered in 12% of adrenal carcinomas and adenomas.'? Subsequent studies may clarify whether a

Adrenocortical Carcinoma: Nonfunctioning and Functioning - - 607

FIGURE 69-2. Anderson's syndrome (ectopic hyperinsulinism) in a patient with a 2.2-kg adrenocortical carcinoma showing a confluent area of necrosis.

subset of adrenal adenomas are susceptible to malignant change or whether adrenocortical carcinomas begin de novo. The likelihood of malignancy for tumors increases with size from 1.5 to 6 em in diameter but remains limited because only I in 4000 cases (0.03%) are malignant," Operating on all patients with incidentalomas would probably result in more surgical deaths than patients cured by removing small adrenocortical carcinomas. However, in young patients, life-long observation may be unacceptable and may not be cost-effective, and benign adrenocortical adenomas are less common in young patients. For patients with adrenal tumors larger than 6 em in diameter, adrenocortical carcinomas account for up to 15% of cases. 6,12,20,21 Surgery is therefore recommended.

Preoperative Imaging and Suspicion of Malignancy In addition to distant metastases and tumor size, imaging studies can provide information suggestive of malignancy, Imaging findings suggestive of malignancy include the following: CT Stippled calcifications A poorly delineated, rugged, somewhat square-shaped tumor, with the periodic appearance of prominent buds; very different from the round adenoma (Fig. 69-3) Areas of necrosis Aortocaval adenopathies Evidence of local invasion; note that CT is known to overestimate the extent of liver and caval invasion MRI Heterogeneously increased early T2-weighted signal Weak and late enhancement after injection of gadolinium

FIGURE 69-3. Computed tomography scan showing a budding tumor in a patient with Cushing's syndrome and an adrenocortical carcinoma.

Finding of an intravascular signal identical to the tumor signal is of paramount importance and diagnostic of malignancy 131I-6~-iodomethylnorcholesterol (NP-59) scintigraphy Lack of or very weak uptake in the presence of a normal contralateral uptake" However, 18 cases of adrenocortical carcinomas exhibiting clear uptake of NP-59 have been described." Virtually all of them were highly differentiated carcinomas with overt clinical hypersecretion. Bone scintigraphy-Tc 99m Should be performed routinely in all patients with a suspicion of adrenocortical carcinoma When disseminated metastases are seen a palliative treatment rather than surgical resection is indicated As mentioned, needle biopsy should not be used because of its lack of sensitivity and risk of a capsular tear with tumor spillage, except in some patients for diagnosis of probable metastatic tumors to the adrenal.

Staging, Surgical Indications, and Preoperative Treatment Adrenocortical carcinomas are classified according to stages described by MacFarlane and modified by Sullivan (Table 69-3). This classification has one major drawback (i.e., malignancy in stage I is based on histologic criteria only). Whether all of these tumors are malignant is unknown, and the assumption that all are malignant may lead to an overly optimistic affirmation of the results of surgery. All tumors at stage I, II, or III, whether diagnosed preoperatively or intraoperatively, should be resected, The need to

608 - - Adrenal Gland

operate on patients with stage IV disease and distant metastases is controversial because these patients have an average postoperative survival of 3 months and a l-year actuarial survival of 10%. Widespread metastases in elderly patients should dissuade against surgical treatment. Conversely, in young patients, a solitary metastasis should not be a contraindication to surgery, and in rare cases pre- and postoperative adjunctive chemotherapy has provided long-lasting survival with complete remission. Preoperative treatment with mitotane (8 to 12 g/day) is indicated in two situations: metastatic disease and severe hypercortisolism. Mitotane successfully treats Cushing's syndrome in up to 75% of patients-" and sometimes causes partial or dramatic shrinkage of the primary tumor and the metastases. Cortisol replacement therapy is essential because hypocortisolism results in some patients. Unfortunately, many patients cannot tolerate the nausea and other side effects of mitotane, which limits its successful application. We recommend using mitotane for 3 or 4 weeks before surgery, and patients who respond to mitotane have a more favorable prognosis. Mitotane has a long half-life, and monitoring of serum levels can allow a lower maintenance dose for better tolerance. Alternatively, ketoconazole (400 mg/day) can be used to control the hypercortisolism.

Macroscopic Morphology, Preoperative Imaging, and Surgical Strategy At the time of surgery, most adrenocortical carcinomas are large tumors, ranging from 5 to 28.5 em in diameter (average, 12.4 em) and from 33 to 3100 g in weight (average, 849 g) according to Javadpour.P In our experience, the largest tumor weighed 4600 g (see Fig. 69-1A and B). The capsule of these grayish white tumors can be thick or thin. When thin with large superficial veins, the capsule is susceptible to rupture and local seeding. When thick, the capsule sticks to adjacent organs, the liver or the kidney, which may be invaded. Such adhesions may lead to extensive surgery; thus, it is often wiser to search for a plane of cleavage under the liver or the kidney capsule. It is necessary to bear in mind that CT scans often overestimate the local invasion. Macroscopic venous invasion is common and more often observed on the right side (20% of surgical cases), often encompassing the inferior vena cava. Surgeons should

obviously be prepared for this situation. The neoplastic thrombus of an adrenocortical carcinoma invades the venous wall more frequently than a renal adenocarcinoma and can reach up to the right atrium. Assessment or exclusion of venous invasion may influence the surgical strategy, and in some cases it is necessary to use cardiopulmonary bypass. Therefore, careful evaluation of the inferior vena cava, suprahepatic veins, and the right atrium by MRI, Doppler flow studies, and right atrium echography is mandatory. The effectiveness of MRI has eliminated the need for inferior vena cava phlebography. Involved regional nodes occur in 10% to 45% of cases and should be resected with the tumor. They do not impede the surgical strategy."

Surgical Strategy and Technical Operative Risks A wide surgical exposure is mandatory for primary vascular control, tumor removal with associated lumbar fossa clearance, and aortocaval node dissection, with a possible extension to the adjacent organs and sometimes to the inferior vena cava. Therefore, a posterior approach is not indicated in these patients with large and often invasive tumors. There currently appears to be no place for laparoscopic surgery. Some huge right-sided tumors, creeping behind the liver, still require a thoracoabdominal approach. In all other cases, either right- or left-sided, an extended subcostal transverse laparotomy is the best choice, with a view to possible extension by sternotomy if extensive inferior vena cava extension is suspected or present. Access to the right adrenal vein is difficult, especially in patients with large tumors. On the left side, by contrast, it is relatively easy if Catell's maneuver is used as a first step, combining mobilization of the right colon to the left and a Kocher maneuver to expose the left renal and adrenal veins at the vena cava before tumor manipulation. All adjacent invaded organs should be resected while ensuring a functioning kidney on the contralateral side. Formal liver resection is rarely needed and may require vascular exclusion of the liver. Often, a cleavage plane can be found under the liver capsule. Left pancreatectomy with splenectomy is sometimes indicated on the left side for adequate resection of large invasive tumors. The adjacent kidney is rarely invaded by the tumor, but nephrectomy is often helpful, if there are dense adhesions, to obtain proper aortocaval clearance.

Adrenocortical Carcinoma: Nonfunctioning and Functioning - - 609

Liberal use of resorbable clips is recommended for adequate lymphostasis and sometimes for control of the thoracic duct at its origin. Extension to the inferior vena cava is the major surgical challenge, especially on the right side (15% to 20% of cases). Direct invasion, if extensive, makes resection difficult and cure unlikely. Limited invasion can often be treated by wedge resection. Occasionally, segmental caval resection is necessary, with or without a graft, utilizing a bypass procedure. Limited intracaval thrombus can be flushed either directly? or with a combination of caval clamping, vascular exclusion of the liver, and the use of a large Fogarty catheter in the atrium." If the thrombus extends superiorly to the right atrium, a thoracoabdominal or combined sternotomylaparotomy is mandatory for primary control of the inferior vena cava in the pericardium. If it invades the right atrium, cardiopulmonary bypass with cardiac arrest is required. Use of external venovenous bypass remains controversial, but it appears to be useful in selected cases. I,29,30 A solitary liver metastasis should be removed when it can be done safely. Care must be taken to avoid rupturing the capsule to prevent local recurrence. We always use drains and recommend cryopreserving tumor tissue for subsequent biochemical and genetic studies.

Specific Postoperative Care Not uncommonly, within hours after surgery, patients may exhibit hemodynamic manifestations of septic shock with negative blood cultures. This may be due to release of TNF and TNF-like or other factors during tumor manipulation. Symptomatic treatment is effective. Initially, stress doses and then maintenance doses of hydrocortisone are mandatory for patients with secretory tumors and for patients treated preoperatively with mitotane and ketoconazole. Drains are removed after the resumption of food intake to decrease the chance of a problematic chylous fistula.

Overall Results and Prognostic Factors Unfortunately, the intra- and postoperative mortality within 30 days of operation is about 10%.1,4 Most of the mortality occurs in poor-risk patients with stage III or IV disease undergoing an extensive resection, with an occasional death from pulmonary embolism after isolated adrenalectomy. A review of 548 patients with adrenocortical carcinomas from seven large series in the literature from 1980 to 1990,1 of whom 290 were operated on with curative intent, revealed the following 1. Overall mean survival was 29 months, ranging from 33 to 71 months for the curative group and from 6 to 27 for the noncurative group. 2. Actuarial5-year survival rates ranged from 16% to 34% overall and from 32% to 62% for the curative group. The results of a French nationwide survey during the same period are shown in Figure 69-4. The overall survival rate was 34% and for the curative group was 42%. The survival

- Overall patients (n=156) --- Complete resection (n=128) ._-- Incomplete resection (n=28)

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rate for patients undergoing an incomplete resection was 9% at 1 year,' Tumor stage was the most important factor predicting prognosis, with a 5-year actuarial survival of 53% for locally invasive carcinomas (stage I, 33% and stage II, 55%). The survival rate was 24% in patients with stage III disease and 0% in patients with stage IV disease (Fig. 69_5).1,4,17 The patients who were younger than 35 years with nonfunctioning tumors or with tumors that secreted androgen had slightly better survival. Gender, tumor size, associated nephrectomy, and cellular lymphadenectomy had no impact on survival.v'v'?

Surgery of Metastases and Recurrences Metachronous surgery for solitary metastases is rarely helpful, but reoperation for local recurrences is advisable when complete resection is possible. Such patients have a 5-year survival rate of 28%.1,17,29,30

Adjuvant Therapy Mitotane, or o,p'-DDD, is the only drug that has proved to be effective in some patients. Recommended dosages of

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FIGURE 69-6. Stage IV survival. Effect of mitotane (o,p'-DDD). (From Icard P, Goudet P, Charpenay C, et al. Adrenocortical carcinomas: Surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 2001;25:891.)

8 to 12 g1day are unfortunately associated with neurotoxicity, nausea, intractable diarrhea, and adrenal insufficiency requiring cortisol substitution. Thus, only 60% to 70% of patients can tolerate this therapy." Numerous studies have shown that mitotane fails to improve overall survival l,2,4.32-35 and that no more than 20% of patients respond in terms of tumor growth. In patients with metastases, however, mitotane can improve survival. In a French retrospective study of 253 patients with adrenocortical carcinoma, mitotane was given as an adjuvant therapy in 53.8% of the cases. The survival advantage of mitotane was apparent only in stage IV disease (Fig. 69-6). Each of the preceding series also included more than a few anecdotal cases of tumor recurrences and metastases shrinking impressively for I to 2 years, with survival up to 8 years, and even a few cases of surgically verified disappearance of metastases in patients who received mitotane.I.30.32.36 We are also aware of unpublished data on overgrowth or reappearance of metastases when mitotane was discontinued after years of response to the drug. The only long-term survivors after surgery for metastatic adrenocortical carcinoma have received mitotane therapy. Personally, even after surgery for stages I and II adrenocortical carcinoma, we would recommend life-long treatment with mitotane if it is tolerated because it is the best hope for long-term survival. Various other combination chemotherapy regimens are currently under evaluation. In one phase II trial using a combination of mitotane with infusional doxorubicin, vincristine, and etoposide in patients with metastatic adrenocortical carcinoma, responses were obtained in 22% of patients.'? The superiority of this regimen over single-agent mitotane is debatable, however. More effective P-glycoprotein antagonists are needed. Radiation therapy is usually ineffective.i-"

Adrenocortical Carcinoma in Childhood Patients younger than 16 years with adrenal neoplasms are more likely to have malignant tumors than adults. A survey

of the English literature between 1956 and 1986 provided 209 cases of children with adrenocortical neoplasms.t? 66% of which were malignant. Average size and weight of malignant versus benign tumors were 9 versus 4 em and 466 versus 43 g, respectively. The female/male ratio was 2.2:1, and the mean age at presentation was 4.6 years (range, 5 days to 16.5 years). Hirsutism was the most common presenting symptom (51%), followed by hypercortisolism (30%) and feminization (10%); 8% of the tumors were nonfunctional. Of interest is the association with congenital abnormalities such as hemihypertrophy, Beckwith-Wiedemann syndrome, vascular malformations, urologic abnormalities, and tumors of the central nervous system. Adrenal neoplasms have also been reported in patients with salt-losing congenital hyperplasia." The biochemical profile in children is similar to that in adults. Surgery is the only means offering cure. The role of adjuvant therapy is unproved. Average survival is 24 months but can reach up to 8 years. It should also be kept in mind that 40% of neuroblastomas are located in the adrenals and are now commonly diagnosed by antenatal ultrasonography.

Summary Adrenocortical carcinoma is a rare tumor, and, unfortunately, patients with this neoplasm have a grim prognosis. Early detection and surgical removal offer the only chance of cure. Further studies must be done to detect and then treat patients with small malignant tumors and to develop new forms of adjuvant therapy.

REFERENCES 1. Icard P, Chapuis Y, Andreassian B, et al. Adrenocortical carcinoma in surgically treated patients: A retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 1992; 112:972. 2. Venkatesh S, Hickey RC, Sellin RV, et al. Adrenal cortical carcinoma. Cancer 1989;64:765. 3. Copeland PM. The incidentally discovered adrenal mass. Ann Surg 1984;199:116. 4. van Heerden JA, Grant CS, Weaver AL. Primary carcinoma of the adrenal cortex: An institutional surgical perspective. Acta Coo Aust 1993;25:216. 5. Proye C, Jafari Manjili M, Combemale F, et al. Experience gained from operation of 103 adrenal incidentalomas. Langenbecks Arch Surg 1998;383:330. 6. McLeod MK. Adrenal incidentaloma. Acta Chir Aust 1993;25:202. 7. Aupetit-Faisant B, Tabarin A, Battaglia C, et al. Incoherence de la voie des mineralocorticoides dans les carcinomes surrenaliens: Un signe de malignite? Ann Endocrinol (Paris) 1991;52: 149. 8. Weiss LM. Comparative histological study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1995;8: 163. 9. Aubert S, Wacrenier A, Leroy X, et al. Weiss system revisited: A clinicopathological and immunohistochemical study of 49 adrenocortical tumors. Am J Surg PathoI2002;26:1612. 10. Hosaka Y, Rainwater LM, Grant CS, et al. Adrenal carcinoma: Nuclear DNA study by flow cytometry. Surgery 1987;102:1027. 11. Weiss LM, Medeiors LJ, Vickery AL. Pathological features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13:202. 12. Chapuis Y, Icard P. Cortico-surrenalomes malins: In: Chapuis Y, Peix JL (eds), Chirurgie des Glandes Surrenales, Paris, Arnette, 1994, p 61. 13. Vargas MP, Vargas ill, Kleiner DE, et al. Adrenocortical neoplasms: Role of prognostic markers MIB-l, P53, and RB. Am J Surg Pathol 1997;21:556.

Adrenocortical Carcinoma: Nonfunctioning and Functioning - - 611 14. Ludwig B, Nierderle B, Roka R, et aI. Isolieter prirnarer aldosterismus bei nebennierenkarzinom. Kasuitik und leteraturiibersicht. Acta Chir Aust 1993;25:212. 15. Proye C, Fossati P, Ben Soussan D, et aI. Syndrome d' Anderson avec pseudo-hyperparathyroi"disme. Chirurgie (Paris) 1985;111:364. 16. Gicquel C, Lelond-Rrancillard M, Bertagna W, et al. Clonal analysis of human adrenocortical carcinomas and secreting adenomas. Clin Endocrinol (Oxf) 1994;40:465. 17. Icard P, Louvel A, Chapuis Y. Survival rates and prognostic factors in adrenocortical carcinoma. World 1 Surg 1992;16:453. 18. Gicquel C, Bertagna X, Schneid H, et al. Rearrangements at the IIpl5 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumours. 1 Clin Endocrinol Metab 1994;78:1444. 19. Yashiro T, Hara H, Fulton NC, et aI. Point mutations of ras genes in human adrenal cortical tumors: Absence in adrenocortical hyperplasia. World 1 Surg 1994;18:455. 20. Khafagi FA, Gross MD, Shapiro B, et aI. Clinical significance of the large adrenal mass. Br 1 Surg 1991;78:828. 21. Peix lL. Incidentalomes. In: Chapuis Y, Peix lL (eds), Chirurgie des Glandes Surrenales. Paris, Arnette, 1994, p115. 22. Gross MD, Shapiro B, Francis IR, et aI. Scintigraphic evaluation of clinically silent adrenal mass. 1 Nucl Med 1994;35:1145. 23. Pasieka JL, McLeod MK, Thompson NW, et aI. Adrenal scintigraphy of well-differentiated (functioning) adrenocortical carcinomas: Potential surgical pitfalls. Surgery 1992;112:884. 24. Lack EE, Travis WO, Oertel JE. Adrenal cortical neoplasms. In: Lack EE (ed), Pathology of the Adrenal Glands. Edinburgh, Churchill Livingstone, 1990, p 115. 25. lavadpour N. Principles and Management of Adrenal Cancer. Berlin, Springer-Verlag, 1987. 26. Icard P, Louvel A, Chapuis Y. Frequence et valeur pronostique de r extension ganglionnaire et renale dans les corticosurrenalomes. Lyon Chir 1990;86:151. 27. Ritchey M, Kinard R, Novicki DE. Adrenal tumors: Involvement of the inferior vena cava. 1 Urol 1987;138:1134.

28. Benoit G, Darteville P. Ablation d'un thrombus cave retro-hepatique sans abord thoracique. Ann Urol (Paris) 1990;24:384. 29. Pommier RF, Brennan ME An eleven year experience with adrenal carcinoma. Surgery 1992;112:963. 30. Decker RA, Kuehner ME. Adrenocortical carcinoma. Am Surg 1991;57:502. 31. Decker RA, Elson P, Hogan TF, et aI. Eastern cooperation oncology group study 1879: Mitotane and Adriamycin in patient with advanced adrenocortical carcinoma. Surgery 1991;111:1006. 32. Luton JP, Cerdas S, Billaud L, et aI. Adrenocortical carcinoma: Clinical features, prognostic factors and therapeutic results in 105 patients from a single center (1967-1987). N Eng11 Med 1990;322:1195. 33. Henley Dl, van Heerden lA, Grant CS, et aI.Adrenal cortical carcinoma: A continuing challenge. Surgery 1983;94:926. 34. Cohn K, Gottesman L, Brennan ME Adrenocortical carcinoma. Surgery 1986;100:1170. 35. Icard P, Goudet P, Charpenay C, et al. Adrenocortical carcinomas: Surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World 1 Surg 2001; 25:891. 36. Boven E, Verrnoken JB, Siotten HV, et al. Complete response of metastasized adrenal cortical carcinoma with o,p'-DDD: Case report and literature review. Cancer 1984;53:26. 37. Abraham 1, Bakke S, Rutt A, et aI. A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: Continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist. Cancer 2002;94:333. 38. Percarpio B, Knowlton AH. Radiation therapy of adrenal cortical carcinoma. Acta Radiother 1976;15:288. 39. Scott HW Jr, Experience with adrenocortical neoplasms in children. Arn Surg 1987;53:117.

Cushing's Syndrome Gennaro Favia, MD • Franco Lumachi, MD • Maurizio Iacobone, MD

In 1932 Harvey W. Cushing, a Boston neurosurgeon, defined a syndrome characterized by muscular weakness, obesity, abdominal striae, diabetes, and arterial hypertension, which he called "pituitary basophilism," implying that it was a specific pituitary disease. 1 Today, all conditions resulting in chronic glucocorticoid excess are known as Cushing's syndrome. Iatrogenic Cushing's syndrome is due to increased glucocorticoid intake and should be distinguished from the primary form. Spontaneous Cushing's syndrome may be of pituitary or ectopic origin (corticotropin dependent) or of adrenal origin (corticotropin independent).

Epidemiology and Pathogenesis Cushing's syndrome account for only 0.2% of all causes of arterial hypertension in the general population, with a prevalence of 1 to 10 cases per million per year.' Corticotropindependent Cushing's syndrome is found in more than 80% of patients. Chronic corticotropin hypersecretion results in hyperplasia of the reticularis and fasciculata zones of the adrenal cortex, with hyperproduction not only of cortisol but also of deoxycorticosterone and androgens. Two forms of Cushing's syndrome result from increased corticotropin levels: pituitary-dependent Cushing's syndrome and ectopic Cushing's syndrome. Pituitary-dependent Cushing's disease is the more common form (70%) of Cushing's syndrome and is caused by corticotropin-secreting pituitary adenomas or microadenomas that are usually smaller than 1 em; 50% are 5 mm or less. Invasive adenomas and malignant pituitary tumors have rarely been reported. These tumors are more common in women than in men (male/female ratio, 1:8) and occur most often during the second and third decades of life, but the age at diagnosis may range from childhood to 70 years.' Ectopic Cushing's syndrome accounts for 10% of patients, and patients usually present clinically with a rapidly progressive course. The most common tumors causing ectopic Cushing's syndrome are small cell carcinoma of the lung (50%), malignant tumors of the thymus (20%) or the pancreas (10%), carcinoid tumors, medullary thyroid carcinomas, and pheochromocytomas.t-' Ectopic Cushing's syndrome occurs

612

more often in men (male/female ratio, 2: 1) and in the fourth and fifth decades of life. The second type is corticotropin-independent Cushing's syndrome. Cushing's syndrome may be caused by a unilateral cortisol-secreting adrenocortical adenoma (10%) or carcinoma (10%). Primary adrenal hyperplasia is a rare cause of corticotropin-independent Cushing's syndrome. Because adrenocortical tumors secrete increased amounts of cortisol, corticotropin production is suppressed. In patients with adrenal carcinoma, the typical features of Cushing's syndrome are often accompanied by signs of virilization. Corticotropin-independent Cushing's syndrome occurs more frequently in women (adenoma: male/female ratio, 1:3; carcinoma: male/female ratio, 1:2) and in the third and fourth decades of life."

Clinical Features The clinical manifestations of Cushing's syndrome usually begin gradually (Table 70-1). Patients frequently report increasingly severe asthenia, enhanced appetite, and weight gain. In premenopausal women, oligomenorrhea is common and may occur before any other apparent clinical change. Typically, these patients have centripetal obesity with "moon face," fullness of the supraclavicular fat pads, and a "buffalo hump." The limbs look thin in relation to the rest of the body, and muscular hypotrophy accentuates this characteristic appearance (Fig. 70-1A). Subsequently, skin changes take place: the epiderrnidis and subcutaneous tissue become thinner, and purplish red striae can be seen on the flanks, the abdomen, and the limbs. The skin becomes fragile, with loss of its elasticity, and extensive bruising is common even after only minimal injury (Fig. 70-1B). Mild or moderate arterial hypertension is quite characteristic of Cushing's syndrome and occurs in 70% of patients, as does osteoporosis. More rarely, pathologic fractures, muscular weakness, renal stones, poly arthralgia, and, in some cases, neuropsychiatric signs and symptoms occur. Laboratory abnormalities are listed in Table 70-2. An abnormal oral glucose tolerance test, postprandial hypoglycemia, and secondary hyperinsulinemia are relatively common. The most frequently observed case is that of an obese women 30 to 35 years old,

Cushing's Syndrome - - 613

with oligomenorrhea, slight hirsutism, and moderate arterial hypertension. Today, because of the precision of laboratory and imaging studies, Cushing's syndrome is being diagnosed earlier in its course, so that clinical and laboratory manifestations are less apparent. Representativepatients with cortisolsecreting adrenal adenomas treated during the years 1980 to 1990 are shown in Figure 70-2.

Diagnostic Procedures When Cushing's syndrome is suspected and iatrogenic causes have been excluded, the diagnosis should be confirmed by both an overnight dexamethasone suppression test (1 mg of dexamethasone is given at 11 PM, and a plasma cortisol measurement is obtained in the morning) and the 24-hour urinary free cortisol measurement. When the dexamethasone suppression test is normal (plasma cortisol < 50 mmol/L) and the urinary free cortisol is normal «135 nmol/24 hours), the patient does not have Cushing's syndrome. False-positive tests may occur as a result of (1) chronic intake of certain drugs (barbiturates, phenytoin, rifampicin) or alcohol

(which accelerates cortisol metabolism); (2) the presence of a serious illness or stressful event, chronic diseases (renal failure), or major depressive states (which stimulate the secretion of glucocorticosteroids); and (3) obesity and highestrogen states (estrogen therapy, pregnancy), but in the obese patients the urinary free cortisol is usually normal. When the results are equivocal, the 2-day test (0.5 mg dexamethasone every 6 hours for 2 days) lowers the plasma cortisol concentration below 50 nmol/L in patients without endogenous Cushing's syndrome. To establish whether the form is corticotropin dependent or independent, the following are performed: (1) measurement of basal plasma corticotropin and urinary free cortisol excretion after high-dose (8 mg) dexamethasone (2 mg every 6 hours for 2 days, or 8 mg at 11 PM as a single dose) administration (patients with pituitary Cushing's syndrome suppress to less than 10% of baseline, whereas those with cortisol-secreting adrenocortical tumors or ectopic corticotropin production do not); (2) corticotropin-releasing hormone (CRH) stimulation test (patients with pituitarydependent Cushing's syndrome are responsive, increasing plasma cortisol levels by more than 50%); and (3) bilateral selective venous catheterization of the inferior petrosal veins after CRR stimulation (patients with pituitary Cushing's syndrome have an increase in corticotropin versus peripheral or prestimulation levels greater than 50%).7 In pituitary Cushing's syndrome, plasma corticotropin levels are slightly increased or normal and are suppressed by high-dose dexamethasone. One should be aware that some carcinoid tumors behave metabolically like corticotropinsecreting pituitary tumors. In ectopic corticotropin syndrome, plasma corticotropin levels are generally markedly elevated and cortisol secretion is not suppressed by dexamethasone. Patients with cortisol-secreting adrenal tumors have a suppressed hypothalamic-pituitary axis. Plasma corticotropin levels are low or undetectable, and there is no suppression by dexamethasone. If the results are doubtful, one should carry out a CRH stimulation test; patients with pituitary Cushing's syndrome have an exaggerated response regarding both corticotropin and cortisol compared with that obtained in patients with an adrenal tumor or in normal subjects (Fig. 70-3).

Localizing Procedures FIGURE 70-1. A, Typical clinical features of a patient with marked Cushing's syndrome. B, Abdominal cutaneous striae.

The adrenal imaging techniques used as localizing procedures are adrenal scintigraphy, computed tomography (CT),

614 - - Adrenal Gland

FIGURE 70-2. Differentclinical appearances of patients withCushing's syndrome in relation to earlydiagnosis. A to C, The faces of some patientsobserved in 1982, 1987, and 1995, respectively.

and magnetic resonance imaging (MRI) scanning. Radiocholesterol scintigraphy is very useful in patients with Cushing's syndrome because it evaluates both adrenals simultaneously.S? In patients with adrenocortical hyperplasia resulting from a corticotropin-dependent syndrome, scintigraphy shows bilateral uptake (Fig. 70-4A). In the presence of a cortisol-secreting adenoma, focal uptake is observed, and scintigraphy accurately depicts the suppression of the contralateral adrenal gland (Fig. 70-4B). When an adrenal tumor is present, either CT or MRI scanning localizes the tumor and documents the size of the mass and its relationship to the surrounding structures (Fig. 70-4C and D). In selected patients with a unilateral adrenal mass, image-guided fine-needle aspiration cytology may be performed when requested for surgical planning." MRI scanning is preferable to CT scanning for identifying pituitary adenomas. MRI scanning, however, may fail to localize pituitary tumors smaller than 5 rnm, and nonfunctioning micropituitary tumors occur in up to 25% of the population. Bilateral selective venous catheterization of the inferior petrosal sinus with CRR stimulation is the most sensitive test for confirming the presence of a pituitary adenoma and in most cases can identify the side

of the microadenoma.!' Furthermore, plasma values of corticotropin (ipsilateral, peripheral) with a ratio higher than 1.5: I rule out ectopic corticotropin secretion.' Selective venous catheterization of other veins is occasionally helpful for identifying ectopic corticotropin-secreting tumors, as is MRI with Tl- and TI-weighted images for bronchial adenomas in the chest or pancreatic carcinoid tumors in the abdomen. Figure 70-5 shows a useful algorithm for the evaluation of a patient with Cushing's syndrome, as suggested by Kaye and Crapo."

Treatment Pituitary-Dependent Cushing's Syndrome The aim of treatment of Cushing's syndrome is to reduce cortisol secretion to normal. Formerly, bilateral adrenalectomy was used for treating patients with pituitary-dependent Cushing's syndrome, but this treatment has long been replaced by direct pituitary surgical treatment. Patients with pituitary-dependent Cushing syndrome can be treated by (I) trans sphenoidal microsurgery with tumor

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Cushing's Syndrome - -

615

FIGURE 70-4. A, Bilateral uptake with ?5Se-norcholesterol scintigraphy in a case of bilateral adrenal hyperplasia resulting from pituitary-dependent Cushing's syndrome. B, Scintigraphic pattern in a 30-year-old woman with a cortisol-secreting adenoma of the left adrenal gland. Computed tomography scan (C) and magnetic resonance imaging (D).

removal, (2) pituitary irradiation, (3) pharmacologic therapy, or (4) bilateral adrenalectomy. Selective pituitary transsphenoidal microsurgery is the treatment of choice in pituitary-dependent Cushing's syndrome when an experienced neurosurgeon is available. A rhinoseptal approach is utilized with an operating microscope. Incising through the sublabial mucosa, the surgeon removes the nasal spine and the lower part of nasal septum to reach the sphenoid bone. The floor of the sella is entered through the sphenoidal sinus. The dura mater, on which the pituitary rests, is incised. If the adenoma has not previously been visualized by MR!, the anterior pituitary is incised horizontally; this enables a microadenoma to be removed in more than 65% of cases." When no tumor is evident, a partial hypophysectomy is usually performed, and approximately two thirds of the gland is removed. The cure rate is about 90% 2 years after surgery and 70% or less at 10 years.P:" The best results are obtained in patients who have had micro- or macroadenomas localized by CT or MR scanning preoperatively and the pituitary tumor completely removed. Because a second trans sphenoidal operation has a success rate of less than 50%, pituitary irradiation may represent an alternative second-line treatment." Major complications after selective microsurgery, such as meningitis or oculomotor dysfunction, are uncommon, accounting for less

than I % of cases. I? However, most patients develop transient corticotropin, thyroid-stimulating hormone (30% to 40%), and gonadotropin (35% to 50%) deficiency, requiring postoperative glucocorticoid and L-thyroxine support, usually for less than 6 months. Transient (20%) or, rarely, permanent diabetes insipidus may also occur.15.17.18 Pituitary irradiation has limitations because it is not selective and may be used as first treatment only in adult patients in whom any surgical approach has been excluded (high surgical risk, low compliance).19 Reported response rates are 50% to 60%, and the resolution of clinical manifestations is slow (2 to 4 years or longer) and unpredictable. Moreover, after pituitary irradiation, about 50% of patients experience hypopituitarism and require replacement therapy with glucocorticoids, L-thyronine, testosterone, estrogen, or a combination." Newer forms of radiotherapy involving stereotactic computer-assisted linear accelerators or cobalt 60 radiation sources (gamma knife) have been used in patients with pituitary-dependent Cushing's syndrome, both as first-line treatment and after failed pituitary surgery. 20.2I Radiosurgery using photon energy with a gamma beam should be considered a valuable complement to transsphenoidal surgery, but its effectiveness has still to be confirmed, long-term prospective studies are needed, and delayed recurrences or hormone deficiencies may occur. 21,24

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Pituitary MRI

)

FIGURE 70-5. Algorithm for the evaluation of a patient with suspected Cushing's syndrome. The asterisk indicates that if the overnight high-dose dexamethasone suppression test is validated in the outpatient setting, it should be used at this point. The classic high-dose dexamethasone suppression test or corticotropin-releasing hormone (CRH) stimulating test may be used. CT = computed tomography; MRI =magnetic resonance imaging; RIA =radioimmunoassay. (Modified from Kaye TB, Crapo L. The Cushingsyndrome: An update on

diagnostic tests.Ann Intern Med 1990;112:434.)

Medical treatment is usually used for limited periods of time or before surgery to control corticotropin and cortisol hypersecretion. The drugs that influence pituitary secretion (cyproheptadine, lisuride, bromocriptine) have produced only temporary results in a very few patients. Ketoconazole, 600 to 1200 mg/day orally, inhibits the cytochrome P-450 enzymes P-450scc and P-450cll and subsequently various steps of steroid biosynthesis. It has been used for long-term therapy, even though its therapeutic effects tend to decrease with time, and transient hepatotoxicity may be observed.P'" Mitotane (o,p'-DDD), 2 to 4 g/day orally, is a relatively effective drug for inhibiting cortisol secretion. It causes selective destruction of the fasciculata and reticularis zones of the adrenal cortex and subsequently inhibits adrenal steroidogenesis. Although mitotane is highly effective, the decrease of cortisol production requires several weeks to be useful for patients, and strict monitoring of urinary free cortisol is required. About 80% of patients, unfortunately, have several side effects (nausea, vomiting, diarrhea, skin rash) and toxic effects, so that it is used almost exclusively for treating patients with adrenal carcinoma.P?" Metyrapone, an l1~-hydroxylase (cytochrome P-450cll) inhibitor, may be effective for reducing cortisol secretion, blocking the last step of adrenal steroid biosynthesis. However, it often results in adverse general effects (dizziness, nausea) and increases both corticotropin and androgen levels, resulting in unbearable worsening of hirsutism in women. Aminoglutethimide, which inhibits the cytochrome P-450scc, has also been utilized in combination with metyrapone, with similar side effects, especially in patients

who do not respond to mitotane." Mifepristone (RU 486) is a 19-norsteroid antiprogestin and a potent glucocorticoid antagonist that has both contraceptive and abortifacient effects." It has selective affinity for glucocorticoid receptors, resulting in increased hypercortisolism. Clinical improvement requires high doses (10 to 20 mglkg per day) of drug, and experiences are limited." Bilateral adrenalectomy is therapeutically effective for treating patients with corticotropin-dependent Cushing's syndrome, especially in the following situations'": (l) after unsuccessful pituitary treatment or when transsphenoidal surgery is technically difficult, dangerous, or impossible; (2) in patients with rapidly progressive and severe hypercortisolism; (3) for the palliative treatment of patients with ectopic corticotropin syndrome; and (4) in patients with primary adrenal bilateral hyperplasia. The rapid cure of Cushing's syndrome after bilateral adrenalectomy is associated with occasional morbidity, but life-long replacement therapy is required.P-? When the need for adrenalectomy has been established, preoperative treatment both to restrict cortisol secretion and to correct its metabolic effects must be undertaken. Ketoconazole, which inhibits steroid production, is used most often for this purpose. Liver function studies should be evaluated periodically. Before surgery, diabetes mellitus and hypertension should be treated and coagulation studies done. Prophylactic anticoagulation using low-molecularweight heparin (enoxaparin, 40 to 80 mg once daily) or unfractionated heparin (5,000 to 15,000 units twice daily) for at least 2 weeks is started 6 to 8 hours after operation

Cushing's Syndrome - -

to prevent thromboembolic complications, which in the past have affected such patients. 19 After bilateral adrenalectomy, steroid replacement therapy with glucocorticoids (hydrocortisone or cortisone acetate) must be given and mineralocorticoids (fluorhydrocortisone acetate) are also sometimes required (Table 70-3). The immediate and late complications of adrenal surgery vary according to the surgical approach and expertise. Anterior, lateral, and posterior approaches were used in the past. We preferred the flank incision because that provided excellent exposure and was associated with fewer complications compared with anterior approaches.v" More recently, a bilateral laparoscopic approach has been proposed, and it represents a safe and effective procedure.P-" Potential advantages of this technique include shorter hospitalization, decreased requirement for postoperative analgesia, and decreased postoperative morbidity related to incisional complications." Cure rate and morbidity are similar for laparoscopic and open adrenalectomies, and the main complication is due to capsular disruption, with adrenal tissue spreading and, consequently, recurrences of hypercortisolism." Laparoscopic adrenalectomy does not modify the risk of thromboembolism and the intraoperative or early postoperative bleeding compared with open adrenalectomy; thus, heparin prophylaxis is mandatory, and use of intermittent compression devices has also been suggested.v-" In 1960, Nelson and colleagues'" reported on patients who experienced cutaneous hyperpigmentation and pituitary neoplasm after bilateral adrenalectomy. Nelson's syndrome is an important sequela of bilateral adrenalectomy in patients with Cushing's syndrome. The estimated cumulative risk of development of Nelson's syndrome after adrenal surgery is 13% after 2 years and 29% after 10 years.'? Symptoms include headache, visual field defects, and hypopituitarism resulting from the aggressive expanding intrasellar neoplasm. These patients need to be treated by pituitary surgery, radiotherapy, or both. Prophylactic pituitary irradiation does not always prevent the onset of Nelson's syndrome, and the time of adrenalectomy is a predictive factor for its development.v-v-" To avoid or limit this complication and obviate the need for life-long replacement therapy, some surgeons relied on subtotal adrenalectomy. Because of the high incidence of recurrence in Cushing's disease, subtotal adrenalectomy has been abandoned. Adrenal autotransplantation has been used to avoid hypoadrenalism, but successful results are uncommon.w" Unilateral adrenalectomy followed by external pituitary irradiation has also been proposed as an alternative to bilateral adrenalectomy." We believe that

617

bilateral adrenalectomy is indicated for some patients with pituitary Cushing's syndrome. When CT, MRI, or inferior petrosal venous sampling reveals a pituitary adenoma, transsphenoidal surgery, pituitary irradiation, or radiosurgery is the treatment of choice. However, when these localizing procedures fail to demonstrate the site of corticotropin hyperproduction, bilateral adrenalectomy rather than a "blind" hypophysectomy should be considered.P-" Figure 70-6 shows the therapeutic approaches for treating patients with pituitary-dependent Cushing's syndrome.

Ectopic Corticotropin Syndrome When the site of the tumor causing ectopic corticotropin syndrome is known and the tumor can be completely resected, this is the most effective treatment. Unfortunately, small benign and malignant carcinoid tumors may not be localized. In these patients the aim of therapy is to reduce adrenal corticosteroid synthesis. Ketoconazole or the somatostatin analogs (octreotide) are more effective and rapid in action than mitotane.v-" Bilateral adrenalectomy is recommended for patients whose increased cortisol secretion cannot be controlled with medication and for patients who acquire carcinoma of the lung or pancreatic carcinoids and have a dismal prognosis. Patients with malignant thymomas or metastatic medullary thyroid carcinoma can live for years

PITUITARY-DEPENDENT GUSHING'S SYNDROME

transsphenoidal microsurgery radiation therapy

I I

relapse------,

/

cure

I

follow-up

transsphenoidal microsurgery radiation therapy

I I

relapse

I

bilateral adrenalectomy 1

_

FIGURE 70-6. Therapeutic ways of correcting pituitary-dependent Cushing's syndrome (see text).

618 - -

Adrenal Gland

with incurable neoplasms. The mean survival is even better for patients with bronchial carcinoids.v'?

Corticotropin-Independent Cushing's Syndrome ADRENAL ADENOMAS

Patients with corticotropin-independent Cushing's syndrome resulting from an adrenal adenoma can be successfully treated by unilateral adrenalectomy. The preoperative treatment is the same as that described for patients undergoing bilateral adrenalectomy. The postoperative replacement therapy is also similar except that cortisone acetate alone is used. The replacement therapy is gradually reduced to enable the remaining adrenal gland and pituitary to function normally. This can usually be accomplished by 6 months but occasionally takes as long as 18 months after unilateral adrenalecromy.P-" Laparoscopic adrenalectomy has now become the "gold standard" for adrenalectomy in patients with cortisol-secreting adenomas, but it should be performed by skilled teams to avoid complications such as capsular disruption, which may lead to recurrences.34.36.49 In the past, the morbidity rate after unilateral adrenalectomy was 30%, with appreciable (l % to 5%) mortality. 50 In more recent series, major complications (splenectomy, hemorrhage, pulmonary embolism, respiratory failure) and minor complications (wound infection, bronchopneumonia) have been reduced to less than 5% and 10%, respectively, approaching the rate reported for patients with other adrenal diseases.v-" The longterm cure rate with surgical removal of a cortisol-secreting adrenal adenoma is virtually 100%. ADRENAL CARCINOMA

Adrenal carcinoma accounts for only 5% to 10% of cases of Cushing's syndrome. Malignancy is often suspected because of the rapid onset of symptoms and the mixed pattern of hormonal secretion and because the tumors are usually large (greater than 5 em), irregular, and heterogeneous on MRI or CT scanning. Surgical removal is the only potentially curative procedure, and an open transabdominal approach is mandatory. For patients with stage IV disease, the only possible treatment, at least initially, is chemotherapy. Unfortunately, adrenocortical carcinoma is an aggressive tumor, and extensive surgery does not appear to improve survival. 6.52 Adjuvant radiotherapy has a limited impact on prognosis, even when initiated soon after tumor resection, and it is effective in only about 15% of patients. 6.53 Mitotane therapy is effective in about 20% of patients, and in some patients an impressive reduction occurs in the adrenal tumor itself as well as in the metastases, with long-term survival of up to 8 years. 25.26 If mitotane produces no response, occasional favorable results have been reported with cisplatinum, but survival is usually only 2 or 3 years and long-term results are disappointing, especially in patients with stage ill or IV disease, who make up more than 60% of cases. 47.53 PRIMARY ADRENAL HYPERPLASIA

A corticotropin-independent syndrome of hypercortisolism resulting from multiple bilateral hyperfunctioning adrenal nodules ranging from microscopic to 3 em in size, with suppression of corticotropin secretion, has been described.l"

The pathologic and radiologic features are difficult to distinguish from those of bilateral hyperplasia that occurs in patients with pituitary-dependent Cushing's syndrome.55 Familial cases in patients with hyperpigmentation and cardiac or cutaneous myxomas are reported (Carney's syndromej.v In patients with nodular adrenal hyperplasia, cortisol levels do not decrease after dexamethasone, plasma corticotropin levels are undetectable, and scintigraphy reveals bilateral adrenal uptake." When corticotropin independence is demonstrated, bilateral adrenalectomy is recommended.

Results In patients with adrenal adenoma, unilateral adrenalectomy gradually leads to the disappearance of the signs and symptoms of Cushing's syndrome, and these patients have excellent long-term survival. The first clinical and metabolic changes disappear within 4 to 6 weeks. Muscular weakness also disappears, and female patients may become pregnant. Resolution of the cutaneous alterations, including hirsutism and hypertension, takes longer. Obesity and the abdominal fat distribution regress slowly, and it often takes 12 months for the physical appearance of these patients to recover (Fig. 70-7). Recovery is slower after bilateral adrenalectomy for pituitary-dependent Cushing's syndrome. Moreover, some patients remain hypertensive (30%) with diabetes (20%) and obesity (20%).30 These patients may have a reduced working capacity, but their survival is similar to that seen in the general population. 14 In 30% of cases, Nelson's syndrome is a problem. All patients after bilateral adrenalectomy must undergo periodic check-ups. Supplemental steroid treatment must be taken at times of stress.

Summary Cushing's syndrome may be classified as either corticotropin dependent (Cushing's disease or pituitary Cushing's syndrome and ectopic corticotropin syndrome) or corticotropin independent (adrenal adenoma or carcinoma). Cushing's disease accounts for about 70% of all cases. Clinical features of Cushing's syndrome include obesity, facial plethora, hirsutism, menstrual disorders, hypertension, and other manifestations, as listed in Table 70-1. An overnight dexamethasone suppression test and measurement of free cortisol in a 24-hour urine sample establish the diagnosis. When the plasma cortisol is normal «50 mmol/L) after overnight l-mg dexamethasone administration, and urinary free cortisol is also normal, Cushing's syndrome is excluded. MRI scanning of the pituitary or adrenals is useful for identifying the site of the tumor. Selective venous sampling of the inferior petrosal veins bilaterally is helpful in some patients in whom it is difficult to determine whether pituitary or ectopic Cushing's syndrome is present. Pituitary Cushing's syndrome is treated by transsphenoidal microsurgery or by radiation therapy. Bilateral adrenalectomy or medical adrenalectomy is usually used for recurrent cases. Ectopic Cushing's syndrome is treated, when possible, by removing the corticotropin-secreting tumor.

Cushing's Syndrome - -

619

FIGURE 70-7. Results in patients before and after adrenalectomy for Cushing's syndrome. A and B, A 27-year-old man with pituitary-dependent Cushing's syndrome at operation and 18 months after bilateral adrenalectomy, respectively. C and D, The same patient for whom data were presented in Figure 70-4 before and 15 months after left adrenalectomy, respectively.

Unfortunately, most of these neoplasms cannot be localized, so that bilateral adrenalectomy is required. Primary adrenal neoplasms should be removed by adrenalectomy.

REFERENCES I. Cushing HW. The basophilic adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 1932;50:137. 2. Orth DN. Cushing's syndrome. N Engl J Med 1995;332:791. 3. Aron DC, Findling JW,Tyrrell JB. Glucocorticoids and adrenal androgens. In: Greenspan FS, Gardner DG (eds), Basic and Clinical Endocrinology. New York, McGraw-Hill, 2001, p 334. 4. Wajchenberg BL, Mendonca BB, Liberman B, et al. Ectopic adrenocorticotropic hormone syndrome. Endocr Rev 1994;15:752. 5. de Perrot M, Spiliopoulos A, Fischer S, et al. Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing's syndrome. Ann Thorac Surg 2002;73:675.

6. Icard P, Goudet P, Charpenay C, et al. Adrenocortical carcinomas: Surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 2001; 25:891. 7. Kaye TB, Crapo L. The Cushing syndrome: An update on diagnostic tests. Ann Intern Med 1990;112:434. 8. Yu KC, Alexander HR, Ziessman HA, et al. Role of preoperative iodocholesterol scintiscanning in patients undergoing adrenalectomy for Cushing's syndrome. Surgery 1995;18:981. 9. Lumachi F, Zucchetta P, Marzola MC, et al. Usefulness of CT scan, MRI and radiocholesterol scintigraphy for adrenal imaging in Cushing's syndrome. Nucl Med Comrnun 2002;23:469. 10. Lumachi F, Borsato S, Brandes AA, et al. Fine-needle aspiration cytology of adrenal masses in noncancer patients. Clinicoradiologic and histologic correlations in functioning and nonfunctioning tumors. Cancer 2001;93:323. II. Kaltsas GA, Giannulis MG, Newell-Price JDC, et al. A critical analysis of the value of simultaneous inferior petrosal sampling in Cushing's disease and the occult ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 1999;84:487.

620 - - Adrenal Gland 12. Chapuis Y. Hypercortisolisme. In : Chapuis Y, Peix JL (eds), Chirurgie des Glandes Surrenales, Paris, Arnette, 1994, p 33. 13. Freda PU, Wardlaw SL. Diagnosis and treatment of pituitary tumors. J Clin Endocrinol Metab 1999;84:3859. 14. Swearingen B, Biller BM, Baker FG, et al. Long-term mortality after trans sphenoidal surgery for Cushing disease. Ann Intern Med 1999;18:821. 15. Rees DA, Hanna FW, Davies JS, et al. Long-term follow-up results of transsphenoidal surgery for Cushing's disease in a single center using strict criteria for remission. Clin Endocrinol (Oxf) 2002;56:541. 16. Estrada J, Boronat M, Mielgo M, et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing's disease. N Engl J Med 1997;336:172. 17. Ciric I, Ragin A, Baumgartner C, et al. Complications of transsphenoidal surgery: Results of a national survey, review of the literature, and personal experience. Neurosurgery 1997;40:225. 18. Aron DC, 'TYrrell JB, Wilson CB. Pituitary tumors. Current concepts in diagnosis and management. West J Med 1995;162:340. 19. Boscaro M, Barzon L, Fallo F, et al. Cushing's syndrome. Lancet 2001 ;357:783. 20. Izawa M, Hayashi M, Nakaya K, et al. Gamma knife radiosurgery for pituitary adenomas. J Neurosurg 2000;93: 19. 21. Sheehan JM, Vance ML, Sheehan JP, et al. Radiosurgery for Cushing's disease after failed transsphenoidal surgery. J Neurosurg 2000;93:73. 22. Thoren M, Hoybye C, Grenback E, et al. The role of gamma knife radiosurgery in the management of pituitary adenomas. J Neurooncol 2001;54:197. 23. Tabarin A, Navarranne A, Guerin J, et al. Use of ketoconazole in the treatment of Cushing's disease and ectopic ACTH syndrome. Clin Endocrinol (Oxf) 1991;34:63. 24. Sonino N, Boscaro M, Paoletta A, et al. Ketoconazole treatment in Cushing's syndrome: Experience in 34 patients. Clin Endocrinol (Oxf) 1991;35:347. 25. Luton JP, Cerdas S, Billaud L, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N EnglJ Med 1990;322:1195. 26. Khorram-Manesh A, Ahlman H, Jansson S, et al. Adrenocortical carcinoma: Surgery and mitotane for treatment and steroid profiles follow-up. World J Surg 1998;22:605. 27. Sonino N, Boscaro M. Medical therapy for Cushing's disease. Endocrinol Metab Clin North Am 1999;28:211. 28. Spitz 1M, Bardin CWO Mifepristone (RU 486). A modulator of progestin and glucocorticoid action. N Engl J Med 1993;329:404. 29. Chu JW, Matthias DF, Belanoff J, et al. Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone (RU 486). J Clin Endocrinol Metab 2001;86:3568. 30. Favia G, Boscaro M, Lumachi F, et al. Role of bilateral adrenalectomy in Cushing's disease. World J Surg 1994;18:462. 31. Atkinson AB. The treatment of Cushing's syndrome. Clin Endocrinol (Oxf) 1991;52:560. 32. Imai T, Funashami H, Tanaka Y, et al, Adrenalectomy for treatment of Cushing syndrome: Results in 122 patients and long-term follow-up studies. World J Surg 1996;20:781. 33. Favia G, Lumachi F, Basso S, et al. Management of incidentally discovered adrenal masses and risk of malignancy. Surgery 2000; 128:918. 34. Henry JF, Defechereux T, Raffaelli M, et al. Complications of laparoscopic adrenalectomy: Results of 169 consecutive procedures. World J Surg 2000;24:1342. 35. Vella A, Thompson GB, Grant CS, et al. Laparoscopic adrenalectomy for adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab 2001 ;86:1596.

36. Acosta E, Pantoja JP, Gamino R, et al. Laparoscopic versus open adrenalectomy in Cushing's syndrome and disease. Surgery 1999; 126:1111. 37. Gagner M, Pomp A, Heniford BT, et al. Laparoscopic adrenalectomy: Lessons learned from 100 consecutive adrenalectomies. Ann Surg 1997;226:238. 38. Nelson DH, Meakin JW, Thorn Gw. ACTH producing pituitary tumors following adrenalectomy for Cushing's syndrome. Ann Intern Med 1960;52:560. 39. Sonino N, Zielezny M, Fava GA, et al. Risk factors and long-term outcome in pituitary-dependent Cushing's disease. J Clin Endocrinol Metab 1996;81:2647. 40. Kemink L, Pieters G, Hermus A, et al. Patient's age is a simple predictive factor for the development of Nelson's syndrome after adrenalectomy for Cushing's syndrome. J Clin Endocrinol Metab 1994;79:887. 41. Jenkins PJ, Trainer PJ, Plowman PN, et al. The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab 1995;80:165. 42. Demeter JG, Jong SA, Brooks MH, et al. Long-term results of adrenal autotransplantation in Cushing's disease. Surgery 1990;108:1117. 43. Miyauchi A, Kihara M, Matsusaka K, et al. Successful autotransplantation of an adrenal gland using a new method of omental wrapping: report of a case. Surg Today 1999;29:960. 44. Nagesser SK, van Seters AP, Kievit J, et al. Treatment of pituitarydependent Cushing's syndrome: Long-term results of unilateral adrenalectomy followed by external pituitary irradiation compared to transsphenoidal pituitary surgery. Clin Endocrinol (Oxf) 2000;52:427. 45. Winquist EW, Laskey J, Crump M, et al. Ketoconazole in the management of paraneoplastic Cushing's syndrome secondary to ectopic adrenocorticotropin production. J Clin Oncol 1995;13: 157. 46. De Herder WW, Lamberts SW. Octapeptide somatostatin-analogue therapy of Cushing's syndrome. Postgrad Med J 1999;75:65. 47. Kasperlik-Zaluska AA, Pietraszek A, Makowska AM, et al. Occult ectopic adrenocorticotropic hormone syndrome. Lancet. 2001; 358:149. 48. Doherty GM, Nieman LK, Cutler GB Jr, et al. Time to recovery of the hypothalamic-pituitary-adrenal axis after curative resection of adrenal tumors in patients with Cushing's syndrome. Surgery 1990;108:1085. 49. Brunt LM, Moley IF, Doherty GM, et al. Outcomes analysis in patients undergoing laparoscopic adrenalectomy for hormonally active adrenal tumors. Surgery 2001;130:629. 50. Welbourn RB. Survival and causes of death after adrenalectomy for Cushing's disease. Surgery 1985;97:16. 51. Bonjer HI, Sorm V, Berends FJ, et al. Endoscopic retroperitoneal adrenalectomy: Lessons learned from 111 consecutive cases. Ann Surg 2000;232:796. 52. Favia G, Lumachi F, D' Amico DF. Adrenocortical carcinoma: Is prognosis different in nonfunctioning tumors? Results of surgical treatment in 31 patients. World J Surg 2001;25:735. 53. Pommier RF, Brennan MF. An eleven-year experience with adrenocortical carcinoma. Surgery 1992;112:963. 54. Kirshner MA, Powell RD Jr, Lippsett MB. Cushing's syndrome: Nodular cortical hyperplasia of adrenal glands with clinical and pathological features suggesting adrenocortical tumor. J Clin Endocrinol Metab 1964;24:947. 55. Swain IM, Grant CS, Schlinkert RT, et al. Corticotropin-independent macronodular adrenal hyperplasia: A clinicopathologic correlation. Arch Surg 1998;133:541. 56. Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985;64:270.

Pheochromocytoma Clive S. Grant, MD

...in the right adrenal gland a tumor was palpable...the patient's blood pressure had been running at a normal level, perhaps 150 systolic. She almost immediately then went into cardiac arrest. Cardiac massage through the diaphragm was not effective and accordingly after this was tried for thirty or forty seconds the chest was opened and inside another thirty or forty seconds, 1 didfeel a satisfactory beat was established. As soon as the heart began to beat again, the blood pressure was very high being well over 250.... We proceeded with the operation and with some difficulty from bleeding and exposure, removed the pheochromocytomas from the right side.... As soon as the tumor was removed on this side, the bottom fell out of the patient's blood pressure and she required a triple amount ofLevophed to maintain her pressure at 100 mm Hg. From the operative note on a patient operated by Dr. Priestley in August 1961. The patient survived and recovered well. From a surgeon's perspective, the ultimate surgical challenge might be characterized as one that requires careful thought and preparation preoperatively, a technically challenging operative procedure in the presence of risk and pressure, and the gratification that follows when the tumor has been successfully excised and the patient can be reassured that the tumor, which may have posed even life-threatening risk, has been removed and he or she is cured. In every regard, the surgical excision of a pheochromocytoma fulfills these criteria. To achieve a successful outcome requires specific knowledge and careful attention to detail throughout the entire course of the patient's management. Patients look to surgeons as the key individuals in the overall management of this tumor. However, to accept this role responsibly requires a team effort with close interaction with the endocrinologist, radiologist, and anesthesiologist, who play integral parts in the patient's care. This central leadership role of the surgeon requires an understanding of all facets of the care.

History In 1886, Frankel first described pheochromocytoma at autopsy. I Not until 1926 did May0 2 at the Mayo Clinic and

Roux ' in Switzerland successfully remove these adrenal tumors. Interestingly, neither of these tumors was diagnosed preoperatively. As late as 1951, only 125 operations for pheochromocytoma had been reported, which included 33 deaths resulting from both severe hypertension during resection and hypotension after removal of the tumor," With the use of two new pharmacologic agents, phentolamine for hypertension and noradrenaline for hypotension, only 5 years later, Priestley and colleagues reported the successful excision of 61 pheochromocytomas in 51 patients without a death.'

Incidence Pheochromocytoma has an incidence of 2 to 8 cases per million persons annually.-" which constitutes a curable form of hypertension in 0.1% to 1% of hypertensive patients," and as many as 800 persons may die annually in this country from associated complications." Of patients with pheochromocytomas discovered only at the time of autopsy, 75% died suddenly from either myocardial infarction or a cerebrovascular catastrophe. Moreover, one third of the sudden deaths occurred during or immediately after unrelated minor operations. 10

Clinical Features The overwhelming majority of pheochromocytomas are sporadic in origin (80% to 90%) but may be associated with other diseases (see later). Pheochromocytoma has been termed a "10% tumor" because roughly 10% of these tumors are malignant, multifocal, bilateral, arise in extra-adrenal sites, and occur in children. Manifestations of catecholamine excess form a wide spectrum in these patients, the foremost being hypertension. In our experience, nonfunctioning pheochromocytomas are distinctly uncommon, as nearly all patients with these tumors, at least in retrospect, demonstrate some characteristic symptom or sign, especially accentuated at the time of operative tumor manipulation. However, between 1978 and 1995,15 (10%) of 150 patients with benign sporadic adrenal pheochromocytomas diagnosed at the Mayo Clinic had the tumors discovered serendipitously on radiologic examination as an incidental adrenal mass lesion. 11 The constellation of

621

622 - - Adrenal Gland headache, sweating, palpitations, and paroxysmal hypertension is prototypical of these symptoms.F The hypertension may be so severe that peripheral blood pressure measurements may be difficult to obtain because of the extreme vasoconstriction. Cardiac decompensation suggestive of acute myocardial infarction can also occur, sometimes precipitated by partial necrosis of the tumor with sudden release of a bolus of epinephrine and norepinephrine into the bloodstream (Fig. 71-1). After these acute episodes the blood pressure may remain elevated, return to normal, or even fall to hypotensive levels. Sustained hypertension is present in approximately 50% of patients with pheochromocytoma, mimicking the more common "essential" hypertension. A number of factors, some simply causing mechanical pressure on the tumor, have been identified as causative of the paroxysms: urination (with tumors of the urinary bladder), vigorous physical exercise, defecation, sexual intercourse, and ingestion of alcohol. In unprepared patients, severe and even lethal paroxysms have been associated with invasive procedures such as angiography, labor and delivery, diagnostic needle biopsy," general anesthesia, and surgical procedures. Less stereotypical are symptoms such as nausea, lassitude, heat intolerance, anxiety,

FIGURE 71-1. A, CT scan of patient coincidentally found to have pheochromocytoma during medical evaluation in preparation for knee surgery as a result of excessive sweating. B, CT scan of the same patient only 10 days later, 2 days after patient was admitted through the emergency room with chest pain, vasoconstriction, and electrocardiographic changes worrisome for myocardial infarction. Note that the back wall of the tumor is blurred, consistent with acute necrosis and release of catecholarnines.

abdominal pain, and pallor, plus signs of Raynaud's phenomenon, fever, or the glucose intolerance of diabetes.

Diagnosis Biochemical testing for pheochromocytoma, in addition to patients with obvious characteristic paroxysmal episodes, should include patients with unusually labile or intermittent hypertension or pregnant patients with new hypertension (in the absence of preeclampsia), those with a family history of pheochromocytoma or one of the associated conditions (see later), and children with hypertension. Also, when an adrenal tumor is discovered by computed tomography (CT) or magnetic resonance imaging (MRI) scans in the evaluation of other symptoms, screening tests for pheochromocytoma should be performed. Even though some controversy may exist regarding the optimal single test to establish the diagnosis, we have long relied on 24-hour urine collection for metanephrines and fractionated catecholarnines, determined by high-pressure liquid chromatography. Increases in "mets and cats" have been diagnostic in 99% of our pheochromocytoma patients in the last 20 years. 14 This is dependent on eliminating interfering substances or recognizing other situations that might render the tests inaccurate. For example, methylglucarnine, a component of many iodine-containing contrast media, may falsely lower metanephrine levels for up to 72 hours after their use.? In addition, labetalol, a combination of a and ~ blockers, must be avoided prior to testing. Tricyclic antidepressants are the agents that interfere most frequently with the interpretation of 24-hour urine metanephrines and catecholarnines. They should be tapered and discontinued prior to hormone determinations.P Also, measurements of urinary catecholamines and metabolites may be invalid in patients with advanced renal insufficiency, patients taking levodopa, or patients under major physical stress (e.g., stroke, surgery, or obstructive sleep apnea). Provocative pharmacologic testing using glucagon, histamine, metocloprarnide, or naloxone, coupled with timed samples for plasma catecholarnines, was useful previously. However, because in 542 patients with normal urinary metanephrines and catecholarnines, not a single patient tested positively with provocative tests, they are no longer utilized. 16 Plasma free metanephrine has an extremely high sensitivity rate of 99% for the presence of pheochromocytoma'? and is valuable in testing for the presence of a pheochromocytoma in genetically predisposed patients. However, used as a general screening test, it has a troubling 10% falsepositive rate. We rely on urinary testing as the primary method of diagnosis and screening. Tumor size has been related to the ratio of unmetabolized catecholarnines versus their metabolic products. Tumors weighing less than 50 g have more rapid turnover rates, releasing norepinephrine and epinephrine directly into the circulation. In contrast, a larger fraction of the catecholarnines in larger tumors are metabolized into metanephrines and vanillylmandelic acid prior to release into the circulation. 18 None of the biochemical tests is specific for the presence of malignancy.

Pheochromocytoma - - 623

FIGURE 71-2. Patient with multiple endocrine neoplasia type 2A with gross bilateral pheochromocytomas imaged well by CT scan (A) and showing the tumors (B).

Localization Computed Tomography Whereas 3 decades ago bolus nephrotomography or angiography might have provided the mainstay of localization, three excellent localization modalities are currently available. Soon after the development of CT scanning, the adrenal was noted to be exceptionally well depicted.'? and CT is now considered the most reliable, efficient, precise, and widely available localization technique (Fig. 71-2). Because 90% of tumors are located in the adrenal glands, a high-quality CT scan is likely to identify virtually all of these tumors as well as image the normal contralateral gland. However, because it is a purely anatomic representation, additional extra-adrenal pheochromocytomas may be overlooked. Therefore, patients should be routinely scanned from the diaphragm to at least below the bifurcation of the aorta. In addition, the radiologist must be reminded to avoid use of glucagon during the examination as this may precipitate a paroxysmal attack.

Magnetic Resonance Imaging MRI not only defines the anatomy but on T2-weighted images, pheochromocytomas and paragangliomas frequently show a characteristic and nearly unique high-intensity signal (Fig. 71-3). Owing to this special imaging distinction, which was 100% effective in the series by Doppman and

FIGURE 71-3. A, T2-weighted MRI image of paraganglioma located between aorta and inferior vena cava, which it compresses. The bright white appearance of the tumor is typical of pheochromocytoma or paraganglioma when imaged by T2-weighted MRI. B, Gross appearance of paraganglioma showing somewhat gelatinous cut surface with some central necrosis.

colleagues.P MRI provides both anatomic and physiologic imaging capabilities, in contrast to CT scanning. Other advantages that may cause MRI to challenge CT scanning as the optimal localization test include its lack of radiation exposure, the clear definition of surrounding vascular structures, and the lack of interference from preexisting metal clips. The disadvantages at present include relative lack of availability, claustrophobia that some patients feel during the examination, cost, and the anatomic detail, which is not quite as precise as that shown by current CT technology. In fact, MRI can miss small pheochromocytomas, as depicted in the scan in Figure 71-4. Both CT and MRI provide excellent images of the liver and periaortic lymph nodes, both possible sites of metastatic disease.

Metaiodobenzylguanidine Using either 1311_ or 1231-tagged metaiodobenzylguanidine (MIBG) nuclear medicine scintigraphy, abnormal adrenergic

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FIGURE 71-4. A, MRI scan demonstrated the characteristic bright white appearance of a pheochromocytoma on the right (short arrow) but was not interpreted to show the small tumor on the left (area just beyond the long, angled arrow). B, Gross cut specimens of the right (top) and left (bottom, less than I em in size).

tissue can be demonstrated. MIBG is taken up and concentrated within adrenergic vesicles in pheochromocytomas, paragangliomas, and their metastases with 80% to 90% sensitivity.P-" MIBG scans are most valuable to image or search for bilateral tumors such as in multiple endocrine neoplasia (MEN) type 2 syndromes or to identify multiple tumors (Figs. 71-5 and 71-6). The advantage of physiologic localization is unfortunately somewhat offset by the added complexity of the examination. To prevent its ablation, the thyroid must be blocked by oral iodine consumption before and after administration of the radioactive iodine. Repeated scans may be required for up to 72 hours to obtain optimal images, and localization is not precise, usually requiring correlation with anatomic detail provided by either CT or MRl scans (Fig. 71-7). However, mediastinal and intracardiac tumors" have been localized by this method as well as bone metastases missed by conventional bone scans.s' These three examinations complement each other and should be used for their specific advantages as indicated by the clinical situation. In a large series of 315 patients from the University of Michigan, where this test was developed, 1231 did not reveal unsuspected metastatic or bilateral disease in any of the 48 patients with a unilateral pheochromocytoma." It was concluded that in this setting, the addition of 1231 MIBG scintigraphy was unnecessary. This contradicts a report from the National Institutes of Health26 that supports

FIGURE 71-5. A, Metaiodobenzylguanidine scan, anterior view, demonstrating bilateral adrenal pheochromocytomas in a patient with multiple endocrine neoplasia (MEN) type 2A syndrome. B, Of importance, in the photograph of the gross appearance of the bilateral tumors is the multinodular appearance of the right adrenal, characteristic of MEN syndrome.

the addition of MIBG scintigraphy as a minimum confirmatory test (and to exclude malignancy) in all patients with an adrenal pheochromocytoma.

Preoperative Management Ever since the sentinel publication by Priestley and colleagues' that linked their dramatic improvement in surgical mortality to the use of pre- and intraoperative pharmacologic agents to blunt the wide swings in blood pressure, we have utilized a-blockade routinely. Even when the patient's blood pressure is normal preoperatively, severe hypertension can occur with mild tumor manipulation intraoperatively, especially with inadequate preparation. One full week of phenoxybenzamine (Dibenzyline) should be considered the minimum interval for this preparation and has largely prevented these occurrences in our experience. This drug is a long-acting, noncompetitive a blocker with a starting dose of 10 mg twice a day, which is increased until hypertension is controlled and the patient experiences some degree of

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FIGURE 71-6. A, MRI clearly shows right adrenal pheochromocytoma, compressing the posterior aspect of the inferior vena cava-a common finding. B, Metaiodobenzylguanidine scan of the same patient does not image the tumor.

FIGURE 71-7. A, Metaiodobenzylguanidine (MIBG) scan shows intense uptake on the right (arrows), inferior to the liver (L) and below the usual location for an intra-adrenal tumor. R = rib. B. CT scan of same patient as in A shows the tumor (arrow) between the aorta (A) and vena cava (V). C = renal cyst; K = kidney; L = liver. C, MIBG scan of a patient with von Rippel-Lindau syndrome who had a right adrenal pheochromocytoma (short arrow) plus a paraganglioma (long arrow) located in the left renal hilum. (Bright sites on each side are anatomic markers.) This patient also had cerebellar hemangioma, optic nerve tumor, multiple, bilateral renal cell carcinomas, and pancreatic cysts. D, Cut sections of right adrenal tumor (center), remaining normal right adrenal (left), and small left paraganglioma (right) removed from patient with MIBG shown in C.

626 - - Adrenal Gland orthostatic hypotension. The daily doses may be increased to 160 mg. This process is carefully monitored on an outpatient basis, with liberal use of fluids and salt to help replenish the contracted intravascular volume. Commonly encountered side effects include nasal stuffiness, lassitude, nausea, indigestion, and sedation and may also serve as a monitor for adequacy of preparation. In contrast to findings of others who have used a-blockade selectively with success," a reduction in operative mortality from 18% to 2% was attributed to appropriate preoperative blockade." Reasonable alternative medications, with which we have minimal experience, are the selective ai-antagonists prazosin/? (Minipress) and doxazosin (Cardura)." They are shorter acting than phenoxybenzamine and have the theoretical advantage of shortening the postoperative hypotensive effect. Calcium channel blockers have been successfully utilized in some European centers on the basis of the arterial vasodilation without the side effects of u-blockade.i? These agents inhibit calcium influx at the cellular level, thereby modifying hormone synthesis, release, and action." Somewhat more controversial and certainly less critical is the use of a ~-blocker. We may initiate this medication 3 days preoperatively to help control preoperative tachycardia and intraoperative arrhythmias. Propranolol (lnderal), in a dosage of 10 mg three times daily, has been our choice. Alternative cardioselective agents include atenolol (Tenormin) and metoprolol (Lopressor). Typically, arrhythmias occur during times of hypertension coincident with tumor manipulation. Discontinuing tumor manipulation is the most important step to reduce the hypertension and can be supplemented with pharmacologic agents. Controlling the hypertension is often the most effective method of controlling the arrhythmias. ~-Blockade should not precede a-blockade because it could lead to unopposed a-mediated vasoconstriction with the potential for resultant congestive heart failure." The combined a and ~ blocker labetalol (Trandate) has been effective in our as well as others' experience.F Conceptually, however, less flexibility exists with the fixed combined effect.

Intraoperative Management Before the patient undergoes induction of anesthesia, appropriate pharmacologic agents must be available. Adequate peripheral access plus a radial arterial catheter, in addition to a urinary catheter, is routinely utilized and, rarely a Swan-Ganz catheter may be placed if indicated on the basis of cardiac disease or other problem. Sodium nitroprusside (Nipride) was previously the intraoperative agent of choice for rapid control of acute hypertension. It is a powerful direct-acting vasodilator that can deliver profound hypotension immediately after its infusion. In contrast to the bolus effect of phentolamine (Regitine), it has the advantage that within seconds of discontinuing the infusion, the hypotensive effect ends, allowing nearly second-by-second blood pressure control. However, in the last 10 years, Nipride has been used only on rare occasion, replaced by intermittent small doses of esmolol (Brevibloc). Dopamine was the agent previously used to treat hypotension coincident with tumor excision. It has been replaced by short bolus administration of

ephedrine or phenylephrine. Blood infusion to replace hemorrhagic loss as well as to fill the dilated vascular tree after tumor removal was much more commonly needed previously than in current practice. Lidocaine is rarely necessary initially as a bolus followed by a constant infusion if ventricular arrhythmias persist.

Operative TechniqueLaparoscopic Approach Since the publication of the last edition of this text, a dramatic and exciting change in the overall approach to adrenalectomy has occurred. Whereas previously only a limited number of laparoscopic adrenalectomies had been reported in total,32 some involving significant bleeding" and a few including removal of pheochromocytomas.t->' laparoscopic adrenalectomy has become the accepted standard method, even to remove pheochromocytomas. Multiple advantages of the laparoscopic approach have been demonstrated, including reduced pain, smaller incisions, more rapid recovery both in hospital and after dismissal, and fewer complications.P''? Using a lateral decubitus position, a pneumoperitoneum is established and three or four trocars are placed coursing around beneath the costal margin toward the flank. On the right, the triangular ligament is dissected and the liver is retracted medially. On the left, the spleen and pancreas are mobilized and, by gravity, fall anteriorly and medially, thereby exposing the left adrenal area. On either side, methodical, careful dissection and controlling of all vessels are critical to success. Placing the pheochromocytoma into a bag facilitates extraction of the tumor, and it is withdrawn through one of the larger trocar sites, which may need to be enlarged somewhat. Improvements in the optics of the camera, the use of a harmonic scalpel, and refinements to the instrumentation have further enhanced this approach. Relatively few studies have been devoted to laparoscopic adrenalectomy specifically of pheochromocytoma. Cheah and coworkers" published a series of 39 laparoscopic adrenalectomies for pheochromocytoma, only 1 required hand assistance for a 15-cm tumor. The postoperative hospitalization was limited to 1 to 2 days, facilitated by adequate preoperative preparation and definitive localization studies in addition to the laparoscopic approach. In three series,39.41 a 20% to 23% major complication rate was reported for laparoscopic adrenalectomy for pheochromocytoma, but this is the exception in most published series. Comparing 22 patients with pheochromocytoma evenly divided between laparoscopic and conventional anterior adrenalectomy, Inabnet and coauthors-? found no clinically important differences in intraoperative hemodynamic parameters between the two groups. The surgical experience with pheochromocytomas at the Mayo Clinic during the era of laparoscopic adrenalectomy started in October 1995. A total of 131 pheochromocytomas were operated from October 1995 through April 2004, including 86 (66%) laparoscopic adrenalectomies, 7 (5%) that were converted from laparoscopic to open, 35 (27%) performed as an open anterior approach, and 1 (1%) each utilizing a posterior approach and a hand-assisted

Pheochromocytoma - -

laparoscopic approach. One patient had the operation aborted because of extreme hypertension with induction of anesthesia; the patient was more aggressively prepared with additional a-blocking medication and subsequently underwent successful laparoscopic adrenalectomy. This singledisease experience is extracted from 393 laparoscopic adrenalectomies on 345 patients from 1993 through April 2004. The mean operative time for the laparoscopic patients was 141 minutes (range, 48 to 324 minutes) and mean hospital stay was 2.6 days, which compare favorably with 216 minutes and 3.1 days reported by Brunt and colleagues.f These pheochromocytoma patients included six (5%) with MEN 2A, four (3%) each with MEN 2B and von HippelLindau (VHL) syndrome, and three with neurofibromatosis. Phenoxybenzamine (Dibenzyline) was the medication used in 94% of patients for preoperative a-adrenergic blockade, extending for an average of 15 days (range, 2 to 40 days). Despite this preparation, 69% of patients developed either hypertensive or hypotensive episodes intraoperatively, for which they were given intravenous medication. The mean maximum and minimum systolic blood pressures were 192 (peak, 310) and 83 mm Hg (lowest, 31), respectively. However, no patient had a complication related to these episodes. A single patient died postoperatively because of a bowel perforation unrelated to the adrenalectomy. No patient has suffered recurrent or metastatic disease, including peritoneal or port site contamination.f Nearly 40% of these tumors were discovered as "incidentalomas" in an abdominal imaging study obtained for unrelated reasons. The open anterior approach was utilized in patients who were undergoing other open abdominal operations, patients with tumors larger than approximately 8 em, or at times when a partial adrenalectomy was elected in patients with some form of familial disease. The principles for excision of pheochromocytomas irrespective of surgical method include complete removal with the tumor intact, minimizing wide blood pressure fluctuations. Laparoscopic adrenalectomy for pheochromocytoma is a challenging technique that should be undertaken only by experienced laparascopists who also have knowledge and operative experience in managing adrenal disorders.

Anterior Approach At times, either for intra-abdominal procedures that cannot be accomplished laparoscopically or for other reasons, an anterior open approach may be chosen. A surgical headlight may be helpful in the dissection of these tumors, which can be situated very high and deep in the retroperitoneum.

Right Adrenal We prefer the exposure of a right adrenal pheochromocytoma through a long right subcostal incision with the patient positioned supine, sometimes with elevation of the right side of about 15 degrees. After standard exploration, the liver is retracted superiorly and its attachments are freed from the retroperitoneum. A mechanical retractor is helpful to elevate the right costal margin, and the assistant retracts medially and inferiorly on the duodenum and porta hepatis.

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Occasionally, mobilization of the hepatic flexure of the colon and kocherization of the duodenum may be helpful to gain wider exposure. Because the most critical zone of dissection is the superomedial aspect ofthe right adrenal, the adrenal vein, the safest method involves dissecting toward it from both above and below. Initially, the retroperitoneal attachments to the liver are incised, allowing some elevation of the liver. The retroperitoneum is incised over the superolateral aspect of the tumor and then carried medially until curving slightly over its superomedial aspect. Similarly, the retroperitoneal layer overlying the inferior vena cava (IVe) above the duodenum is incised, the lateral edge of the IVC is defined, and dissection proceeds superiorly. As the IVC is dissected toward the tumor, transection of one or two small branches from the anterior surface of the IYC to the caudate lobe of the liver further opens the dissection space. At least one fourth of the tumor may reside behind the IVC, and a vein retractor should be positioned to retract the vein medially and slightly anteriorly. Gentle lateral and inferior traction by the surgeon on the tumor helps exaggerate the angle between the adrenal vein and vena cava to facilitate visualization of the short, broad adrenal vein as it enters the posterior aspect of the vena cava. This is preferably controlled by large clips or suture ligated and the vein is transected. Typically, a significant drop in blood pressure occurs with this step, but other small venous connections are not rare, usually emptying into the renal vein inferiorly. Sometimes identified only by palpation as a tethering band at the superomedial "comer" of the tumor is the arterial branch from the inferior phrenic artery. This should be controlled, because failure to attend to this vessel probably accounts for significant bleeding that may be falsely attributed to adrenal venous bleeding. Other important arterial blood supply and less constant veins are located inferomedially, connecting to the aorta, renal arteries, and the renal vein. Control of these vessels completes the dissection.

Left Adrenal A left adrenal tumor is exposed through a long left subcostal incision, with rib retraction similar to that for the right adrenal. Exposure can be achieved either by gaining access through the lesser sac and approaching the tumor directly under the pancreas or by mobilizing the spleen and pancreas out of their bed to the patient's right, thereby widely exposing the adrenal area. Usually, we mobilize the omentum from the midtransverse colon to the splenic flexure. Adhesions from the posterior wall of the stomach to the pancreas are lysed, and the pancreas is elevated by incising along its inferior border and mobilized by gentle blunt dissection. A retractor under the stomach and pancreas exposes the adrenal gland and tumor. The spleen can often be left in its bed but, if necessary, can be fully mobilized from its lateral attachments and short gastric vessels. Particularly when the tumor is quite large, the spleen and the body and tail of the pancreas are retracted out of the operative field to the patient's right upper quadrant. The critical zone of the left adrenal-the adrenal vein-is located inferomedially. If the renal vein can be visualized easily, early in the dissection, it should be ligated. Often, however, the tumor is large enough

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to overlap the renal vessels, and initial dissection to gain more mobility of the tumor should be directed to free the superior border of the gland. As with the right side, the arterial branch of inferior phrenic artery must be controlled. As the renal vein is dissected, a branch of the renal artery commonly courses immediately adjacent to the posterior and lateral aspect of the tumor, in jeopardy of inadvertent injury. Care must be exercised to protect this vessel by dissecting it away from the tumor. Once the adrenal vein is transected, the inferomedially located arterial branches must be controlled.

Posterior Approach In contrast to prior recommendations by us and others, we now feel that the technology is sufficiently accurate to allow a posterior approach for pheochromocytomas as well as most other benign adrenal tumors. The minimum investigations to allow this approach include both physiologic and anatomically precise preoperative imaging tests to ensure that the tumor is intra-adrenal and to exclude additional tumors (Fig. 71-8). Key technical points for excision of pheochromocytomas from the posterior approach include the following: (1) manipulation of the tumor by this approach may exceed that by the anterior approach; (2) on both sides, the tumor is initially exposed by dissecting its superior border first, with anatomic landmarks being the

diaphragm superiorly, the inferior phrenic vein superomedially on the left, and the liver on the right.

Paragangliomas By virtue of their location, paragangliomas may present difficult challenges and require special care to prevent serious hemorrhage. However, even when located between the aorta and vena cava and obscured by the portal triad, it is rare for these vessels to be invaded, and meticulous dissection is rewarded with tumor removal, protecting these vessels. Because 40% of these tumors are malignant, careful search for and removal of lymph node and liver metastases should be undertaken if possible.

Postoperative Management When the blood pressure has reached stability in the operating room with the use of fluids, blood, and vasopressors, if necessary, patients often remain remarkably normotensive throughout their remaining hospital course. However, persistent need for vasopressors may be required until the combined effect of the phenoxybenzarnine plus lack of the intense catecholamine stimulation resolves. Monitoring in an intensive care unit may be indicated for 24 hours but is rarely necessary beyond this time. Approximately 2 weeks after the operation, a 24-hour urine collection for metanephrines and catecholarnines should be obtained. This establishes that all tumor has been removed and sets a baseline for future reference. Because metastatic disease may not become apparent for over 5 years," similar annual screening should continue for at least that long.

Pathology

FIGURE 71-8. A, CT scan of a relatively large right pheochromocytoma, located in the adrenal gland. B, Gross photograph demonstrates a tumor slightly larger than 5 cm. This tumor was removed by a posterior approach.

Pheochromocytomas are of variable size, ranging from 1 em to several kilograms, but are normally between 50 to 200 mg. In sporadic pheochromocytomas, even though lobulated, the tumor is actually a single neoplasm. In contrast, familial tumors are often bilateral and usually multicentric.v In MEN 2 syndromes, even though synchronous bilateral pheochromocytomas may not be present, the adrenal medulla is hyperplastic and is thought to represent pretumor change analogous to C-cell hyperplasia and medullary thyroid carcinoma. Fed by a rich blood supply, pheochromocytomas often have a purplish gray hue when resected and frequently show demarcated areas of cystic necrosis. As stated previously, nearly 90% of pheochromocytomas are located within the adrenal glands. The remaining 10% to 15% are found from the neck to the bladder, typically along the course of the sympathetic chain. The most frequent extra-adrenal site is at the aortic bifurcation, the so-called organ of Zuckerkandl. Nearly 98% of pheochromocytomas are located in the abdomen, but they can be found in the neck, mediastinum, intracardiac area, or along the sympathetic chain in the chest. Extra-adrenal tumors are more frequently malignant, approximately 40% in our experience.v-'? There is consensus agreement that histopathology, even including intratumoral capsular and vascular invasion or

Pheochromocytoma - -

FIGURE 71-9. A, Posterior view of metaiodobenzylguanidine scan demonstrating an obvious, single, left adrenal pheochromocytoma. B, The gross tumor shows that the adrenal vein has been split down into the tumor capsule, and the bulging tumor can be seen pouting out through the cut end of the adrenal vein. There was no sign of malignancy in this patient, and catecholamines and metanephrines returned to normal postoperatively.

marked cellular pleomorphism, is unreliable to predict malignancy in pheochromocytomas (Fig. 71_9).44,48,49 However, in a review of 184 patients with pheochromocytomas and paragangliomas, approximately one third each had diploid, tetraploid, and aneuploid patterns on flow cytometric nuclear DNA analysis. None of the diploid tumor patients died of disease, and the only disease recurrence was a new, primary contralateral intra-adrenal tumor in a patient with MEN 2 syndrome who was subsequently cured following adrenalectomy."

Special Situations Malignancy As has been emphasized previously, there are no certain cytologic characteristics that distinguish benign from malignant pheochromocytomas. The presence of local invasion into surrounding soft tissue or the presence of these tumors in sites other than along the sympathetic chain is the only reliable indicator of malignancy. Patients with apparently benign, sporadic, well-encapsulated tumors have developed

629

distant metastases that have proved fatal (Fig. 71-10).51 The most common sites of metastases are bone (especially spine, skull, and ribs), lung, liver, and retroperitoneal Of mediastinal lymph nodes. 52 Even though in isolated instances patients with distant metastases have lived for long periods of time, the usual 5-year survival ranges from 30% to 45%.8 Most recurrent pheochromocytomas are functioning, similar to the primary tumor. Detection is-reliable utilizing 24-hour urine determinations for metanephrines and catecholamines. The extent and locations of the metastases can be determined most accurately with MIBG scanning (see earlier)," although false-negative scans occur in about 10% of patients. If recurrences are surgically resectable, reoperation seems worthwhile and we have used this effectively for long-term palliation or even cure.P Bone pain can be palliated effectively with external beam radiation treatment. Between 50% and 75% of patients with metastatic pheochromocytomas gain benefit from therapeutic 1311 MIBG as measured by tumor shrinkage or decrease in circulating catecholamines.>' A report of 33 patients with metastatic disease showed a median survival of 4.7 years and a 5-year survival rate of 45% after treatment." A survival advantage seemed to correlate with a higher initial dose of approximately 500 mCL Bone marrow suppression occurred in 12%, and three treatment-related deaths were recorded. Combination chemotherapy using cyclophosphamide, vincristine, and dacarbazine has been proved effective against malignant pheochromocytoma, with tumor and biochemical responses of 57% and 79%, respectively.'
Extra-Adrenal Pheochromocytomas (Paragangliomas) For purposes of this discussion, the terms extra-adrenal pheochromocytoma and paraganglioma are used interchangeably. Even though chemodectomas and glomus jugulare tumors are technically included within this category, they are part of a group termed branchiomeric paragangliomas and are usually negative for chromaffin staining and rarely functional. 58 They are much more frequent (69%) than those located below the neck (31%).59 In addition, paragangliomas arising in the retroperitoneal region along the aorta and iliac bifurcation (along the sympathetic chain) are most often functional. Paragangliomas are often multicentric, malignant in 40% to 50%, functional, may be associated with intra-adrenal pheochromocytomas, occur more often in children, and may be associated with familial syndromes such as neurofibromatosis, VHL disease, and Carney's syndrome (see later). Sixty-six patients had surgery at the Mayo Clinic for catecholamine-producing paragangliomas between 1952 and 1992.60 Familial disease was present in 9 patients (14%), and 10 patients (15%) also developed adrenal pheochromocytoma. Fifty-three tumors developed in 14 patients with multiple paragangliomas, 38 abdominal and 15 thoracic. Disease persisted in 15 patients postoperatively,and 9 of 50 patients initially cured developed recurrence.

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FIGURE 71-10. A, CT scan of a patient with a 7-cm

well-circumscribed left adrenal pheochromocytoma. B, Metaiodobenzylguanidine scan, posterior thorax view, showing several "hot spots" along the vertebral column that corresponded to metastatic pheochromocytoma. C, Gross appearance of the tumor. No gross local invasion outside the tumor capsule was evident.

Nevertheless, the 5-, 10-, and 20-year survival rates were 86%, 80%, and 80%, respectively. Risk factors for death from paragangliomas were tumor size greater than 5 em, metastatic disease, and tumor invasion. Paragangliomas located in the bladder are most often located near the trigone, and more than 80% can be identified by cystoscopy." They are malignant in about 15% of cases. Symptoms are most frequently associated with micturition, and hematuria occurs in over half of cases. Treatment usually requires partial cystectomy rather than transurethral resection.

Pheochromocytoma and Pregnancy Even though extremely rare, the combination of pheochromocytoma and pregnancy would rank in the "life-threatening" risk category. Reports of maternal mortality of 40% and a fetal death rate of 40% to 56% have been published.P Critical to appropriate management is considering and testing for the diagnosis. Urinary catecholamines do not fall outside the normal values during normal pregnancy/? MRI is the localization test of choice because it does not involve any radiation. Preoperative a-blockade is like that in nonpregnant patients, using phenoxybenzarnine or prazosin. The addition of ~-blockade is also recommended for the usual 2 to 3 days preoperatively. Beyond the 24th week, a reasonable attempt to bring the fetus to a safe gestation is reasonable but requires very close monitoring.P Most commonly, under a single anesthetic,

cesarean section followed immediately by tumor excision can be accomplished successfully.v' One case report gave a detailed description of a patient managed with initial cesarean section followed by a successfullaparoscopic adrenalectomy 2 weeks later. 65

Multiple Endocrine Neoplasia Type 2 Syndrome Pheochromocytomas constitute one component of several unusual syndromes, including MEN type 2 (medullary thyroid carcinoma, pheochromocytoma, primary hyperparathyroidism, or mucocutaneous neuromas). Whereas nearly all individuals who inherit the ret protooncogene for these autosomal dominant diseases develop medullary thyroid carcinoma, the penetrance of pheochromocytoma and hyperparathyroidism is variable." This is clearly related to the kindred, with all affected members developing pheochromocytomas in some families whereas fewer than 10% may develop these tumors in other families. Overall, approximately 40% develop pheochromocytomas. When a patient develops biochemical evidence of pheochromocytoma and also has confirmed MEN 2 syndrome, bilateral adrenal medullary hyperplasia is always present." However, synchronous true tumors are not always present, and this has raised considerable controversy about the appropriate management of the contralateral "normal" gland. Arguments against routine bilateral adrenalectomy include the following?": (1) as many as 50% do not need it

Pheochromocytoma - - 631 at least within 5 years, (2) no hypertensive crises developed in the patients who had undergone only unilateral adrenalectomy, and (3) 23% of patients in whom bilateral adrenalectomy was performed experienced at least one attack of acute addisonian crisis. Others have advocated contralateral adrenalectomy only when a tumor of 5 cm or larger has developed/" We previously advocated bilateral adrenalectomy even if a macroscopic contralateral tumor was not identified by preoperative imaging." Reasons for this included (1) the risk of malignancy, rare but identified in two patients; (2) the uncertain timing of catastrophic complications of even small pheochromocytomas; and (3) the uncommonly serious nature of problems resulting from bilateral adrenalectomy, both early postoperatively and in the long term.?" However, we have changed our viewpoint and recommend, similarly to Lairmore and colleagues.F delaying contralateral adrenalectomy until symptoms develop or a tumor becomes obvious on CT scan. The risk of developing a contralateral pheochromocytoma in patients with MEN 2 was 33% by 5 years and 52% by 12 years of follow-up.f and the average time to develop a contralateral pheochromocytoma was 13 years. Partial adrenalectomy for pheochromocytoma in patients with MEN 2 and VHL disease has been reported,":" but 20% recurred in one series 74 and there has been variable success in preserving adrenocortical function. For example, despite normal basal cortisol levels, a subnormal response to corticotropin (ACTH) stimulation was present in two reported patients." In 1998, Janetschek and colleagues" were the first to report laparoscopic adrenal-preserving surgery for bilateral adrenal tumors. In the MD Anderson experience," cortical-sparing adrenalectomy was performed in 22 patients with bilateral pheochromocytoma, of whom 13 (59%) were steroid independent, but only 4 of 15 (27%) treated patients had a normal response to cosyntropin stimulation. Three (10%) had recurrent pheochromocytoma in the remnant.

of pheochromocytoma developing in patients with VHL varies from 10% to 19%, but the key is the particular family transmission pattern, which ranges from 0% to 92%.79 These tumors are more frequently bilateral, extra-adrenal, and may be malignant. Even apparently sporadic unilateral pheochromocytomas have been diagnosed with VHL. In an unselected series of patients with resected pheochromocytomas, 19% were eventually found to be carriers ofVHL.80That VHL and pheochromocytomas may be associated with a MEN variant is suggested by the coexistence of these two conditions plus nonfunctioning islet adenomas or carcinomas.t'-" Carney's syndrome includes the association of gastric epithelioid leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma.83

Summary The triad of headaches, sweating and hypertension is classical for pheochromocytoma, but these potentially lifethreatening tumors can be clinically silent, and approximately 10% present as incidentally discovered tumors on imaging tests. Urinary total metanephrines and fractionated catecholarnines are 98% sensitive and specific in establishing the diagnosis. At least 90% of pheochromocytomas are benign, but long-term follow-up remains necessary as specific criteria for malignancy are lacking except local extratumoral invasion and proven metastases. Paragangliomas may be located anywhere along the sympathetic chain from the neck to the bladder, and are more frequently malignant and multiple than intra-adrenal pheochromocytomas. Preoperative preparation with a-blockade is required and most intra-adrenal tumors can be safely removed by laparoscopic adrenalectomy. Intraoperative blood pressure is most volatile at the time of induction of anesthesia and tumor manipulation, but can usually be well managed pharmacologically. Adrenergic symptoms are cured and hypertension is ameliorated or cured with tumor removal.

Children In nearly 20 years at a major referral center for pheochromocytomas, only 14 children with this tumor were surgically treated." As with adults, the diagnosis relies on urinary metanephrines, the localization studies include CT, MRI, and MIBG scans, and preoperative blockade remains equally important with the same medications. However, as opposed to the disease in adults, pheochromocytomas in children are more often associated with the MEN 2 syndromes, more often bilateral, extra-adrenal yet less commonly malignant, and arise more frequently with sustained hypertension. After resection, all 14 of these children were reportedly alive and well and normotensive without medication."

Associated Conditions Pheochromocytoma can develop in association with other neuroectodermal disorders such as von Recklinghausen's neurofibromatosis, Sturge-Weber syndrome, tuberous sclerosis, and VHL syndrome (retinal hemangiomatosis, cerebellar hemangioblastoma, pheochromocytoma, renal cysts or carcinomas, and pancreatic cysts and tumors). The incidence

REFERENCES I. Frankel F. Ein fall von doppelseitigen vollig latent verlaufen nebennierentumor und gleichseitiger nephritis mit veranderungen am circulation sappart und retinitis. Virchows Arch A 1886;103:244. 2. Mayo CH. Paroxysmal hypertension with tumor of retroperitoneal nerve. JAm Med Assoc 1927;89:1047. 3. Welboume RB. Early surgicalhistory of phaeochromocytoma. Br J Surg 1987;74:594. 4. Graham 18. Pheochromocytoma and hypertension. An analysis of 207 cases. IntAbstr Surg 1951;92:105. 5. Kvale WF, Roth GM, Manger WM, Priestley JT. Pheochromocytoma. Circulation 1956;14:622. 6. Stenstrom G, Svardsudd K. Pheochromocytoma in Sweden 1958-1981. An analysis of the National Cancer Registry Data. Acta Med Scand 1986;220:225. 7. Sheps SG, Jiang N-S, Klee GG. Diagnostic evaluation of pheochromocytoma. Endocrinol Metab Clin North Am 1988;17:397. 8. Samaan NA, Hickey RC, Shutts PE. Diagnosis, localization, and management of pheochromocytoma; pitfalls and follow-up in 41 patients. Cancer 1988;62:2451. 9. Graham 18. Phaeochromocytoma and hypertension. Int Abstr Surg 1951;92:105. 10. SI. John Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc 1981;56:354.

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II. Kudva Y,Young WF, Thompson GB, et al. Adrenal incidentaloma: An important component of the clinical presentation spectrum of benign sporadic adrenal pheochromocytoma. Endocrinologist 1999;9:77. 12. Bravo E, Tagle R. Pheochromocytoma: State-of-the-art and future prospects. Endocr Rev 2003;24:539. 13. McCorkell SJ, Niles NL. Fine-needle aspiration of catecholamineproducing adrenal masses: A possibly fatal mistake. AJR Am J RoentgenoI1985;145:113. 14. Sawka A, Jaeschke R, Singh R, Young W Jr. A comparison of biochemical tests for pheochromocytoma: Measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 2003; 88:553. 15. Young W. Pheochromocytoma and primary aldosteronism: Diagnostic approaches. Endocrinol Metab Clin North Am 1997;26:8091. 16. Young W. Phaeochromocytoma: How to catch a moonbeam in your hand. Eur J EndocrinoI1997;136:28. 17. Lenders J, Pacak K, Walther M, et al. Biochemical diagnosis of pheochromocytoma: Which test is best? JAMA 2002;287:1427. 18. Bravo EL. Pheochromocytoma: New concepts and future trends. Kidney Int 1991;40:544. 19. Welch TJ, Sheedy PF, van Heerden JA, et al. Pheochromocytoma: Value of computed tomography. Radiology 1983;148:501. 20. Doppman JL, Reinig JW, Dwyer AJ, et al. Differentiation of adrenal masses by magnetic resonance imaging. Surgery 1987;102:1018. 21. Taieb D, Sebag F, Hubbard J, et al. Does iodine-I 3 I meta-iodobenzylguanidine (MIBG) scintigraphy have an impact on the management of sporadic and familial phaeochromocytoma? Clin Endocrinol (Oxf) 2004;61:102. 22. Shapiro B, Gross MD. Pheochromocytoma. Crit Care Clin 1991;7:1. 23. Shapiro B, Sisson J, KalffV, et al. The location of middle mediastinal pheochromocytomas. J Thorac Cardiovasc Surg 1984;87:814. 24. Pommier RF, Brennan ME Management of adrenal neoplasms. Curr Probl Surg 1991;28:657. 25. Miskulin J, Shulkin B, Doherty G, et al. Is preoperative iodine 123 metaiodobenzylguanidine scintigraphy routinely necessary before initial adrenalectomy for pheochromocytoma? Surgery 2003;134:918. 26. Ilias I, Pacak K. Anatomical and functional imaging of metastatic pheochromocytoma. Ann NY Acad Sci 2004;1018:495. 27. Modlin 1M, Farndon JR, Shephard A, et al. Phaechromocytomas in 72 patients: Clinical and diagnostic features, treatment and long term results. Br J Surg 1979;66:456. 28. Prys-Roberts C, Farndon J. Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg 2002;26:1037. 29. Inabnet W, Pitre J, Bernard D, Chapuis Y. Comparison of the hemodynamic parameters of open and laparoscopic adrenalectomy for pheochromocytoma. World J Surg 2000;24:574. 30. Proye C. Modem trends in the management of pheochromocytomas and abdominal paragangliomas. Endocrinol Surg 1996;13:109. 31. Wark JD, Larkins RG. Pulmonary edema after propranolol therapy in two cases of phaeochromocytoma. Br Med J 1978;1: 1395. 32. Gagner M, Lacroix A, Bolte E. Laparoscopic adrenalectomy in Cushing's syndrome and pheochromocytoma. N Engl J Med 1992; 327:1033. 33. Suzuki K, Kageyama S, Ueda D, et al. Laparoscopic adrenalectomy: Clinical experience with 12 cases. J Urol 1993; 150: 1099. 34. Gagner M, Lacroix A, Prinz RA, et al. Early experience with laparoscopic approach for adrenalectomy. Surgery 1993;114:1120. 35. Thompson G, Grant C, van Heerden J, et al. Laparoscopic versus open posterior adrenalectomy: A case-control study of 100 patients. Surgery 1997;122:1132. 36. Prinz R. A comparison of laparoscopic and open adrenalectomies. Arch Surg 1995;130:489. 37. Brunt LM, Langer JC, Quasebarth MA, Whitman ED. Comparative analysis of laparoscopic versus open splenectomy. Am J Surg 1996; 172:596. 38. Cheah W, Clark 0, Hom J, et al. Laparoscopic adrenalectomy for pheochromocytoma. World J Surg 2002;26: 1048. 39. Kim A, Quiros R, Maxhimer J, et al. Outcome of laparoscopic adrenalectomy for pheochromocytomas vs aldosteronomas. Arch Surg 2004; 139:526. 40. Gill 1. The case for laparoscopic adrenalectomy. J Urol 2001;166:429. 41. Williams D, Dann S, Wheeler M. Phaeochromocytoma-Views on current management. Eur J Surg Oncol 2003;29:483.

42. Brunt L, Lairmore T, Doherty G, et al. Adrenalectomy for familial pheochromocytoma in the laparoscopic era. Ann Surg 2002;235:713. 43. Jaroszewski D, Tessier D, Schlinkert R, et al. Laparoscopic adrenalectomy for pheochromocytoma. Mayo Clin Proc 2003;78:1501. 44. Mahoney EM, Harrison JH. Malignant pheochromocytoma: Clinical course and treatment. J Urol 1977;118:225. 45. Webb TA, Sheps SG, Carney JA. Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrine neoplasia, type 2. Am J Surg PathoI1980;4:121. 46. Orchard T, Grant CS, van Heerden JA, Weaver A. PheochromocytomaContinuing evolution of surgical therapy. Surgery 1993;114: 1153. 47. van Heerden JA, Sheps SG, Hamberger B, et al. Pheochromocytoma: Current status and changing trends. Surgery 1982;91:367. 48. Neville AM, O'Hare MJ. Aspects of structure, function, and pathology. In: James VHT (ed), Comprehensive Endocrinology: The Adrenal Gland. New York, Raven Press, 1979, p 1. 49. Scott HW, Reynolds V, Green N, et al. Clinical experience with malignant pheochromocytomas. Surg Gynecol Obstet 1982;154:801. 50. Nativ 0, Grant CS, Sheps SG, et al. The clinical significance of nuclear DNA ploidy pattern in 184 patients with pheochromocytoma. Cancer 1992;69:2683. 51. van Heerden JA, Roland CF, Carney JA, et al. Long-term evaluation following resection of apparently benign pheochromocytoma(s)/paraganglioma(s). World J Surg 1990;14:325. 52. Thompson NW. Malignant pheochromocytoma. Acta Chir Aust 1993; 4:235. 53. Thompson NW, Allo MD, Shapiro B, et al. Extra-adrenal and metastatic pheochromocytoma: The role of 1311 meta-iodobenzylguanidine (1 311 MIBG) in localization and management. World J Surg 1984; 8:605. 54. Krempf M, Lumbroso J, Mornex R, et al. Use of m-[ l31I]iodobenzyl-

55.

56. 57. 58. 59.

60. 61. 62. 63. 64. 65.

66. 67. 68. 69. 70.

guanidine in the treatment of malignant pheochromocytoma. J Clin Endocrinol Metab 1991;72:455. Loh K, Fitzgerald P, Matthay K, et al. The treatment of malignant phaeochromocytoma with iodine-131 metaiodobenzylguanidine (l3II-MIBG): A comprehensive review of 116 patients. J Endocrinol Invest 1997;20:648. Siddiqui MZ, Von Eyben FE, Spanos G. High-voltage irradiation and combination chemotherapy for malignant pheochromocytoma. Cancer 1988;62:686. Averbuch SD, Steakley CS, Young RC, et al. Malignant pheochromocytoma: Effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 1988;109:267. Whalen RK, Althausen AF, Daniels GH. Extra-adrenal pheochromocytomas. J UroI1992;147:1. Erickson D, Kudva Y, Ebersold M, et al. Benign paragangliomas: Clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab 2001;86:5210. O'Riordain D, Young W, Grant C, et al. Clinical spectrum and outcome of functional extraadrenal paraganglioma. World J Surg 1996;20:916. Sweetser PM, Ohl DA, Thompson NW. Pheochromocytoma of the urinary bladder. Surgery 1991;109:677. Schenker JG, Granat M. Pheochromocytoma and pregnancy-An updated appraisal. Aust N Z J Obstet GynaecoI1982;22:1. Freier DT, Thompson NW. Pheochromocytoma and pregnancy: The epitome of high risk. Surgery 1993; 114: 1148. Leak D, Carroll 11, Robinson DC, Ashworth EJ. Management of pheochromocytoma during pregnancy. Can Med Assoc J 1977; 116:371. Dugas G, Fuller J, Singh S, Watson J. Obstetrical and pediatric anesthesia: Pheochromocytoma and pregnancy: A case report and review of anesthetic management. Can J Anesth 2004;51: 134. Howe JR, Norton JA, Wells SA. Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: Results of long-term follow-up. Surgery 1993;114:1070. Lairmore TC, Ball DW, Baylin SB, Wells SA. Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg 1993;217:595. Tibblin S, Dymling J-F, Ingemansson S, Telenius-Berg M. Unilateral versus bilateral adrenalectomy in multiple endocrine neoplasia ITA. World J Surg 1983;7:201. van Heerden JA, Sizemore GW, Carney JA, et al. Surgical management of the adrenal glands in the multiple endocrine neoplasia type IT syndrome. World J Surg 1984;8:612. Telenius-Berg M, Ponder MA, Berg B, et al. Quality of life after bilateral adrenalectomy in MEN 2. Henry Ford Hosp Med J 1989;37:160.

Pheochromocytoma - - 633 71. Baghai M, Thompson G, YoungW, et aJ. Pheochromocytomas and paragangliomas in von Hippel-Lindau disease. Arch Surg 2002; 137:682. 72. van Heerden JA, Sizemore GW, Carney JA, et aJ. Bilateral subtotal adrenal resection for bilateral pheochromocytoma in multiple endocrine neoplasia type 2A: A case report. Surgery 1985;98:363. 73. Walther M, Keiser H, Choyke P. Management of hereditary pheochromocytoma in von Hippel-Lindau kindreds with partial adrenalectomy. J Urol 1999;161:395. 74. Lee J, Curley S, Gagel R, et aJ. Cortical-sparing adrenalectomy for patients with multiple endocrine neoplasia types I and 2. Surgery 1996;120:1064. 75. Hamberger B, Telenius-Berg M, Cedermark B, et aJ. Subtotal adrenalectomy in multiple endocrine neoplasia type 2. Henry Ford Hosp Med J 1987;35:127. 76. Janetschek G, Finkenstedt G, Gasser R, et aJ. Laparoscopic surgery for pheochromocytoma: Adrenalectomy, partial resection, excision of paragangliomas. J Urol 1998;160:330. 77. Yip L, Lee J, Shapiro S, et aJ. Surgical management of hereditary pheochromocytoma. J Am Coil Surg 2004;198:525.

78. Caty MG, Coran AG, Geagen M, Thompson NW. Current diagnosis and treatment of pheochromocytoma in children. Arch Surg 1990;125:978. 79. Richard S, Beigelman C, Duclos J-M, et aJ. Pheochromocytoma as the first manifestation of von Hippel-Lindau disease. Surgery 1994; 116:1076. 80. Neumann HPH, Berger DP, Sigmund G, et aJ. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 1993;329:1531. 81. Binkovitz LA, Johnson CD, Stephens DH. Islet cell tumors in von Hippel-Lindau disease: Increased prevalence and relationship to the multiple endocrine neoplasias. AJR Am J Roentgenol 1990;155:501. 82. Carney JA, Go VLW,Gordon H, et aJ. Familial pheochromocytoma and islet cell tumor of the pancreas. Am J Med 1980;68:515. 83. Carney JA. The triad of gastric epithelioid leiomyosarcoma, pulmonary chondroma, and functioning extra-adrenal paragangliomas: A five year review. Medicine (Baltimore) 1983;62:159.

Addison's Disease and Acute Adrenal Hemorrhage Patricia J. Numann, MD

Adrenal insufficiency was first recognized in 1855, when Thomas Addison 1 published the monograph, "On the Constitutional and Local Effects of Disease of the Supraadrenal Capsules." He described 11 patients with "general languor and debility, remarkable feebleness of the heart's action, irritability of the stomach, and a peculiar change of the color of the skin." The primary cause historically was adrenal destruction from tuberculosis. By the tum of the 20th century, surgery of the adrenal glands was being performed. Death after adrenalectomy was thought to be due to the accumulation of toxic products they were believed to remove. In 1927, the development of an adrenal extract named "cortin" improved the management of adrenalectomized patients.' In 1937, deoxycortisone was synthesized; in 1948, cortisone was isolated; and between 1952 and 1955, aldosterone was isolated and synthesized. Availability of these steroids and the understanding of their physiologic role dramatically altered the course of adrenal insufficiency. The adrenal gland produces glucocorticoids and mineralocorticoids. Glucocorticoid production is regulated by the hypothalamic-pituitary-adrenal axis. In response to a variety of stimuli from within the brain, corticotropin-releasing factor (CRF) is released into the portal circulation of the pituitary, which in tum stimulates the secretion of adrenocorticotropin (corticotropin). Corticotropin then enters the systemic circulation, where it stimulates the production and secretion of glucocorticoids and, to a lesser extent, mineralocorticoids. In the adrenal cortex, corticotropin stimulates the conversion of cholesterol to corticosteroids. Adequate circulating levels of corticosteroids returning to the brain inhibit the production of CRF and corticotropin. Cortisol, corticotropin, and CRF are secreted with a diurnal variation, with levels higher in the morning than in the afternoon. Plasma cortisol levels are highest at 8 AM and lowest between 10 PM and 2 AM. Stress disrupts the diurnal variation of steroids. Cortisol levels remain high until the stress has subsided. Harris and colleagues demonstrated baseline cortisol levels averaging 28 mg/dL after surgery for trauma (normal < 10 mg/dl.j.' Even with no postoperative complications, urinary cortisol levels remained elevated for 4 days. The magnitude and length of the stress determine the magnitude and length of

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the increased cortisol production. The physician's ability to recognize the increased need for cortisol and to replace it in the surgical patient depends on knowing this response to stress. Adrenal insufficiency (Addison's disease) is rare. Although the exact incidence in the United States is currently unclear, in 1974, in Denmark, the incidence was 60 per 1 million." The decline of tuberculosis transiently reduced the incidence of Addison's disease, but now acquired immunodeficiency syndrome (AIDS) and autoimmune adrenalitis are again increasing the rate. Recognition and appropriate treatment of adrenal insufficiency in the surgical patient are critically important because the failure of the corticosteroid response during stress is usually fatal. Many patients come to surgery with an established diagnosis of adrenal insufficiency resulting from primary adrenal or pituitary disease. Although the diagnosis should have been established in most patients with primary adrenal insufficiency, some may inadvertently come to surgery without a diagnosis and may experience addisonian crisis as a result of surgical stress. Many other patients come to surgery with the potential for adrenal insufficiency because of chronic suppression of their adrenal by exogenous corticosteroid therapy or by a hyperfunctional adrenal or pituitary tumor. A small group of surgical patients experience acute adrenal insufficiency during the course of their illness (Table 72-1).

Primary Insufficiency Autoimmune adrenalitis is the most common form of adrenal insufficiency, accounting for two thirds or more of primary adrenal failure cases. Association of Addison's disease with other autoimmune diseases is common. In 1981, Neufeld and coworkers proposed a classification system for these polyglandular autoimmune (PGA) syndromes that divided those associated with Addison's disease into type I and type 11. 5 Patients with PGA-I syndrome have hypoparathyroidism, chronic mucocutaneous candidiasis, or both, as well as infrequent other autoimmune diseases associated with their

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Addison's disease. PGA-I syndrome usually arises in childhood or early adulthood. In PGA-II syndrome, Addison's disease occurs in association with autoimmune thyroiditis and insulin-dependent diabetes but without hypoparathyroidism or chronic mucocutaneous candidiasis. PGA-II syndrome occurs in older patients, generally between the second and fifth decades of life.! Both of these entities may occur in the familial form. PGA-II syndrome is more common and accounts for more than 50% of patients with Addison's disease.t Young women with spontaneous premature ovarian failure should also be suspected of having autoimmune adrenal insufficiency." Discoveries in genetics have provided valuable insights into the development of these syndromes and adrenal function," AIDS patients are at risk for adrenal insufficiency from multiple causes. AIDS patients' adrenal glands may be infiltrated by multiple infections and malignant processes, including cytomegalovirus, Mycobacterium tuberculosis or M. avium-intracellulare, Pneumocystis carinii, toxoplasmosis, histoplasmosis, Kaposi's sarcoma, and lymphoma. The human immunodeficiency virus may invade the adrenal. The adrenal is the preferred site of cytomegalovirus in the AIDS patient." Autoimmune adrenalitis also occurs. Drugs used in the treatment of AIDS-related diseases such as ketoconazole, corticosteroids, rifampin, and phenytoin may also contribute to impaired adrenal function. Thrombocytopenia may lead to acute adrenal hemorrhage. The severe hypocholesterolemia seen in some AIDS patients may lead to impaired corticosteroid production. 10 The basic illness of AIDS mimics adrenal insufficiency with lethargy, hyperpigmentation, weight loss, and hyponatremia. A high index of suspicion must be maintained to diagnose Addison's disease appropriately in the AIDS patient. Similarly, surgeons consulted to see the AIDS patient with abdominal pain, hypotension, or sepsis must keep Addison's disease in the differential diagnosis. Standard endocrine testing and computed tomography (CT) scans of the abdomen help establish the diagnosis. Empirical corticoid therapy in the severely ill patient may be

indicated because the delay to obtain appropriate testing might prove fatal. Tuberculosis, which was once the most common cause of adrenal insufficiency, had diminished in incidence for many years but is now again increasing. Tuberculosis is an opportunistic infection in patients with AIDS and other debilitated patients, and it may insidiously or acutely produce adrenal insufficiency with the classic symptoms. Disseminated histoplasmosis, which occurs more commonly in the Ohio, Tennessee, and Piedmont plateau areas of the United States, commonly results in adrenal insufficiency. 1 I Other fungal infections such as blastomycosis, cryptococcosis, and coccidioidomycosis may also lead to adrenal insufficiency. The clinical picture is further confused because drugs such as ketoconazole, fluconazole, and rifampin used to treat some of these disorders may also result in adrenal insufficiency. Rare genetically determined diseases such as familial glucocorticoid deficiency, adrenoleukodystrophy, and adrenomyeloneuropathy also produce adrenal insufficiency. The diagnosis in these patients is usually clearly established before surgery, and appropriate perioperative steroid management is the only issue in these patients. Adrenal insufficiency also results from pituitary dysfunction such as pituitary adenomas, postpartum pituitary hemorrhage (Sheehan's syndrome), and corticotropin deficiency. These conditions must be recognized as requiring additional steroid coverage during surgical stress.

Surgical Adrenal Insufficiency Bilateral adrenalectomy and hypophysectomy are obvious causes of adrenal insufficiency. Not so obvious is the adrenal suppression that may result from removal or infarction of a hyperfunctional unilateral adrenocortical tumor or a functioning adrenal tumor. Certainly, all patients undergoing hypophysectomy, bilateral adrenalectomy, or unilateral adrenalectomy should receive stress-dose steroid therapy. Infarction of a unilateral functioning adrenal tumor may be more difficult to recognize. Steroid coverage is sometimes given for unilateral adrenalectomy even when no corticoid production of the tumor can be identified preoperatively.

Secondary Adrenal Insufficiency Related to Exogenous Steroid Usage Overall, the most common adrenal insufficiency is the secondary adrenal insufficiency resulting from exogenous steroid usage. Numerous and diverse conditions are treated with corticosteroids: inflammatory bowel disease, asthma, arthritis, and dermatologic conditions, to name a few. Inhaled steroids are a mainstay of therapy for asthma and can produce the potential for adrenal insufficiency in both children and adults.P Corticosteroids are part of the therapeutic regimen of transplantation immunosuppression and cancer chemotherapy. Short courses of high-dose corticosteroids are used in numerous inflammatory conditions. Corticosteroid use is so common that an inquiry regarding corticosteroid

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use should be made of every patient preoperatively. The trauma patient unable to give a history should be suspected of having used steroids. Exogenous corticosteroid therapy even for only a few days may produce some inability of the pituitary-adrenal axis to respond to stress. The generally accepted rule is to provide stress-dose steroids to any patient undergoing surgical stress who has received steroids for more than 1 week within the previous year. Adrenal suppression has been identified in patients using high-dose steroids for very short periods of time, and the longer the steroid use, the longer the impairment may last. No study has definitively answered how short an exposure to how much steroid is the minimum amount to suppress adrenal function. Graber and colleagues studied 14 patients: 8 after resection of a functioning cortical adenoma and 6 after supraphysiologic doses of steroids for 1 to 10 years. During the first month without therapy, corticotropin failed to increase in these patients, despite low cortisol levels. During the second to fifth months, plasma corticotropin rose to normal or supernormal values but the plasma corticosteroid response to corticotropin remained subnormal. During the sixth to ninth months, the plasma and urinary corticoid levels were normal, but adrenal responsiveness could be demonstrated only with supernormal levels of corticotropin. After 9 months, pituitary-adrenal responses returned to normal. 13 Even though the series is small, this study demonstrates the fallacy of using baseline steroid levels to determine the adequacy of adrenal function and the length of time necessary for return to normal.

Stress-Induced Adrenal Insufficiency Merry and colleagues, in 1994, reported on a small group of patients who had transient corticotropin deficiency, which caused postoperative acute adrenal failure." These patients presented with unexplained postoperative hypotension. Schlaghecke and coworkers, in a series of 279 patients, demonstrated that corticosteroid reserve cannot be reliably determined on the basis of dose and duration of therapy.P Plasma baseline cortisol levels were similarly unreliable. Because there is no simple, reliable method of determining the adrenal response to stress and definitive testing is time consuming and costly, empirical steroid administration to cover the period of stress is conventional. The magnitude and duration of stress requiring increased corticosteroid production have been studied in numerous circumstances. In particular, the methods of assessing adequacy of adrenal function and the routine use of corticosteroids in the critically ill, septic, intensive care unit patient have been the subject of extensive controversy. Manglik and associates, in a prospective clinical trial involving 100 patients, found that 9% of septic patients failed the ACTH stimulation test and 4% of septic patients had occult pituitary disease or secondary adrenal insufficiency." Jurney and colleagues demonstrated no advantage of routine evaluation of baseline cortisol or corticotropin stimulation studies in the intensive care unit.'? Baseline cortisol levels were not useful in predicting adrenal insufficiency. Patients with low baseline cortisol levels did not necessarily have impaired corticotropin stimulation. Although baseline cortisol levels did correlate with survival, patients with the highest levels

had the worst prognosis. Barton and coworkers demonstrated a positive correlation of plasma cortisol with injury severity score (ISS) in patients with minor or moderate injuries but a negative correlation with high ISS scores, no difference between head-injured and non-head-injured patients, and no difference with age or time of day when samples were taken. 18 A study of intensive care unit patients performed by Rivers and coworkers again raises the question of critical illness increasing the probability of adrenal insufficiency. They studied 104 patients with severe sepsis or septic shock. They described a group with functional hypoadrenalism, who exhibited any hypoadrenal laboratory values. They found an improvement in vasopressor-dependent refractory hypotension, even in the group with normal adrenal function. This study suggests that we need to reconsider our assessment of adrenal insufficiency and our use of corticosteroids in the severely ill. They recommended considering hydrocortisone treatment in patients older than 55 years in the presence of continued need for vasopressors after adequate volume resuscitation. 19 Corticotropin stimulation studies remain reliable at determining adrenal response in the trauma victim. The cosyntropin stimulation test is used to determine whether the adrenal cortex is able to respond normally to this corticotropin analog by increasing the production of corticosteroids. Serum cortisol level is measured at 0, 30, and 60 minutes after intravenous or intramuscular injection of 250 ug of cosyntropin. Patients with a normal adrenal response should increase the serum cortisol level by at least 7 ug/dl, or have a peak level of at least 20 ug/dl., Harris and colleagues performed urinary and plasma cortisol and cosyntropin (synthetic corticotropin) stimulation studies on 30 patients after traumatic injury and 125 after extensive elective abdominal or thoracic operation. Levels were similar in both groups. With an uncomplicated clinical course, the levels returned to normal in 1 to 2 days." They found a mean stimulated serum cortisol level of 44.5 ± 12.0 ug/dl, and concluded that a stimulated mean cortisol level of greater than 20.5 ug/dl, would include 97.5% of normal subjects. Any value less than 20.5 ug/dl, should be considered indicative of adrenal insufficiency. Stress levels of steroids should, therefore, be maintained at high doses for at least 48 hours and raised again if complications ensue. Current recommendations for steroid coverage of patients anticipated to have adrenal insufficiency as a result of previous steroid therapy are empirical. For major surgical procedures, 100 mg of hydrocortisone hemisuccinate is administered intravenously the evening before surgery, the morning of surgery, and every 8 hours for 24 hours until the major stress of the operation is resolved. Usually, 48 hours is required for major operations with continued high-dose steroids if complications arise. If high-dose steroids are required for fewer than 72 hours, rapid tapering over 5 to 7 days can safely prevent adrenal insufficiency. For minor outpatient procedures, 100 mg of hydrocortisone at the induction of anesthesia followed by the usual oral doses postoperatively is sufficient. Numerous other steroid regimens exist, but advantages of one over the other are unproved. Rarely is the addition of mineralocorticoid necessary in this acute setting."

Addison's Disease and Acute AdrenalHemorrhage - - 637

Adrenal Insufficiency Occurring Acutely in the Surgical Patient Acute adrenal insufficiency occurring in the surgical patient is rapidly fatal if unrecognized. Bilateral adrenalectomy and hypophysectomy are obvious causes of acute adrenal insufficiency. Numerous drugs used in the surgical patient may cause adrenal insufficiency. The most treacherous condition is bilateral adrenal hemorrhage, which may occur in association with anticoagulant therapy, thrombocytopenia, hypercoagulable states, trauma, or the stress of sepsis or bums.

Acute Adrenal Insufficiency Related to Bilateral Adrenal Hemorrhage Although historically bilateral adrenal hemorrhage is associated with meningococcemia in children (WaterhouseFriderichsen syndrome), bilateral adrenal insufficiency occurs most commonly in adults in association with anticoagulant therapy. Clinical conditions producing coagulopathies such as thrombocytopenia, anticardiolipin antibody, and lupus anticoagulant also result in bilateral adrenal hemorrhage. Trauma, either directly or through the destruction of the blood supply to the adrenal, may result in bilateral adrenal hemorrhage. Septicemia, although more commonly a cause of adrenal hemorrhage in children, may lead to adrenal hemorrhage in adults. Stress associated with illness, sepsis, or bums may lead to bilateral adrenal hemorrhage. Because of the rapidly fatal outcome of bilateral adrenal hemorrhage, the surgeon must suspect this clinical entity in these settings. Although Goolden in 1857 22 recognized the clinical entity of bilateral adrenal hemorrhage, not until the advent of CT scans was the diagnosis made premortem. In 1965, Amador reviewed the 20 cases previously reported as well as 10 cases gleaned from the 4325 autopsies performed at Peter Bent Brigham Hospital in Boston from the widespread use of anticoagulant therapy in 1949 until December 1962. 23 Amador suggested that this form of acute adrenal insufficiency, which resulted from bilateral adrenal hemorrhage, might not be so rare; adrenal insufficiency was not suspected during the lifetime in any of the 10 cases studied." Of the 20 previously reported cases, 3 were suspected and treated premortem.P The first case of successful diagnosis and treatment was reported by Thorn and colleagues in 1956. 24 In 1978, Xarli and coauthors reviewed 135 cases and added 22 of their own." They found the incidence to be as high as 1.1% of autopsied patients.P Siu and associates reported only 11 patients successfully diagnosed and treated premortem before 1981. 26 Between 1981 and 1990, Siu found 18 cases at the Mayo Clinic that were successfully diagnosed." In 16 of the 18 cases, CT scans of the abdomen established the finding of adrenal hemorrhage. Fortuitously, the signs and symptoms of bilateral adrenal hemorrhage led to obtaining a CT scan in many instances. Espinosa and coworkers found a significant incidence of lupus anticoagulant or anticardiolipin antibodies in patients suffering adrenal hemorrhage;

therefore, all patients with adrenal hemorrhage should be checked for antibodies." Stress may lead to bilateral adrenal hemorrhage or may cause acute adrenal insufficiency without hemorrhage. The bum patient is an example of this dual situation apparently related to a similar stress. Among 807 patients treated at Parkland Hospital over the previous 6 years, Murphy and colleague'" found 3 patients in whom acute adrenal insufficiency developed. They reviewed the existing theories of the pathophysiology of adrenal insufficiency in the bum patient. Vaughan and associates demonstrated cortisol levels three to four times higher than normal in patients with bums greater than 30%. These patients lost their diurnal rhythm. Bum size correlated with cortisol but not corticotropin levels." Hemorrhagic cortical necrosis is the most common pathologic finding associated with this acute adrenal insufficiency." The clinical picture is that of sudden and rapid cardiovascular collapse, which is frequently interpreted as sepsis. Surgical stress seems to be a contributing factor to the development of bilateral adrenal hemorrhage or adrenal insufficiency.t" Alford and coauthors reported that 5 of 4364 patients undergoing cardiac surgical procedures experienced bizarre and confusing postoperative courses ultimately proved to be adrenal insufficiency." Adrenal insufficiency has been reported as an unexpected finding in a small number of patients after virtually any surgical procedure or severe physiologic stress (Table 72-2). Although therapeutic anticoagulation with heparin or warfarin is the factor most commonly implicated in bilateral adrenal hemorrhage, even prophylactic subcutaneous heparin has been found to produce this problem.F The cause of the hemorrhage with heparin may be related more to heparin-induced thrombocytopenia than to abnormalities of the coagulation cascade.P Conditions associated with coagulopathies such as idiopathic thrombocytopenic purpura, antiphospholipid antibodies, anticardiolipin antibody, and other thrombogenic states have been associated with adrenal hemorrhage."

638 - - Adrenal Gland The pathophysiology of adrenal hemorrhage remains unclear. Excessive anticoagulant does not seem to be responsible because transient prothrombin time abnormalities occur in only half of the patients." Heparin-induced thrombocytopenia may playa role." The fragile blood supply may contribute to the hemorrhage. The adrenal is supplied by 50 to 60 small arterial branches from three suprarenal arteries. These arteries feed a subcapsular plexus, which drains through a few venules into medullary sinusoids. Vasoconstriction or hypervascularity could raise adrenal venous pressure, causing hemorrhage.P The single central vein and its thick longitudinal muscle bundles may make it vulnerable to formation of platelet thrombi, stasis, and thrombosis." Stress elevates corticotropin levels, which increase oxygen uptake by the adrenals and increase adrenal perfusion.'? Focal necrosis may increase the vulnerability to hemorrhage. Hemorrhagic cortical necrosis is the most common pathologic finding associated with acute adrenal insufficiency" The clinical scenario described by Amador remains unchanged today.P The sudden onset of steady pain in the upper abdomen, flanks, and lower back, accompanied by mild tenderness, heralds the development of rapidly progressive deterioration. Initially, abdominal distention and obstipation are present. Listlessness and fatigue progress to lethargy and disorientation. Tachycardia and hypotension are late signs. Fever, cyanosis, and severe hypotension are terminal events.P Rao and colleagues observed that significant premonitory hypotension did not occur before catastrophic hypotension and shock.'? Only approximately half of the patients had a systolic blood pressure less than 100 mm Hg before shock." In the group of patients receiving anticoagulants, the clinical manifestations usually occurred within 10 days of instituting therapy.P Individuals at risk were usually already severely ill. Elderly patients with preexisting heart disease, thromboembolic disease, or coagulopathy had a higher risk. Adrenal hemorrhage was more likely to happen in the postoperative period." Routine laboratory test results that may suggest the diagnosis of adrenal hemorrhage are a sudden drop in hematocrit, hyponatremia, hyperkalemia, leukocytosis, eosinophilia, mild azotemia, mild acidosis, hypercalcemia, and an elevated serum alkaline phosphatase. Eosinophilia in particular should arouse suspicion, because only 3% of acutely ill patients have eosinophilia. Of those, 23% have acute adrenal insufficiency." Hyponatremia, although not always present, is the most consistent finding. The clinical picture of sepsis and acute adrenal insufficiency may be identical. Invasive monitoring may demonstrate severe hypotension «80 mm Hg), hyperdynamic cardiac indexes (cardiac index > 4 Lrnin/m"), low systemic vascular resistance «500 dyne-sec/em' rrr'), and multipleorgan failure in patients who respond poorly to corticotropin stimulation.'? Lawton described a similar finding and underscored the importance of considering adrenal insufficiency.t" CT scans obtained for evaluation of the clinical symptoms reveal the bilateral adrenal hemorrhage. CT scans reveal bilaterally oval or round adrenal masses of high density relative to the adjacent liver (Fig. 72-1). Initially, these masses may appear similar to lymphoma (Fig. 72-2). Resolution of the masses over time supports the diagnosis of adrenal hemorrhage." Adrenal enlargement persists for at

FIGURE 72-1. Computed tomography scan of the adrenal gland demonstrates large, dense globular adrenals (arrows) consistent with bilateral adrenal hemorrhage.

least 3 to 6 months after adrenal hemorrhage.f Unilateral adrenal hemorrhage is a far more common incidental finding on CT scan. One must consider that unilateral involvement has occurred in an already abnormal adrenal. If it does not resolve, an underlying adrenal tumor must be considered. When the diagnosis of adrenal insufficiency is suspected, immediate treatment with 100 mg of hydrocortisone should be given with a baseline cortisol obtained at the same time. Delay for any further testing is inappropriate in this potentially life-threatening situation. Recovery or stability occurs rapidly, frequently within 1 hour. After initial hydrocortisone therapy, when the clinical situation stabilizes, the patient can be switched to dexamethasone, which, as a synthetic steroid, is not detected in the steroid assays and allows further diagnostic testing. Hydration and correction of the hyponatremia are necessary. Large doses of hydrocortisone,

FIGURE 72-2. Computed tomography scan demonstratesmassive enlargement of right adrenal and less enlargement of the left as a result of non-Hodgkin's lymphoma. Note the similarityof shape to the adrenals in Figure 72-1.

Addison's Disease and Acute Adrenal Hemorrhage - -

100 mg intravenously every 6 hours, should be continued during the period of stress and instability. Mineralocorticoids are not usually necessary at this time. If confirmatory studies are desired, the patient should be switched to dexamethasone at least 24 hours before testing. Hydrocortisone, 100 mg, is equivalent to 3 mg of dexamethasone. Steroid therapy should be tapered to standard replacement therapy (hydrocortisone at 12 to 15 mg/m- per day) as rapidly as possible. However, the risk of adrenal insufficiency is greater than the risk of excess steroids in the seriously ill patient. When maintenance levels are achieved, mineralocorticoid (fludrocortisone acetate [FlorinefAcetate], 0.1 mg) should be added to the regimen if impaired salt-retaining ability is evident." Adrenal insufficiency after bilateral adrenal hemorrhage should be considered permanent. 30 Recovery of adrenal function has been reported, and evaluation for return of function at a later date is appropriate.f

Bilateral Adrenal Metastases Adrenal metastases are common. Adrenal gland metastases have been found at autopsy in as many as 42% of lung cancers, 16% of stomach cancers, 58% of breast cancers, 50% of malignant melanomas, and 25% of lymphomas.f Functional adrenal insufficiency occurs late in the course of the disease. It is estimated that more than 90% of functional tissue must be destroyed before the development of adrenal

insufficiency."

Drugs Causing Adrenal Insufficiency A variety of drugs used in the surgical patient may inhibit adrenal function (Table 72-3). Drugs used to inhibit steroidogenesis or exert adrenolytic activity such as aminoglutethimide, metyrapone, and o,p'-DDD (mitotane) require careful monitoring of adrenal function and frequently require steroid replacement. Rifampin and ketoconazole also cause adrenal insufficiency. Phenobarbital accelerates the catabolism of cortisol. The anesthetic agent etomidate may suppress adrenal steroidogenesis for as long as 4 days."

Summary Although adrenal insufficiency is a relatively rare clinical problem, failure to recognize and treat this condition frequently proves rapidly fatal. Suppression of adrenal function as a result of prior steroid use is the most common cause

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of adrenal insufficiency in the surgical patient. A careful history of steroid usage must be obtained from all patients. Adequate steroid coverage for the duration of stress is necessary in these patients as well as in other patients previously taking steroids for the established diagnosis of adrenal insufficiency. More treacherous is the development of acute adrenal insufficiency in the patient receiving anticoagulants, with a coagulopathy, suffering from a thromboembolic disease, receiving steroid-altering drugs, or with malignancy. Any stressed patient is a candidate for adrenal hemorrhage and insufficiency. Any critically ill patient, particularly septic patients, should be suspected of having adrenal insufficiency. Unanticipated hypotension and shock in any person should always raise the question of adrenal insufficiency.

REFERENCES I. Addison T. On the Constitutional and Local Effects of Disease of the Supraadrenal Capsules. London, Samuel Highley, 1855. 2. Welbourn RB. The adrenal glands. In: Welbourn RB (ed), History of Endocrine Surgery. New York, Praeger, 1990, p 147. 3. Harris MJ, Baker RT, McRoberts W, et al. The adrenal response to trauma, operation and cosyntropin stimulation. Surg Gynecol Obstet 1990;179:513. 4. Nerup 1. Addison's disease-Clinical studies. A report of 108 cases. Acta Endocrinol (Copenh) 1974;76:127. 5. Neufeld M, MacLaren NK, Blizzard RM. Two types of autoimmune Addison's disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore) 1981;60:355. 6. Werbel SS, Ober KP. Acute adrenal insufficiency. Endocrinol Metab C1in North Am 1993;22:303. 7. Bakalov VK, Vanderhoof VH, Bundy CA, et al. Adrenal antibodies detect asymptomatic auto-immune adrenal insufficiency in young women with spontaneous premature ovarian failure. Hum Reprod 2002;17:2096. 8. Storr HL, Savage MO, Clark AJ. Advances in the genetic bases of adrenal insufficiency. J Pediatr Endocrinol Metab 2002;15:1323. 9. Hoshino Y, Yamashita N, Nakamura T, et al. Prospective examination of adrenocortical function in advanced AIDS patients. Endocr J 2002; 49:641. 10. Freda PU, Wardlaw SL, Brudney K, et al. Primary adrenal insufficiency in patients with the acquired immunodeficiency syndrome: A report of five cases. J Clin Endocrinol Metab 1994;79: 1540. II. Alevritis EM, Sarubbi FA, Jordan RM, et al. Infectious causes of adrenal insufficiency. South Med J 2003;96:888. 12. White A, Woodmansee DP. Adrenal insufficiency from inhaled corticosteroids. Ann Intern Med 2004;140:497. 13. Graber AL, Ney RL, Nicholson WE, et al. Natural history of pituitaryadrenal recovery following long-term suppression with corticosteroids. J Clin Endocrinol Metab 1965;25: II. 14. Merry WH, Caplan RH, Wickus GC, et al. Postoperative acute adrenal failure caused by transient corticotropin deficiency. Surgery 1994; 116:1095. 15. Schlaghecke R, Kornfly E, Santen RT, et al. The effects of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin releasing hormone. N Engl J Med 1992;326:226. 16. Manglik S, Flores E, Lubarsky L, et al. Glucocorticoid insufficiency in patients who present to the hospital with severe sepsis: A prospective clinical trial. Crit Care Med 2003;31:1668. 17. Jurney TH, Cockrell JL Jr, Lindberg JS, et al. Spectrum of cortisol response to ACTH in ICU patients: Correlation with degree of illness and mortality. Chest 1987;92:292. 18. Barton RN, Stoner HB, Watson SM. Relationship among plasma cortisol, adreno-corticotropin, and severity of injury in recently injured patients. J Trauma 1987;27:384. 19. Rivers EP, Gaspari M, Saad GA, et al. Adrenal insufficiency in high risk surgical ICU patients. Chest 2001;119:889. 20. Harris MJ, Baker RT, McRoberts JW, et al. The adrenal response to trauma, operation and cosyntropin stimulation. Surg Gynecol Obstet 1990;170:513.

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21. Graham G, Unger BP, Coursin DB. Perioperative management of selected endocrine disorders. Int Anesthesiol Clin 2000;38:31. 22. Goolden RH. Diseases of the supra-renal capsules with the absence of bronze skin. Lancet 1857;2:266. 23. Amador E. Adrenal hemorrhage during anticoagulant therapy: A clinical and pathological study of ten cases. Ann Intern Med 1965;63:559. 24. Thorn GW, Goldfein A, Nelson DH. The treatment of adrenal dysfunction. Med Clin North Am 1956;5:1261. 25. Xarli VP, Steele AA, Davis Pl, et aI. Adrenal hemorrhage in the adult. Medicine (Baltimore) 1978;57:211. 26. Siu SCB, Kitzman DW, Sheedy PF, et aI. Adrenal insufficiency from bilateral adrenal hemorrhage. Mayo Clin Proc 1990;65:664. 27. Espinosa G, Santos E, Cervera R, et aI. Adrenal involvement in the antiphospholipid syndrome: Clinical and immunologic characteristics of 86 patients. Medicine (Baltimore) 2003;82:106. 28 Murphy JF, Purdue GF, Hunt JL. Acute adrenal insufficiency in the patient with burns. 1 Burn Care RehabiI1993;14:155. 29. Vaughan GM, Becker RA, Allen lP, et aI. Cortisol and corticotropin in burned patients. 1 Trauma 1982;22:263. 30. Rao RH, Vagnucci AH, Amico lA. Bilateral massive adrenal hemorrhage: Early recognition and treatment. Ann Intern Med 1989;110:227. 31. Alford WC, Meador CK, Mihalevich 1, et aI. Acute adrenal insufficiency following cardiac surgical procedures. 1 Thorac Cardiovasc Surg 1979;78:489. 32. Hardwicke MD, Kisly A. Prophylactic subcutaneous heparin therapy as a cause of bilateral adrenal hemorrhage. Arch Intern Med 1992; 152:845.

33. Findling lW, Korduchi 1M, Lahiri PK, et aI. Bilateral adrenal hemorrhage associated with heparin-induced thrombocytopenia. Wis Med 11987;86:27. 34. Levy EN, Ramsey-Goldman R, Kahl LE. Adrenal insufficiency in two women with anticardiolipin antibodies. Arthritis Rheum 1992;33:1842. 35. Symington T. The adrenal cortex. In: Bloodworth lB Jr (ed), Endocrine Pathology: General and Surgical, 2nd ed. Baltimore, Williams & Wilkins, 1982, p 419. 36. Fox B. Venous infarction of the adrenal glands. 1 PathoI1976;119:65. 37. Wilbur OM Jr, Rich AR. Study of the role of adrenocorticotropic hormone (ACTH) in pathogenesis of tubular degeneration of the adrenals. Bull Johns Hopkins Hosp 1953;93:321. 38. Loughlin KR. Hypereosinophilic syndrome. N Engl 1 Med 2000;342:442. 39. Claussen MS, Landercasper 1, Cogbill TH. Acute adrenal insufficiency presenting as shock after trauma and surgery: Three cases and review of the literature. 1 Trauma 1992;32:94. 40. Lawton lW. Acute adrenal insufficiency: Hemodynamic and echocardiographic characteristics. Wis Med 11992;91:214. 41. Dahlberg Pl, Goellner MH, Pehling GB. Adrenal insufficiency secondary to adrenal hemorrhage. Arch Intern Med 1990;150:905. 42. Grinspoon SK, Biller BMK. Clinical review 62: Laboratory assessment of adrenal insufficiency. 1 Clin Endocrinol Metab 1994;79:923. 43. Feuerstein B, Streeten DHP. Recovery of adrenal function after failure resulting from traumatic bilateral adrenal hemorrhages. Ann Intern Med 1991;115:785. 44. Kung AW, Pun KK, Lam K, et aI. Addisonian crisis as presenting features in malignancies. Cancer 1990;65:177.

Open Operative Approaches to the Adrenal Gland Roderick M. Quiros, MD • Scott M. Wilhelm, MD • Richard A. Prinz, MD

Adrenal diseases demand a thorough understanding of both endocrine physiology and surgical anatomy. Although they are rare entities, advances in computed tomography (CT) and other imaging modalities have increased detection of adrenal abnormalities that require evaluation to determine if surgical intervention is needed. Several open approaches have been used for adrenalectomy. The transperitoneal approach was first performed by Thornton in 1889 to remove a 20-pound adrenal tumor with the left kidney in a 36-year-old woman.' The flank approach described by Mayo in 1927 was used to resect a pheochromocytoma.? The posterior approach was reported by Young in 1936.3 Each of these approaches has advantages and disadvantages. The appropriatechoice can be made only after weighing a number of factors, such as the nature of the disease (including the possibility of malignancy) and the patient's condition, habitus, and anatomy. Other considerations include the presence of unilateral or bilateral disease and the surgeon's familiarity with the various approaches. Recently, laparoscopy has been used for the surgical treatment of adrenal disease. Since the early reports of this technique, laparoscopy has become the method of choice for removing many adrenal lesions.t" Most surgically treatable adrenal masses are unilateral and/or benign, making them ideal for laparoscopic surgery. The operative principles that underpin the laparoscopic approach, such as familiarity with retroperitoneal anatomy, are identical to those for the open approaches. There are, however, several indications when open adrenalectomy is still warranted. 1. An adrenal mass with preoperative suggestion of malignancy as noted by invasion of surrounding structures, associated lymphadenopathy, or venous extension of the tumor into the renal vein or inferior vena cava (lVC) should be resected through an open approach. 2. Evidence of local invasion found during laparoscopic adrenalectomy should prompt conversion to an open procedure to facilitate a definitive en bloc resection. 3. Bleeding that cannot be controlled during a laparoscopic adrenalectomy,most commonly from an adrenal

vein laceration, requires conversion to an open adrenalectomy. This problem happens more frequently during dissection of the right adrenal vein because it is very short and has a posterior lateral insertion into the IVC. This type of bleeding can be extremely difficult to control laparoscopically, and prompt conversion may be lifesaving. 4. Recurrence of a previously resected adrenal mass necessitates an open adrenalectomy. This is most often encountered with malignant pheochromocytomas or adrenocortical carcinomas. Re-excision is best performed by an open approach because of the scarring and loss of tissue planes after the initial operation. 5. With virilizing adrenal tumors, an open approach should be seriously considered, because 70% to 85% of these rare tumors are actually functional adrenocortical carcinomas.P In light of the extremely high rate of malignancy, we would be cautious and not recommend a laparoscopic approach. 6. Finally, tumor size must be considered. Lesions above 6 cm have a greater risk of malignancy. Even for lesions that are certainly benign, size greater than 8 to 10 em may be a relative indication for an open adrenalectomy, especially for surgeons without substantial knowledge of retroperitoneal anatomy and advanced laparoscopic skills." This chapter reviews the surgical anatomy of the adrenal glands and describes the four primary open approachesanterior, thoracoabdominalllateral transthoracic, posterior, and flank-used to expose the adrenal glands.

Surgical Anatomy The adrenal glands are paired structures adjacent to the upper poles of the kidneys in the retroperitoneum. Each gland weighs 3 to 8 g. The right adrenal is triangular and slightly smaller and more superiorly located than the left gland. The left adrenal gland is elongated and flatter than the right gland. Both glands are contained within Gerota's fascia and are directly surrounded by fat and connective tissue.

641

642 - - Adrenal Gland The glands themselves may be differentiated from the surrounding adipose tissue by their golden, yellow-brown color. The right adrenal gland is bordered by the IVC medially, the bare area of the liver anteriorly, and the diaphragm both superiorly and laterally. Division of the right triangular ligament of the liver, which provides lateral fixation of the liver, can facilitate exposure of the right adrenal by allowing retraction of the right hepatic lobe both anteriorly and medially." The left adrenal gland is bordered by the aorta medially, the cardia of the stomach and the pancreatic tail anteriorly, the left renal vein inferiorly, and the diaphragm superiorly and laterally. The arterial supply to the adrenals may be variable, although in most patients it comes from the inferior phrenic artery superiorly, the aorta laterally, and the renal artery inferiorly. The venous supply is more constant but may pose a greater technical problem if not understood. The right adrenal gland is drained by a short adrenal vein that enters the IVC posterolaterally. Because of its location, and because it can be difficult to visualize, it is at risk for injury. The resultant hemorrhage is often difficult to control. The left adrenal gland drains into the left renal vein and is usually fairly prominent.

Preoperative Preparation Patients undergoing adrenal surgery require thorough preparation. Such preparation is especially necessary when one uses an open approach. Venous thromboembolism is not uncommon postoperatively, so intermittent pneumatic compression of the legs or some other method of preventing deep venous thrombosis should be considered. Caution is necessary when using anticoagulants because of the risk of retroperitoneal hemorrhage postoperatively. A modified bowel prep using a clear liquid diet and cathartics should be given the day before surgery so the large intestine will not be filled with feces. The effects of excess hormone secretion should be reversed whenever possible. Patients with aldosteronomas should have potassium deficits corrected. Preoperative use of spironolactone or arniloride may facilitate this. The adverse effects of cortisol excess can be blunted by giving metyrapone, ketoconazole, or mitotane. Vitamin A can counteract some of the poor wound healing that is seen in Cushing's syndrome; 25,000 to 50,000 IV/day can be given orally for the week before the operation and intramuscularly until the patient is able to resume oral intake. Patients with pheochromocytomas should have their hypertension controlled with an a-blocking agent or a calcium channel blocker. Inhibiting the vasoconstrictive effects of catecholarnines allows the patient to replenish their intravascular volume deficit. Betaadrenergic blockade should be used in patients with tachycardia, arrhythmia, or pure epinephrine-secreting tumors but only after a-adrenergic blockade has been achieved. Autologous blood can be obtained if a need for transfusion is anticipated.

incision is the bilateral subcostal or chevron, which affords easy access to all retroperitoneal structures. This incision provides excellent lateral, superior, and inferior exposure of not only both adrenals but also the surrounding solid organs. A unilateral subcostal incision can be used for disease confined to the ipsilateral adrenal, but this incision can substantially limit the extent of exposure of the opposite adrenal gland and the rest of the abdominal cavity. A midline incision can also be used. The advantage of the anterior approach is that it allows access to both adrenal glands through one incision (chevron or midline) with the patient in one position on the operating table (supine). The anterior approach also allows for exploration of the rest of the peritoneal cavity and provides adequate access and exposure for resection of almost any size tumor. Invasion into structures such as the diaphragm and liver or involvement of the IYC may necessitate a more radical approach, which is discussed in the section devoted to the thoracoabdominal approach. For right-sided lesions, dissection begins with mobilization of the hepatic flexure of the colon to allow it to be retracted inferiorly. This also exposes the C loop of the duodenum, which can be "Kocherized" to allow for improved access to the IVC for identification and ligation of the right adrenal vein. Usually, the Kocher maneuver is unnecessary since the right adrenal vein enters the IYC above the duodenum. Next, the lateral attachments of the right lobe of the liver, the triangular ligament, are mobilized to allow superomedial retraction of the liver (Fig. 73-1). With large adrenal tumors, the gland may extend well beyond Morison's pouch into the retrohepatic space. When this is encountered, complete

Anterior Approach The anterior approach is the most commonly used of the open approaches. This operation is carried out through incisions with which general surgeons are familiar. Our preferred

FIGURE 73-1. Retraction of the liver superiorly usually gives adequate exposure of the right adrenal gland. (From Prinz RA. Mobilization of the right lobe of the liver for right adrenalectomy. Am J Surg 1990;159:337.)

Open Operative Approaches to the Adrenal Gland - - 643

FIGURE 73-2. A, If access to the right adrenal is not obtained by retraction of the liver, the right lobe can be mobilized by incising the triangular ligament. B, Rotation of the right lobe of the liver anteromedially provides wide exposure to both the adrenal and the inferior vena cava. (From Prinz RA. Mobilization of the right lobe of the liver for right adrenalectomy. Am J Surg 1990;159:337.)

A mobilization of the right lobe of the liver may be required to ensure a safe en bloc resection of the tumor (Fig. 73-2).10 This is done by incising the falciform ligament over the anterior surface of the liver and the entire right triangular ligament. This exposes the bare area of the liver, which is carefully dissected away from the diaphragm. Care must be taken to identify any inferior phrenic veins and the right hepatic vein, which can be easily injured as the liver is retracted toward the midline and cause rapid and troublesome hemorrhage. With the liver now mobilized, the adrenal gland can be safely dissected, with improved visualization of the junction of the right adrenal vein and the IVC. Care must also be taken not to rotate the liver so far medially as to compress the IVC and decrease venous return, resulting in hypotension. Proper communication between the surgeon and anesthesia team during this maneuver is critical. Once the gland has been exposed and its relationship to the IVC clarified, the right adrenal vein can be sought. It normally drains the adrenal gland from the superomedial aspect and enters the cava in a posterolateral position. Early vein ligation is important with pheochromocytoma to avoid excessive catecholamine release into the systemic circulation with manipulation of the gland during the rest of the dissection. With large tumors of any type, whether functional or nonfunctional, further dissection of the gland along its superior and medial borders (along the IVe) may make identification of the adrenal vein easier. This vein is typically short (4 to 10 mm) and wide (4 to 7 mm) as it enters the IYC. A suture ligature of the adrenal vein as it enters the IVC is wise since avulsion of a simple free tie placed on this critical venous branch can cause life-threatening hemorrhage. Many large tumors extend posterior to the cava, which necessitates its gentle retraction with a vein retractor or sponge stick to complete the dissection. This retraction can easily dislodge a poorly secured ligature on the adrenal vein, again leading to major hemorrhage. The remainder of the dissection consists of ligating any other accessory venous branches and the circumferential arterial arcade supplying the gland. Alternatively, hand-held harmonic scalpel units are now available that can be used to complete the rest of the dissection without the need for any further ligatures similar to a laparoscopic approach. Of note, the harmonic scalpel should not be used to transect the adrenal vein due to its size and thin-walled nature.

B A small extension of tumor thrombus into the IYC discovered during dissection can be managed through the anterior approach. IVC tumor thrombus is considered regional disease and should not preclude resection of the adrenal tumor. II The tumor thrombus is not typically adherent to the endothelium of the IVC and is often extracted without difficulty. Care must be taken to have adequate control of the proximal and distal IVC to avoid tumor embolization during this maneuver. Preoperative imaging of extension of adrenal tumors into the IVC is discussed further in the section dealing with the thoracoabdominal approach. Left-sided lesions can be approached in a similar fashion depending on the surgeon's preference and the extent and location of the tumor with respect to the pancreas and spleen. The first maneuver entails mobilizing the splenic flexure of the colon at least one third of the distance down the left paracolic gutter, along its lateral peritoneal attachments, and then across the gastrocolic ligament to the area of the inferior mesenteric vein. This allows inferior retraction of the transverse and left colon. Opening the gastrocolic ligament exposes the inferior border of the pancreas, which must be inspected for evidence of invasion. If the adrenal gland extends posteriorly to the pancreas, the lateral attachments of the spleen and the splenocolic ligament can be taken down. Along with opening the retroperitoneum along the inferior border of the pancreas, these maneuvers allow superomedial reflection of both the spleen and pancreas for improved exposure of a retropancreatic adrenal tumor. Care must be taken with the spleen to avoid capsular tears from excessive traction. Splenectomy may become necessary if this occurs and patients should understand the possibility of this complication and the potential for postsplenectomy sepsis. The need for proper immunization is clear should this occur. The left adrenal vein typically exits the left adrenal gland at its inferomedial border and drains directly into the left renal vein. It should be sought in this position and again be appropriately ligated. Tumor extension into the left adrenal vein usually extends into the left renal vein toward the IVC. Options for resection include tumor extraction, as mentioned for the right adrenal gland, or ligation of the left renal vein distally near its insertion into the IVC (assuming the tumor does not extend into the cava) and proximally just medial to the entrance of the adrenal vein. The gonadal and lumbar veins, which enter the renal vein closer to the kidney

644 - - Adrenal Gland (proximal to the entrance of the adrenal vein in the renal vein), are not typically involved with tumor thrombus and should provide adequate drainage for the left kidney. However, the inferior phrenic vein, which enters the renal vein medial to the adrenal vein, is typically involved with tumor thrombus and must be sought and ligated. The remainder of the dissection involves the same principles as those discussed for the right adrenal dissection.

ThoracoabdominallLateral Transthoracic Approach The thoracoabdominalllateral transthoracic approach requires a large incision and opening of both the thoracic and peritoneal cavities. Because it provides only unilateral adrenal gland exposure, it is generally reserved for the following highly specific surgical circumstances: 1. For very large tumors with substantial involvement of surrounding structures (especially the pancreas, spleen, and diaphragm on the left side and the liver, IVC, and diaphragm on the right), this approach affords the widest exposure of the adrenal gland and surrounding structures. 2. For local tumor extension into the IVC, a thoracoabdominal approach can provide the best exposure. Determination of vascular involvement by adrenal tumors preoperatively is critical to planning the operative approach. Ultrasound and CT have both been used for this purpose. Both imaging modalities can often depict a filling defect in the IYC suggestive of tumor extension. However, ultrasound can be limited in the obese patient (especially seen in Cushing's syndrome) or if there is a marked amount of bowel gas present. Magnetic resonance imaging (MRI) has emerged as the best test to evaluate caval involvement and can determine the extent of caval tumor extension all the way to the right atrium.P This may change as CT angiography continues to improve. One other imaging modality that is evolving in determining IVC invasion or tumor thrombus within the IVC is intracaval endovascular ultrasonography, (ICEDS). Here, a 20- to 30-MHz (high-frequency) 360-degree rotating ultrasound probe is inserted into the femoral vein and advanced into the IVC. Kikumori and coworkers demonstrated a 100% sensitivity, 100% specificity, and 100% positive predictive value for ICEDS for accurately determining either IVC wall invasion or tumor thrombus in the IVC in nine patients with adrenal tumors.'? CT scan by comparison in this study had 100% sensitivity, 14% specificity, and only a 25% positive predictive value for these same parameters preoperatively. MRI was not used in this study. This endovascular ultrasonographic technology has also been applied to the portal vein to determine invasion by pancreatic cancer. 14 Although studies with ICEDS have contained small numbers of patients and have not been comparatively evaluated with MRI, this evolving tool may help guide some future adrenal resections. However, its invasive nature and need for special technology and user expertise limit its widespread use. The patient is positioned in either a full lateral or a semioblique (45-degree-angle) position with the operative side up and the opposite side in the decubitus position. We favor

the lateral position, but both can afford adequate exposure. The patient is situated on the operating table such that the IOth rib is superior to the center break in the table and the 12th rib is inferior to the break. The table is then jackknifed to open the space between these ribs and expand the chest wall. The kidney rest can be extended for further exposure but should generally be done after the chest is opened to avoid undo tension with possible rib fracture, especially in patients with Cushing's syndrome who may have very brittle bones due to osteopenia or osteoporosis as a consequence of their hypercortisolemia. For a right-sided approach, the incision begins over the right 10th rib near the lateral border of the sacrospinal muscle (Fig. 73-3). It is carried over the rib along the anterior abdominal wall across the costal cartilage and then down onto the anterior abdominal wall toward the midline rectus muscle. The rib and abdominal muscles are exposed and the lOth rib is resected subperiosteally as far back as its angle. The pleural cavity is then entered. The diaphragm is divided well lateral to avoid injury to the phrenic nerve and its branches. The lung can be protected with moistened laparotomy pads and a large Finochietto retractor is used to open the incision. The dissection in the abdomen can be carried retroperitoneally or, if tumor extension necessitates, the peritoneum can be opened. The lung is retracted superiorly along with the liver, and the renal fascia (Gerota's fascia) is incised. The kidney can then be retracted inferiorly to expose the adrenal gland. The gland is then excised as previously mentioned. On the left side, the adrenal gland resides slightly lower than on the right, just as the kidney does. Therefore, the incision should begin over the 11th rib for proper exposure (Fig. 73-4). On this side, it may be possible to avoid entering the pleural cavity by dissecting the parietal pleura off the diaphragm. The rest of the technique is similar to the rightsided approach. On either side, if the peritoneum has been opened, it is reapproximated along with the diaphragm with a single continuous absorbable suture. A tube thoracostomy is placed in the pleural cavity and the muscle layers of the abdominal and chest walls are reapproximated. For tumors with caval extension into the right atrium, this incision can be combined with a median sternotomy for improved exposure. Either venovenous bypass or full circulatory arrest with extracorporeal bypass and oxygenation can be used if necessary. Preoperative suspicion and proper imaging are critical to

10th Rib

FIGURE 73-3. For removal of the right adrenal gland through a thoracoabdominal approach, the incision follows the course of the 12th rib from the lateral border of the sacrospinalis muscle to just beyond the costal margin.

Open Operative Approaches to the Adrenal Gland - -

11th Rib

645

12th Rib

FIGURE 73-4. Adrenalectomy by the lateral or thoracoabdominal

FIGURE 73-5. The patient is placed in the prone position for a posterior adrenalectomy. Thebreak in thetable should be beneath the 12th rib. Padding is placed to allow chest expansion for respiration and to avoid any pressure points.

avoiding intraoperative surprises necessitating unplanned measures as drastic as this.

midline, and its attachment to the 12th rib is severed. The middle lamella of the lumbodorsal fascia underlying the sacrospinalis is incised to expose the quadratus lumborum and the transversalis fascia. Insertion of the index finger under the incised middle layer of the lumbodorsal fascia and sharp division of the posterior subcostal ligament releases the pleura from the 12th rib. The periosteum of the 12th rib is then incised and stripped before the rib is resected. The 12th intercostal nerve should be identified and preserved throughout these steps. Once the 12th rib is removed, the retroperitoneum is entered. Proper retraction is critical at this point. Typically, upward retraction of the 11th rib reveals the reflection of the parietal pleura and the lateral arcuate ligament of the diaphragm. The pleura is retracted upward. If the pleura is inadvertently opened, it can be repaired over suction catheters that are withdrawn as the incision in the pleura is closed under positive-pressure ventilation. Postoperatively, a chest tube is usually not necessary. With retraction of the 11th rib, a layer of perinephric fat becomes visible. Dissection through this layer reveals Gerota's fascia, which is entered to reveal the kidney. This is then manually depressed to expose the adrenal gland. Rotating the superior pole of the kidney caudally and posteriorly facilitates exposure of the adrenal gland, which can be readily identified from the surrounding perinephric fat by its characteristic gold-brown color.The gland can then be dissected out starting superiorly and progressing caudally. Care must be taken in handling the gland, which can be friable. To reduce the risk of breakage, spillage of cells, and autotransplantation, the gland should be handled by its surrounding adventitia. The multiple tributary blood vessels should be clipped, ligated, or cauterized, although the actual arterial branches to the gland are not typically identified during the procedure. Care must be taken to avoid avulsing the adrenal vein, which itself is doubly ligated or stick-tied with a silk suture and divided. The relative shortness of the right adrenal vein predisposes it to an avulsion or tear with resulting major hemorrhage from the IVC. If this occurs, stick sponges should be applied to the cava proximally and distally to the tear, which is subsequently repaired with a 4-0 Prolene in running or interrupted fashion. Once the gland is dissected out from the perinephric fat and all blood vessels have been appropriately divided, the gland may be removed. The perinephric fat should be carefully inspected for bleeding as well as for ectopic adrenal

approach is performed with the patient in the lateral decubitus position. The incision extends along the bed of the 11th rib for a left adrenalectomy.

Posterior Approach The posterior approach provides the most direct route to the adrenal glands. Compared to the other approaches, no major muscles are transected and little dissection is required to expose the adrenal glands. A large transabdominal wound is avoided. It has the purported advantage of decreased postoperative ileus, since the peritoneal cavity is not entered. Patients are able to ambulate and take a normal diet early after operation, and their hospital stay is often shortened. The posterior approach is effective for the exposure and removal of glands up to 5 em in diameter. Glands larger than this may be difficult to resect with this approach. It has the disadvantage of exposing only one individual gland with each incision, so two incisions are necessary if this approach is used for bilateral adrenal pathology. In addition, exposure of the adrenal veins can prove difficult, mandating close attention to prevent venous avulsion and uncontrolled hemorrhage. This approach should not be used for large adrenal masses that mandate wide exposure and early vascular control; if used, it should be reserved for bilateral hyperplasia (Cushing's disease) or small, benign adenomas. Proper positioning is crucial in facilitating this approach. After the patient is intubated, he or she is placed prone, with the break of the table at the level of the 12th rib (Fig. 73-5). Pillows are placed under the patient's abdomen and lower legs, and the operating table is jackknifed to hyperflex the patient's back. Flexion of the knees, along with placement of sequential compression devices on the lower legs, reduces the likelihood of deep venous thrombosis. A hockey stick incision starting approximately 5 ern lateral to the midline of the vertebral column, progressing downward and outward in curvilinear fashion at the level of the 10th rib, over the 12th rib, and extending toward the iliac crest is typically described. We usually use a straight incision that follows the oblique course of the 12th rib and have found that it provides sufficient exposure. Division of subcutaneous fat exposes the latissimus dorsi. This is transected with cautery, revealing the sacrospinalis muscle, which in turn is divided to expose the 12th rib. The sacrospinalis is retracted toward

646 - - Adrenal Gland rests that may be present. When hemostasis is achieved, and all satellite adrenal tissue removed, the wound may be closed in appropriate layers.

Flank Approach Like the posterior approach, the flank approach is extraperitoneal. It is most useful for obese patients in whom exposure offered by other approaches would be compromised. In these patients, the flank approach uses gravity to assist with retraction by allowing the patient's adipose tissue to fall away from the incision. The flank approach is also useful in the presence of a large adrenal mass in a patient with scarring and adhesions in the abdomen from previous surgeries. Finally, the flank approach is used when a laparoscopic procedure is converted to an open approach, as the patient will already be in the lateral decubitus position. Disadvantages of this approach are that exposure is only unilateral, and may be limited, particularly on the right side. It is therefore best suited to patients with small, unilateral adrenal disease. Compared to the posterior approach, however, the larger flank incision allows the surgeon to place both hands into the incision. The patient is placed in the lateral decubitus position after being intubated. The abdominal pannus, if present, should fall forward. The operating table is flexed to maximize the distance between the costal margin and the iliac crest. An intercostal (Turner-Warwick), transcostal, or subcostal incision may be used. 15,16 The incision is made at the tip of the lith or 12th rib (approximately the midaxillary line) and extends along the border of the rib posteriorly. The latissimus dorsi, external and internal obliques, transversus abdominis, and intercostal muscles are divided along the upper margin of the rib. Intercostal or transcostal incisions provide better exposure than the subcostal incision, particularly for glands in a cephalad position. A plane between the diaphragm and retroperitoneum is then developed, facilitating entry into the retroperitoneal space. Alternatively, the flank approach can be accomplished transthoracically prior to entry into the retroperitoneum. The procedure then follows as in the posterior approach.

Summary There are a number of open and laparoscopic approaches for adrenalectomy. Each has its own particular advantages and disadvantages. Surgeons treating adrenal disease should be familiar with each of the approaches and their indications. This will allow them to select the approach that is best suited for dealing with their individual patient's specific problem.

REFERENCES 1. Thornton JK. Abdominal nephrectomy for large sarcoma of the left suprarenal capsule: Recovery. Trans Clin Soc London 1890;23: 150. 2. Mayo CH. Paroxysmal hypertension with tumor of retroperitoneal nerve. JAMA 1927;89:1047. 3. Young HH. A technique for simultaneous exposure and operation on the adrenals. Surgery 1936;63: 179. 4. Gagner M, Lacroix A, Prinz RA, et al. Early experience with laparoscopic approach for adrenalectomy. Surgery 1993;114:1120. 5. Constantino GN, Mukalian GG, Vincent GJ, Kliefoth WL Jr. Laparoscopic adrenalectomy. J Laparoendosc Surg 1993;3:309. 6. Brunt LM, Molmenti EP, Kerble K, et al. Retroperitoneal endoscopic adrenalectomy: An experimental study. Surg Laparosc Endosc 1993;3:300. 7. Imai T, Tobinaga J, Morita-Matsuyama T, et al. Virilizing adrenocortical adenoma: In vitro steroidogenesis, immunohistochemical studies of steroidogenic enzymes, and gene expression of corticotropin receptor. Surgery 1999;125:396. 8. Derksen J, Nagesser SK, Meinders AE, et al. Identification of virilizing adrenal tumors in hirsute women. N Engl J Med 1994;331:968. 9. Jossart GH, Burpee SE, Gagner M. Surgery of the adrenal glands. Endocrinol Metab Clin North Am 2000;29:57. 10. Prinz RA. Mobilization of the right lobe of the liver for adrenalectomy. Am J Surg 1990;159:336. II. Brennan ME Adrenocortical tumors. CUIT Surg Ther 2001;7:620. 12. Wajchenberg BL, Albergaria-Pereira MA, Medonca, et al. Adrenocortical carcinoma: Clinical and laboratory observations. Cancer 2000;88:711. 13. Kikumori T, Imai T, Kaneko T, et al. Intracaval endovascular ultrasonography for large adrenal tumor [Abstract]. Presented at the American Association of Endocrine Surgeons Annual Meeting, 2003. 14. Kaneko T, Nakao A, Inoue S, et al. Intraportal endovascular ultrasonography in the diagnosis of portal vein invasion by pancreaticobiliary carcinoma. Ann Surg 1995;222:711. 15. Riehle RA, Lavengood R. An extrapleural approach with rib removal for the eleventh rib flank incision. Surg Gyncecol Obstet 1985;161:277. 16. Vaughan ED, Phillips H. Modified posterior approach for right adrenalectomy. Surg Gynecol Obstet 1987;165:453.

Laparoscopic Adrenalectomy Michel Gagner, MD, FRCSC, FACS • Ahmad Assalia, MD

Recent advances in minimally invasive techniques have made it possible to perform complex surgical procedures laparoscopically. The adrenal gland lends itself well to laparoscopic removal because of the small size of the gland, the benign nature of most adrenal tumors, and the difficulty in the access to the glands via the open approach. Since its first description in 1992, I laparoscopic adrenalectomy has proved to be the procedure of choice for the surgical treatment of benign adrenal disease. Multiple reports have consistently demonstrated the well-known benefits of minimally invasive surgery, including decreased analgesic requirements, less blood loss, and shorter hospital stay and recovery time, over the conventional approach.r" These results were not surprising considering that the procedure, similar to laparoscopic cholecystectomy, avoids an upper abdominal incision; does not require any reconstruction; benefits from magnification and clarity of view; is commonly performed for benign disease; and mostly involves small, easily extractable specimens. Proper application of minimally invasive surgery to the adrenal gland must take into account expertise in both endocrine and laparoscopic surgery. For successful adrenalectomy, one must have knowledge of the anatomy and disease process, maintain meticulous hemostasis, and delicately handle tissue. With conventional adrenalectomy, the surgical approach varied according to size, location, possibility of multiple tumors, patient habitus, and tumor invasiveness. These conventional approaches include the posterior, flank, thoracoabdominal, and transabdominal approaches. All these open procedures invariably require large incisions and rib resections with the posterior approaches, resulting in significant postoperative morbidity (including chronic pain syndromes because of injury to intercostal and other nerves)." Although these conventional approaches will undoubtedly still be required for certain adrenal pathologies, laparoscopic adrenalectomy, eliminating many of the problems of open surgery, has become the gold standard for resection of most adrenal diseases.

Indications The indications for laparoscopic adrenalectomy are basically the same as those for open adrenalectomy, with few exceptions. These indications include the following: 1. Functional adrenal cortical masses: (1) Cushing's syndrome caused by benign cortisol-producing adenoma; (2) Cushing's disease after failed pituitary surgery or after failure to control or find an ectopic adrenocorticotropic hormone (ACTH)-producing tumor; (3) aldosterone-producing adenoma (Conn's syndrome); and (4) rare virilizing/feminizing secreting tumors 2. Functional medullary adrenal masses: benign adrenal pheochromocytoma 3. Nonfunctional adrenal tumors: (1) benign-looking incidentalomas (nonfunctioning adenomas) confined to the adrenal glands and meeting accepted criteria for adrenalectomy (>4 cm at presentation or growth during follow-up); (2) benign symptomatic lesions; and (3) rare entities such as cyst and myelolipoma Laparoscopic adrenalectomy has been reported for several other conditions'P''? but is not currently considered standard. These include neuroblastoma and congenital adrenal hyperplasia in children and isolated adrenal metastases. General contraindications for laparoscopy include unacceptable cardiopulmonary risk and uncorrectable/untreated coagulopathy. Additional relative contraindications for laparoscopic approach include previous surgery or trauma in the direct vicinity of the adrenal gland, diaphragmatic hernia, and surgeon's inexperience.' Obesity and previous major abdominal surgery are no longer contraindications for laparoscopic adrenalectomy. Currently, in experienced hands, the only specific absolute contraindications to laparoscopic adrenalectomy are known large adrenocortical carcinoma with frank tumor invasion to adjacent structures and metastatic pheochromocytoma to

647

648 - -

Adrenal Gland

periaortic nodes. In these cases, an open procedure is preferred to allow an en bloc resection and node dissection to be performed. Although controversy exists over the maximum acceptable tumor size for laparoscopic adrenalectomy, laparoscopy may not be generally advisable for adrenal tumors larger than 12 to 14 em because of the technical difficulties associated with such surgery and the malignant potential of these large tumors. Nevertheless, the indications and contraindications of laparoscopic adrenalectomy are currently dictated mainly by the experience of the individuallaparoscopic surgeon.

Preoperative Evaluation and Preparation Adequate metabolic work-up and accurate radiologic evaluation of adrenal disease preoperatively are crucial.

Specific Diseases INCIDENTALOMA

To determine whether an incidental adrenal mass in an asymptomatic patient is functional is obligatory, because virtually all functioning tumors should be excised and preoperative preparation is crucial for minimizing perioperative complications. In these instances, the evaluation should include a thorough history and physical examination and biochemical screening for occult aldosteronomas, pheochromocytomas, and glucocorticoid-producing adenomas. Serum potassium, sodium, free testosterone, dehydroepiandrosterone (DHEA), and estradiol are measured. Plasma cortisol and corticotropin measurement in the morning and in the afternoon, or urine cortisone for 24 hours, are performed to rule out Cushing's syndrome. If there is any suspicion that the cortisol level is abnormal, then measurements are repeated after administration of I mg of dexamethasone (occasionally after 8 mg), and a blood sample is obtained at 8 AM the following morning for plasma cortisol. A 24-hour urine sample is collected, and vanillymandelic acid, metanephrine, catecholamine, and creatinine levels are determined. A metaiodobenzylguanidine (MIBG) nuclear scan is useful for identifying adrenal and ectopic pheochromocytomas as well as metastatic pheochromocytoma, whereas an iodocholesterol scan helps identify adrenal tumors in patients with functional adrenocortical adenomas. Patients with Cushing's syndrome usually experience life-threatening hypocortisolism postoperatively unless they receive replacement cortisol and salt after adrenalectomy. Measurements of DHEA are helpful because these levels are low in patients with adrenocortical adenomas and elevated in patients with adrenocortical carcinomas. PRIMARY HYPERALDOSTERONISM

A computed tomography (CT) scan or magnetic resonance imaging (MRI) scan is obtained, as well as plasma aldosterone level, renin activity, and plasma and urinary sodium and potassium levels. Patients with primary hyperaldosteronism have high plasma aldosterone levels and low renin activity. Patients with aldosterone-secreting adenomas have a paradoxical fall in plasma aldosterone levels after standing for 4 hours, whereas in normal individuals and those with

bilateral adrenal hyperplasia, the plasma aldosterone level increases. If a patient has hyperaldosteronism, bilateral adrenal hyperplasia (i.e., idiopathic hyperaldosteronism) must be ruled out before surgery. Iodocholesterol (NP-59) scanning under dexamethasone suppression is useful for localizing adenomas in these patients, although highresolution CT scanning is the most commonly used test. Occasionally, selective adrenal catheterization is helpful for determining the site of the hyperfunctioning tumor. PHEOCHROMOCYTOMA

Patients with pheochromocytoma should undergo adequate blockade with an a. blocker for at least 7 days before adrenalectomy. Treatment with ~ blockers is useful for tachycardia, but a. blockers and hydration should always be started first. The calcium channel blockers are an alternative for patients who cannot tolerate the a. or ~ blockade. CT scanning is the most commonly used imaging modality, although some groups routinely obtain MRI with a T2-weighted signal to rule out bilateral or metastatic disease." MIBG scans are useful in localizing extra-adrenal tumors and metastatic disease. The finding of positive nodes along the periaortic chain or close to the bladder is a contraindication for laparoscopy' CUSHING'S SYNDROME AND DISEASE

Dexamethasone suppression test is performed with samples obtained at 8 AM after the patient has been given I mg of dexamethasone (occasionally after 8 mg) at 11 PM the previous evening. For some patients, documenting the 8 AM and 8 PM cortisol levels is helpful to determine whether the normal diurnal levels are lost. CT or MRI scans of the pituitary and adrenal area as well as iodocholesterol nuclear scanning are also useful in selected patients. For Cushing's disease or pituitary Cushing's syndrome, the work-up is similar. For patients with Cushing's syndrome, petrosal sinus venous sampling after stimulation of corticotropin secretion by corticotropin-releasing factor (CRF) is helpful in determining whether a patient has pituitary or ectopic Cushing's syndrome. Patients with pituitary Cushing's syndrome have a threefold increase in ACTH in the petrosal vein after CRF stimulation. Bilaterallaparoscopic adrenalectomy is useful in patients with failed transsphenoidal surgery for pituitary Cushing's syndrome and in some patients with ectopic Cushing's syndrome when the corticotropin-secreting tumor cannot be removed.

Patient Preparation Symptomatic patients with functional tumors require correction of fluid and metabolic abnormalities (e.g., hypokalemia, metabolic alkalosis, and hyperglycemia) and control of hypertension and other symptoms related to hormone excess. Patients with Cushing's syndrome can be treated with ketokenazole or the antiglucocorticoid agent RU 486. Postoperatively, these patients require glucocorticoid replacement to avoid postoperative adrenal insufficiency. Patients with hyperaldosteronism are treated with spironolactone. Patients with pheochromocytoma are managed with fluids, a. blockade and, if necessary, ~ blockade. Finally, in patients with suspected malignancy, a thorough evaluation for metastatic disease should be undertaken.

Laparoscopic Adrenalectomy - - 649

Operative Technique

Anesthesia

Several laparoscopic approaches to the adrenal glands are recognized, including the following: 1. Transabdominal lateral-with the patient in the lateral decubitus position 2. Transabdominal anterior-with the patient in the supine position

3. Retroperitoneal endoscopic adrenalectomy-lateral or posterior Although the retroperitoneal approach is advocated by some authors.U"? the technique of choice by most surgeons performing laparoscopic adrenalectomy is the transabdominallateral approach, originally described by us in 1992.1,18 Positioning of the patient in the lateral decubitus position uses gravity to help retract the surrounding organs (including the bowel), and effectively exposes the adrenal gland for laparoscopic intervention. As a result, there is reduced dissection and minimal retraction of the vena cava and other adjacent structures. Herein, the details of our originally described transabdominallateral approach are followed by short comments on other techniques. The patient is positioned to maximize the distance between the costal margin and the iliac crest. This is achieved by adjusting the operating table in the jackknife position, with the patient placed in the lateral decubitus position with the operated side up. Sufficient padding is placed over pressure points and the patient is strapped and taped in position. The surgical prep should extend from the nipple to the anterosuperior iliac spine, and from the midline anteriorly to the spine posteriorly. This allows for conversion to an open procedure should this be necessary.

Transabdominal Laparoscopic Left Adrenalectomy Patients are placed in the lateral decubitus position with the left side up. The surgeon and the assistant stand on the side opposite the diseased gland (Fig. 74-1). A flank cushion is positioned under the patient's right side and the table is flexed so that the left side is hyperextended (Fig. 74-2). The left arm is extended and suspended. The surgical area is prepared as previously described. An open technique is used to access the abdominal cavity in the left subcostal area at the level of anterior axillary line, and carbon dioxide, up to 15 mm Hg of pressure, is insufflated. One lO-mm trocar is then inserted into this site, and a 30-degree, lO-mm laparoscope is introduced, through which the abdominal cavity is explored. If the inspection is satisfactory, two more 5- or lO-mm trocars are inserted under direct vision into the flank, depending on available instrumentation: one under the 11th rib and one slightly more anteriorly and medially to the first trocar. Occasionally, a fourth trocar is needed for retraction and is inserted at the costovertebral junction dorsally (see Fig. 74-2). All trocars should be at least 5 em and, more optimally, 8 to 10 em apart. The laparoscope is then inserted in the most anterior trocar and the surgeon works with a twohand technique through the other two trocars. Working with the laparoscopic scissors with cautery or the ultrasonic scalpel in the right hand and a curved dissector in the left hand, the surgeon mobilizes the splenic flexure medially to

surgeong

Instrument table

FIGURE 74-1. Laparoscopic left adrenalectomy: operating room

layout.

move the colon from the inferior pole of the adrenal and expose the lienorenal ligament (Fig. 74-3). This mobilization allows instruments to be inserted more easily and helps prevent inadvertent trauma to the colon or spleen during instrument insertion. Then, the lienorenal ligament is incised inferosuperiorly approximately 1 cm from the spleen (Fig. 74-4). The dissection is carried up to the diaphragm and stopped when the short gastric vessels are encountered posteriorly behind the stomach. This maneuver allows the spleen to fall medially, thus exposing the retroperitoneal space (Fig. 74-5). The lateral edge and anterior portion of the adrenal gland become visible in the perinephric fat superiorly and medially. If necessary, a fourth 5-mm trocar is inserted dorsally at the costovertebral angle to gently retract largesized spleens and open the space or to push the left kidney or the surrounding fat downward to better expose the inferior pole and lateral edge of the adrenal gland. This trocar should always be inserted after the previous three because the splenorenalligament must be opened first, so the trocar can pass over the lateral and superior borders of the kidney. This port, however, is usually not necessary in patients with a normal-sized spleen. Laparoscopic ultrasound may be used as an adjunct to identify the adrenal gland, the mass within the gland, and the adrenal vein.' The dissection ofthe adrenal gland can be easy or difficult, depending on the type of perinephric fat that is present. 1\\'0 types of fat are encountered: (1) the soft, nonadherent, areolar fat that is easy to dissect; and (2) dense, adherent fat that contains multiple small

650 - - Adrenal Gland

Table flex point

Bean bag

Scope--4e Grasper Endoshear

Retractor ..--.."....-.>,---lIiac crest

FIGURE 74-2. Upper, Positioning of the patient for left laparoscopic adrenalectomy. Lower, Trocar sites for left laparoscopic adrenalectomy.

veins originating from the retroperitoneum. To avoid fracture of the adrenal capsule, it is helpful to leave a little periadrenal fat on the adrenal, so that this tissue, rather than the adrenal itself, is retracted. Grasping the perinephric fat, the surgeon dissects the lateral and anterior part of the adrenal gland. Hook electrocautery or ultrasonic scalpel is a useful

FIGURE 74-3. Dissection of the splenic flexure.

FIGURE 74-4. Dissection of the lienorenal ligament and splenic mobilization.

instrument for this phase of dissection. Once the lateral portion of the adrenal gland has been exposed, the patient is moved to the Fowler's position to permit further downward migration of the bowel loops and the spleen. Any saline irrigation, bleeding, or oozing flows downward away from the area of the dissection. The dissection can be continued either inferiorly, so that the left adrenal vein can be clipped early in the dissection or start superiorly and go down medially to clip the adrenal vein last. The dissection depends on the exposure gained after the spleen has been mobilized, the type of disease, and the size of the adrenal mass. In large adrenals (>5 em), the left adrenal vein may be difficult to visualize. In such cases, dissecting the lateral and superior adrenal poles first allows better mobilization and makes clipping the adrenal vein easier later during the dissection. In smaller adrenals «5 em), it is feasible and easy to dissect and clip the adrenal vein. Most left adrenal veins are about 10 mm in diameter and can be clipped with medium to large

Laparoscopic Adrenalectomy - - 651

FIGURE 74-6. Control of the left adrenal vein.

titanium clips placed with a clip applier. With a right-angled dissector, the adrenal vein is dissected from its insertion into the left adrenal gland. It is not necessary to identify and dissect the origin of the vein from the left renal vein. The adrenal vein is clipped about 1 cm from the renal vein: two clips are placed proximally to the gland and two are positioned distally (Fig. 74-6). The vein is then divided with laparoscopic straight scissors. At this point, adrenal mobilization becomes easy. It is grasped on the perinephric fat with the left-hand grasper and pushed upward and laterally to permit dissection of the medial and superior portions. This dissection is accomplished with hook cautery or ultrasonic scalpel. The inferior phrenic arterial branches often require ligation as they approach the superior pole of the left adrenal gland. Once the adrenal gland is free, hemostasis is verified by repeated irrigation and aspiration. The gland is then extracted in total after it is placed in an appropriately sized impermeable nylon bag. The bag is removed through the most anterior trocar by spreading the abdominal wall musculature using a Kelly clamp. The incision may have to be enlarged to remove large specimens (>4 to 5 em) without rupturing the bag. Drainage is seldom necessary unless pancreatic injury is suspected. All fascial incisions are closed with 2-0 absorbable sutures, and skin incisions are closed with 4-0 subcuticular absorbable sutures.

which seldom needs to be mobilized. The third trocar is then inserted into the most anterior position of the subcostal area between the epigastrium and the anterior axillary line. This most medial trocar should be lateral to the edge of the ipsilateral rectus muscle. The last trocar is introduced at the costovertebral subcostal angle after the peritoneal reflection of the lateral edge of the right kidney has been dissected to avoid injury to the right kidney. Four trocars are necessary because the right lobe of the liver must be retracted to expose the most medial aspect of the right adrenal gland (Fig. 74-7). It is, therefore, crucial that the liver retractor be inserted under direct vision, through the most anterior port, so that the right hepatic lobe can be lifted and pushed anteromedially. The laparoscope is removed from the first placed trocar and inserted in the second one, and the surgeon works with the two most lateral trocars. The camera can also be positioned dorsally, and the surgeon works with the two trocars in the middle to obtain another view of the dissection field. This is especially useful for dissecting the superior aspect of the adrenal gland. The liver often must be mobilized to obtain the best exposure of the junction between the adrenal gland and the inferior vena cava (Fig. 74-8). The right lateral hepatic attachments and the triangular ligament are therefore dissected from the diaphragm using laparoscopic scissors or an ultrasonic scalpel. This dissection permits more effective retraction to push the liver medially using a fan or some other atraumatic retractor. This is the key for providing adequate exposure of the right adrenal vein and its entry into the vena cava. We prefer to create a right-angled plane between the anterior aspect of the right kidney and lateral portion of the liver. This plane provides enough space to work and adequate exposure in case of bleeding. Laparoscopic ultrasound may

Transabdominal Laparoscopic Right Adrenalectomy Patients are positioned in the lateral decubitus position with their right side up. Pneumoperitoneum is established in the same way as for left adrenalectomy. An open technique is used to access the abdominal cavity approximately 2 em below and parallel to the costal margin. A lO-mm trocar is inserted at this site for the 3D-degree angled laparoscope. Inspection of the abdominal cavity is carried out. Under direct vision, three additional lO-mm trocars are inserted 2 em below and parallel to the costal margin. The second trocar is positioned in the right flank, inferior and posterior to the tip of the 11th rib just above the hepatic flexure of the colon,

\

FIGURE 74-7. Trocar sites for laparoscopic right adrenalectomy.

652 - -

Adrenal Gland

---:--+"""T'iiJ;-\!-- Stomach

Inferior phrenic vein Adrenal vein

Hepatic flexure

~~~~e!~~~-Adrenal

artery

Kidney--+-_ FIGURE 74-8.

be of assistance in identifying the anatomy. The right gland is dissected next. If the mass is smaller than 4 em in diameter, gaining access to the right adrenal vein initially is possible, which permits easier dissection of the rest of the adrenal gland. The inferolateral edge is mobilized, and dissection is continued medially and upward, along the lateral edge of the vena cava. The adrenal vein should be seen at this stage. This vein is often short and sometimes broad. Usually, the vein can be clipped with medium to large titanium clips, and at least two should be applied at the vena cava side (see Fig. 74-8). If there is not enough space for clips, then a vascular cartridge of a 30- or 35-mm laparoscopic stapler is used for secure division of the right adrenal vein. Smaller veins may be encountered superiorly; these should be clipped or cauterized to prevent bleeding. The superior pole of the gland is dissected next, and small branches from the inferior phrenic vessels can be clipped or cauterized with a hook cautery or ultrasonic scalpel. Again, a Fowler's position permits all fluids to migrate downward. The lateral border of the gland is then dissected from the perinephric fat using the same instruments. Meticulous dissection close to the gland prevents tearing of the lateral branches of the vena cava and other vessels from the retroperitoneum. If a large mass is encountered, we prefer to dissect laterally and

superiorly first and then move down along the vena cava to reach the adrenal vein. Once the mass has been dissected free, it is placed in impermeable nylon bag and removed through the most anterior trocar site. All wounds are closed as described for the left side. The fascia of the fourth (dorsal) trocar site is not closed because of the depth of this wound.

Retroperitoneal Endoscopic Adrenalectomy The retroperitoneal endoscopic approach has been advocated by a few laparoscopic surgeons.I'"!? The main advantage of this approach is that adrenal resection can be performed in a patient with intra-abdominal adhesions due to previous surgery. In our experience, it is rare that conversion to open procedure is required due to adhesions.' Another theoretical benefit of this approach is decreased physiologic impact on the cardiovascular and respiratory systems. However, the initial concerns over hypercarbia and other hypothetical detrimental effects were not supported in a study comparing both approaches." The main drawback is the quite small operative field, usually restricting this approach to small glands of less than 5 to 6 em in diameter. This limited field and exposure can also be a major disadvantage in case of

Laparoscopic Adrenalectomy - -

vascular injury, making control and repair more difficult than in the transabdominal approach. Other disadvantages include the lack of anatomic landmarks and the inability to explore the abdominal cavity, particularly the liver. The retroperitoneal approach can be performed in two ways. Lateral Decubitus Approach. The positioning of the patient is the same as for the lateral transabdominal approach. Creation of the retroperitoneal space is commonly done with disposable dissection balloons, and the peritoneal sac should be mobilized to prevent perforation of the peritoneum and injury to viscera. The trocars are inserted after creation of the space and are close to the costal margin, Prone Jackknife Approach. This approach is essentially the same as the former one, except for the positioning of the patient. The patient is placed in the prone position, with moderately flexed hips and the arms extended cephalad. The advantage of this technique is that it is not necessary to change the patient position for bilateral exploration, theoretically allowing a shorter operative time. However, rapid conversion to open surgery for bleeding is difficult in this position.

Transabdominal Anterior Laparoscopic Adrenalectomy The transabdominal anterior laparoscopic approach can be a lengthy procedure owing to the difficult dissection of the splenic flexure, spleen, and the pancreatic tail on the left side and the duodenum on the right. In addition, on the right side, the adrenal vein, found posteriorly to the vena cava, is difficult to dissect and control. Although in bilateral adrenalectomy it is not necessary to change the position of the patient, the average operating time is similar to the lateral transabdominal approach. Because of its drawbacks, most surgeons have abandoned this approach.

Bilateral Laparoscopic Adrenalectomy The indications for bilateral laparoscopic adrenalectomy include the following": 1. Cushing's disease refractory to transsphenoidal pituitary resection and/or irradiation 2. Cushing's syndrome due to ACTH-independent macronodular or micronodular adrenal hyperplasia 3. Ectopic ACTH syndrome, when the primary tumor cannot be resected or medical treatment has failed 4, Conn's syndrome caused by bilateral adrenal adenomas 5. Bilateral pheochromocytoma Other less prevalent relative and possible indications include (1) unilateral pheochromocytoma in multiple endocrine neoplasia (MEN) type 2A, due to the fact that in 50% of cases a metachronous lesion develop in the contralateral side within lO years of resection of the affected side/"; (2) idiopathic hyperaldosteronism caused by bilateral symmetrical adrenal hyperplasia refractory to medical treatment; and (3) congenital bilateral adrenal hyperplasia, which is difficult to manage medically.'? There are several possible surgical approaches for bilateral laparoscopic adrenalectomy. Transabdominal Lateral Approach. The transabdominallateral approach is the preferred approach in our opinion.

653

The patient is placed in the lateral decubitus position; usually the left side is operated first because it is easier. After all trocar sites are closed, the patient is repositioned and redraped to expose the right side. A 15- to 20-minute turnover time is necessary, not significantly adding to the operative time.' We prefer this bilateral approach, because gravity aids the dissection when the patient is in the lateral decubitus position and it offers a wide operative field and better control of blood vessels. Furthermore, it may be safer than the retroperitoneal approach for the right adrenal, where a better control of a possible major vascular injury (i.e., vena cava) is needed. We have successfully performed bilateral laparoscopic adrenalectomy within a reasonable period using a bilateral lateral technique.' Using this approach, Chapuis and associates," with the largest published series on bilaterallaparoscopic adrenalectomy in 24 patients with Cushing's syndrome, reported no major postoperative complications, The operative lengths have ranged from 243 to 386 minutes for the reported bilateral procedures using this approach. Retroperitoneal Approach. This can be accomplished using the lateral or the posterior methods described earlier. The few series with data on bilaterallaparoscopic lateral and posterior retroperitoneal approaches have not shown greater hypercarbia than with the lateral transabdominal approach. 22-24 Anterior Approach. Despite its theoretical advantage in bilateral adrenalectomy, the drawbacks regarding difficulty in exposure and dissection have led most surgeons to abandon this approach. No randomized, prospective studies have been conducted to compare laparoscopic bilateral adrenalectomy with open bilateral surgery. However, the available literature on bilateral laparoscopic adrenalectomy is encouraging, with low morbidity and mortality rates. 1,3,2 I,22.25,26 In the setting of Cushing's syndrome, the morbidity and mortality rates of the laparoscopic approach are noticeably lower than for open surgery. 1,3,21,22 The typical operative length for bilateral laparoscopic adrenalectomy, including all approaches, is approximately 300 minutes. 19 There have been some reports of operative times longer than 300 minutes with cases of hypercarbia requiring hyperventilation but without significant sequelae.F" Fernandez-Cruz and colleagues27,28 have recommended helium pneumoperitoneum for the bilateral laparotomy procedure to prevent carbon dioxide retention and acidosis. The use of helium is strongly recommended by this group, especially in patients with pheochromocytoma with previous cardiovascular or respiratory disorders.P

Laparoscopic Partial Adrenalectomy Possible indications for adrenal-sparing surgery include bilateral pheochromocytoma and well-circumscribed bilateral cortisol or aldosterone-producing adenomas. The purpose is to avoid life-long cortisol replacement therapy." The operative technique involves basically the same initial steps as for total adrenalectomy. After exposing the adrenal glands, dissection is first performed at the inferior borders and then carried upward along the lateral aspect using a hook cautery or ultrasonic scalpel and a gentle grasping forceps. Ultrasound of the gland is then performed using a flexible 7.5-MHz, lO-mm diameter probe to demonstrate the location

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of the adrenal vein and the arterial supply and to confirm the location and borders of the adrenal lesion. At this stage, the adrenal lesion can be easily dissected free and elevated. While concomitantly displaying the margins of the tumor with the ultrasound, the harmonic shears are used to bloodlessly transect the adrenal gland away from the lesion. The excised specimen is then placed in a bag, retrieved, and sent for immediate histopathologic examination to confirm histology and assess the margins. At least a 5-mm rim of normal adrenal tissue is preferred.

Needlescopic Adrenalectomy The availability of 2-mm instrumentation and camera technology has triggered the emergence of needlescopic surgery. The rationale behind this technique is to further minimize the abdominal wall trauma, and hence speed the convalescence and improve cosmesis. The positioning of the patient and the number of trocars are similar to the traditional laparoscopic adrenalectomy. A 10 to l2-mm trocar is inserted into the superior aspect of the umbilicus to accommodate the 10-mm angled scope, under which most of the procedure is conducted. It also enables the use of larger instruments should they be required (e.g., vascular endostapler) and the retrieval of the specimen. During these steps, the procedure is monitored through the 2-mm needlescope. In the left side, two additional trocars of 2- and 5-mm are used, and in the right side, a fourth 2-mm trocar is used for liver retraction. Placement of the 2-mm ports does not require skin incisions. These ports can be readily inserted through a needle-like puncture. Thus, at the end of the procedure, these miniature puncture sites require no skin closure, except for Steristrips. The 5-mm port is used by the surgeon's dominant hand to accommodate larger instruments such as scissors, electrocautery, suction-irrigation devices, and clip appliers. Dissection is carried out using 2-mm graspers, scissors, and hook electrocautery, and vascular control is achieved with electrocautery (unipolar or bipolar) and a 5-mm clip applier.

Postoperative Care Oral fluids are started on the day of surgery. Nasogastric tubes are unnecessary for most patients. If a Jackson-Pratt drain has been inserted at surgery, it is removed the next morning. Oral analgesics are provided to help patients tolerate the postoperative pain. However, during the first 12 hours, some patients require parenteral analgesia. The postoperative course is similar to that for laparoscopic cholecystectomy, except that some endocrine disorders necessitate hormonal support and additional clinical laboratory data. Unexplained hypotension, fever, and confusion may be due to acute adrenocortical insufficiency. These patients should have blood drawn to determine cortisol levels and be immediately treated with 100 mg of hydrocortisone intravenously. Most patients are ambulatory by the evening of the procedure, and most are allowed to leave by the third postoperative day. However, discharge may be delayed in patients who require substantial hormonal support or adjustments of antihypertensive medications.

Outcome Since its advent in 1992, laparoscopic adrenalectomy has gained worldwide acceptance, with a rapidly increasing numbers of reports being published in recent years. In a search of the literature, we were able to retrieve more than 500 articles dealing with laparoscopic adrenalectomy. Table 74-1 summarizes the reported results of selected large series of laparoscopic adrenalectomies performed with different laparoscopic techniques. Although no prospective, randomized series exist, numerous studies have compared laparoscopic with open adrenalectomy (either retrospectively or nonrandomized prospectively), documenting the safety, decreased analgesic postoperative requirements, enhanced recovery, shorter hospital stay, and cost-effectiveness of the laparoscopic approach. 4-8,24.30-39 No differences in patient population, indications for surgery, or mean size of lesions were noticed. Our own experience, presented here, with 100 procedures in 88 patients.' further supports the superiority of this procedure. Table 74-2 lists the indications and pathology for our procedures. The overall mean age was 46 years (range, 17 to 84 years), and the ratio of female to male was slightly higher than 2: 1, Fifty-two of the adrenalectomies were performed in the left, and 10 were performed bilaterally, The mean operating time was 132 minutes (range, 80 to 360 minutes). In our initial experience, a right-sided procedure required an average of 138 minutes compared with 102 minutes for a left-sided procedure. However, review of the last 30 cases showed the time required for both sides is essentially equal. The time required for bilateral adrenalectomy averaged approximately 45 minutes longer than the combined averages for the unilateral procedure alone. The indications for bilateral adrenalectomy are listed in Table 74-3. The average length of stay was 2.4 days (range, 1 to 6 days), and the average size of the lesions was 4.95 cm (range, 0,7 to 12 em), The estimated intraoperative blood loss was approximately 70 ml., and the mean number of postoperative narcotic injections was 5.5.

Complications Conversion to open surgery was necessary in three patients (3%). These conversions occurred in our first attempt at laparoscopic adrenalectomy in a patient with a l5-cm right adrenal angiomyolipoma, in a second patient with a locally invasive retroperitoneal sarcoma, and in a third patient with adrenal adenocarcinoma invading into the inferior vena cava, More than half of our patient population (55%) had undergone previous abdominal surgery. We have not viewed this as a contraindication for laparoscopic approach, and no conversions occurred because of adhesions. We performed one procedure 6 weeks after a laparotomy that failed to find the adenoma. In addition, 20 of the 88 patients underwent other associated laparoscopic procedures at the time of their adrenalectomy. These are listed in Table 74-4. Of the 100 procedures, 12% had postoperative complications, which are listed in Table 74-5. Reoperation within 30 days of surgery was required on two occasions (2%) for evacuation of a retroperitoneal

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hematoma in a patient who had been anticoagulated for mitral valve prosthesis and for postoperative acute cholecystitis in the second case. These procedures were accomplished laparoscopically with uneventful recovery thereafter. There have been no wound complications, and there was no mortality. Additional reported complications may result from injury to structures in the area of dissection, adjacent to the adrenals, including the kidney, colon, tail of the pancreas, and the stomach on the left side. On the right side, the liver and the duodenum are at risk.

Because both adrenals are located in close proximity to major blood vessels (the hilum of kidneys and the vena cava), massive bleeding is a potentially disastrous complication. Furthermore, dissection high in the abdomen could result in diaphragmatic injury, leading to potential tension pneumothorax. A multi-institutional study by Terachi and associates from Japan evaluated 370 patients who underwent laparoscopic adrenalectomy" There was no mortality. Overall complications developed in 57 patients (15%), intraoperative in 33 patients (9%) and postoperative in 24 patients (6%). Conversion to open surgery was necessary in 13 cases (3.5%). The 33 intraoperative complications involved vascular injury in 22 patients (5.9%) and visceral injury in 11 patients (3%). The 22 vascular injuries involved injuries to the vena cava in 2 patients, renal vein in 2 patients, adrenal vein in 4 patients, other adrenal vessels in 11 patients, and other vessels in an additional 3 patients. The 11 visceral injuries included the liver in 4 patients, spleen in 3,

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pancreas in 2, gallbladder in 1, and adrenal gland in 1. The 24 postoperative complications involved bleeding in 6 patients, wound infection in 4, atelectasis in 3, ileus in 2, pneumothorax in 1, and other in 8. Most complications were minor and were treated laparoscopically. Henry and coworkers reported the complications of laparoscopic adrenalectomy in 169 consecutive procedures." There was no mortality. Twelve patients (7.5%) had significant complications: three peritoneal hematomas requiring (in two cases) laparotomy, and (in one case) transfusion; one parietal hematoma; three intraoperative bleeding episodes without need for transfusion; one partial infarction of the spleen; one pneumothorax; one tumor disruption; and two venous thromboses. Another large multi-institutional study from France'? reported a similar complication rate of7.7% occurring in 10 patients out of 130 cases of laparoscopic adrenalectomy. Neither this study, nor others,40,43-45 has found significant differences between transperitoneal and retroperitoneal approaches, except for the risk of the intraperitoneal visceral injury. PHEOCHROMOCYTOMA

Pheochromocytoma constituted 25% of the pathologies in our series. These tumors were larger than in patients with other diseases (6.3 vs. 3.9 em [P < 0.05]). In addition, operative time was longer (2.5 vs. 1.8 hours [P < 0.05]). During the removal of these tumors, hypertension occurred in 56% of patients and hypotension in 52%. Moreover, 7 of 12 (",,60%) of our postoperative complications were observed in this subset. Associated MEN 2A syndrome was identified in six patients and MEN 2B was found in two patients. Several studies have addressed the issue of hemodynamic changes

during laparoscopic adrenalectomy for pheochromocytoma compared to open surgery.46-48 The laparoscopic approach has resulted in less" or comparable'<" hemodynamic changes compared to the traditional open surgery, although patients who underwent laparoscopy had a more rapid postoperative recovery. The retroperitoneal approach seems to offer no advantage over the intraperitoneal approach," and carbon dioxide pneumoperitoneum is well tolerated in this subset of patients.f In a literature review of large series of more than 300 laparoscopic adrenalectomies exclusively for pheochromocytoma, no mortality has been reported to date. 28,48.50-61 These cases included familial multiple endocrine hyperplasia syndromes, bilateral pheochromocytoma, and extraadrenal pheochromocytoma. Both transperitoneal and extraperitoneal approaches were used. Although earlier experience was associated with more blood loss, longer operative time, and more complication rate compared to other pathologies.v-" the more recent large series demonstrated no significant difference. The occurrence of hypertension postoperatively is rare, and hypertension was cured in almost all patients. OTHER HORMONE-SECRETING TUMORS

With regard to the functional outcome in other hormonally active tumors, during our follow-up period (range, 1 to 44 months), patients appear to have responded well to laparoscopic adrenalectomy. Two were found to have renovascular hypertension, and none had hormonal recurrence. The renal arteriograms showed no stenosis and, in addition, excluded the possibility of superior arteriolar renal occlusions by metal clips. One patient operated on for Cushing's disease who had a partial response to ACTH stimulation, however, still had serum cortisone levels below the normal range by the end of the follow-up period. Other authors52.62-65 have uniformly reported excellent results comparable with those of open surgery. The Mayo Clinic group reported bilateral laparoscopic adrenalectomy in 19 patients with ACTH-dependent Cushing's syndrome in whom the ACTHsecreting neoplasm could not be removed.f All patients experienced resolution of the signs and symptoms of Cushing's syndrome as well as weight loss, improved glucose tolerance, and improved control of blood pressure. No residual cortisone secretion was detected. Similar success rates were reported by others in more than 100 cases with Cushing's disease and syndrome.21.22.25 Rossi and associates'" reported the effectiveness of laparoscopic adrenalectomy in 30 patients with primary hyperaldosteronism. Twenty-nine of 30 patients (95%) were rendered normokalemic, and persisting hypertension was present in 10 of 30 patients (33%). In these patients, the hypertension was easily controlled medically. Duration of the hypertension before surgery was a significant risk factor for persistent hypertension. Several other articles specifically focusing on laparoscopic adrenalectomy for aldosteronoma revealed that hypertension was cured or significantly improved in greater than 90% of patients.64.66.67 In a recent study by Brunt and colleagues'? involving 72 patients with hormonally active adrenal tumors, laparoscopic adrenalectomy resulted in an excellent clinical outcome. Resolution of clinical and biochemical signs was accomplished in 34 of 34 patients with pheochromocytoma, 25 of 26 patients with

Laparoscopic Adrenalectomy - -

aldosteronomas, 5 of 5 patients with cortisol-producing adenomas, and 3 of 3 patients with ACTH-dependent Cushing's syndrome. Two patients with MEN 2 had contralateral pheochromocytomas removed 4 and 5 years after the initial surgery. Surprisingly, persistent hypertension necessitating medications was present in 72% of patients with aldosteronomas, although 92% of these patients had significantly improved blood pressure control after surgery. Recurrent hypokalemia developed in 1 patient (4%) with a cortical nodule in the contralateral adrenal. The authors concluded'? that the clinical and biochemical cure rates are comparable with those of open adrenalectomy during long-term follow-up.

Outcome for Malignancy Concerning the outcome of laparoscopic adrenalectomy in the setting of malignancy, 8 of our patients had malignant diseases. Six had primary adrenal cancer (3 pheochromocytomas and 3 nonfunctioning tumors that showed microscopic features of carcinoma), and 2 had metastatic adrenal secondaries. None had evidence of local recurrence during follow-up (range, 1 to 44 months). Laparoscopic adrenalectomy for solitary adrenal metastasis or cancer has also been investigated at few centers, and to date, very few references are available in the literature. The experience from the Cleveland Clinic in 11 patients was reported by Heniford and coworkers.f All of the tumors except one were due to metastatic cancer. The metastatic sources included renal cell cancer, lung cancer, colon cancer, and melanoma. The mean size of the tumors was 5.9 em (range, 1.9 to 12 em), One patient required conversion to open surgery due to local invasion of the tumor into the vena cava. At a mean followup of 8.3 months, there were no port site or local recurrences. One patient developed a new hepatic nodule, 10 of the 11 patients were alive by the time of the report, and I died of extensive brain metastasis from melanoma. Valeri and associates'? addressed the same issue of adrenal masses in 8 patients with primary lung cancer (7 patients) and renal cancer (1 patient). The adrenal lesions appeared during follow-up evaluation or at the time of diagnosis of the primary malignancy. All patients underwent laparoscopic adrenalectomy with complete removal of the lesions. Histology confirmed the metastatic origin in 6 patients, and 2 lesions proved to be nonfunctioning adenomas. Three patients died later of brain metastasis, accounting for a 3-year survival rate of 63%. The authors claimed that laparoscopic adrenalectomy allows for a much more aggressive approach to adrenal masses demonstrated at follow-up evaluation in patients with primary lung or kidney cancer with no evidence of masses at other locations. Two other reports on laparoscopic adrenalectomy for large (>6 em) and potentially malignant tumors were recently published and documented favorable outcome. 69 •70 In the study by Henry and associates.s? out of 6 patients with adrenocortical carcinoma, only 1 patient developed liver metastasis and died 6 months after surgery. The other 5 patients were disease free during a follow-up period ranging from 8 to 83 months. The largest series with the longest follow-up to date was recently published by Kebebew and colleagues." It included 23 patients who had a laparoscopic approach for suspected and unsuspected malignant adrenal tumors. Six of the

657

patients had primary adrenal cancers, 13 had adrenal metastasis, 2 had lymphomas, and 2 cases had no evidence of cancer. The tumor resection margin was negative in all adrenalectomies. There were three locoregional recurrences in the 6 patients with primary adrenal cancer and no port site recurrences. There were four distant recurrences in 13 patients with metastatic adrenal tumors. The disease-free survival was 65% at a mean follow-up period of 3.3 years (range, 1 to 7 years). These results were comparable with the known results for conventional surgery.P In all these studies, no major complications occurred. Conversions were required only in patients with intraoperative evidence of tumor invasion. The laparoscopic removal achieved tumor-free resection margins in all patients, and no port site metastasis was reported.

Laparoscopic Ultrasound We used laparoscopic ultrasonography in 15 selected cases. In 1 patient it showed the location of a 0.7-cm aldosteronoma in an adrenal gland after open surgery failed to find the organ. In 2 patients, no adenoma was found, necessitating only biopsy and closure rather than adrenalectomy. In 2 patients with large masses (10 and 12 em), no extra-adrenal or lymph node involvement was found. The masses were completely removed laparoscopically and proved to be histologically benign. In I patient, vascular invasion of an adrenal adenocarcinoma was found, leading to conversion to successful open resection. In I patient with metastatic cancer, the invasion of periadrenal fat was demonstrated, and the lesion was removed with negative margins. In an additional 2 cases, it helped identify the right adrenal vein, which facilitated dissection and control. Finally, bilateral hyperplasia was found in another case, requiring bilateral adrenalectomy. Other groups reported similar results using laparoscopic ultrasonography in adrenalectomy.P'?" Brunt and associates?" used it in 27 patients and concluded that laparoscopic ultrasound provided useful information to the surgeon in 11 of 28 procedures (39%) by (1) localizing the adrenal gland and tumor and/or guiding the dissection, (2) demonstrating that tumors larger than 4 em were confined to the gland, and (3) investigating suspected pathology in other organs. Mean time for ultrasound was 10.9 minutes, and calculated hospital charges were $602. There were no intraoperative complications. Siperstein and colleagues75 found that it helped in identifying small tumors in obese patients operated on through the posterior approach. Especially in patients with nodular hyperplasia, laparoscopic ultrasound enabled the complete excision of all lesions by demonstrating the absence or presence of residual tumor tissue in the adrenal bed after resection." Thus, the information obtained from ultrasonography in many instances can affect the progression of the operation. It is a simple technique that can be easily mastered.

Discussion More than a decade after the advent of laparoscopic adrenalectomy, the worldwide accumulated experience indicates that the procedure is safe and successful, and it is now considered an

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established and preferred treatment for most endocrine and neoplastic disorders affecting the adrenal gland.

Comparison with Open Adrenalectomy The results of laparoscopic adrenalectomy must be compared with those of conventional open surgery. There are no prospective, randomized studies comparing open with laparoscopic adrenalectomy. The excellent results, reported in the available retrospective comparative studies, make such research unnecessary and possibly unethical. In our own retrospective, comparative analysis.' we have found no difference in operating time or dimensions of the adrenal gland. The estimated blood loss was 70 mL for the laparoscopic adrenalectomy versus 200 mL for the open adrenalectomy. The mean hospital stay for the laparoscopic surgery was 3 versus 9 days for the open group. The analgesia requirements and the mean time for ambulation were also significantly lower in the laparoscopic group. Other studies have reported similar outcomes. 4-8. 24,30-39 The Cleveland Clinic retrospective comparison of 110 laparoscopic and 100 open adrenalectomies showed the superior results of the laparoscopic approach." Open adrenalectomy was performed by various standard approaches. The laparoscopic group was superior in surgical time, blood loss, narcotic analgesic requirements, intensive care unit admissions, resumption of oral fluid intake, and mean hospital stay. Although intraoperative complication rate was similar, there were fewer postoperative complications in the laparoscopic group. Of special interest is the study by Thompson and coworkers" from the Mayo Clinic, who compared the laparoscopic transabdominal laparoscopic approach in 50 patients with the open posterior approach in 50 well-matched patients. In addition to the other reported advantages of laparoscopy, late incision neuromuscular complications developed in 54% of the open group, chronic pain syndrome in 14%, and flank numbness in 10%. A recent meta-analysis of the English literature by Brunt" compared the complications of laparoscopic with open adrenalectomy. Complications were tabulated from 50 studies of laparoscopic adrenalectomy involving 1522 patients and 48 studies of open adrenalectomy comprising 2273 patients. Among the reports, 22 compared laparoscopic with open adrenalectomy from within a single institution. They concluded that laparoscopic adrenalectomy resulted in fewer adrenalectomy-related complications than those seen historically with open adrenalectomy. Fewer wound and pulmonary complications and fewer incidental splenectomies are the primary reasons for this improved outcome. Finally, another variable of concern, addressed by several authors, is the cost of the procedure compared with that of open surgery.5,6,8,31,38 Although Thompson and coworkers" found higher costs with the laparoscopic procedure, most other reports found no significant difference in overall cost between the two approaches. However, the earlier return to work in patients undergoing laparoscopic adrenalectomy would be associated with lower costs if is taken into consideration.

Choices of Approach The technique of choice by most surgeons performing laparoscopic adrenalectomy is the transabdominal lateral

approach. Several authors have successfully documented the feasibility, safety, and effectiveness of endoscopic adrenalectomy via the retroperitoneal approach in tumors less than 5 to 6 cm. 14,15.17,78,79 Since the peritoneum is not violated and the bowel is not mobilized with the retroperitoneal approach, it was postulated to be less invasive and lead to better results, especially in small lesions and in obese patients. 17,24 Siperstein and associates.P in a series of 31 patients, concluded that although more demanding, the retroperitoneal approach should be considered in patients with tumors less than 6 em, bilateral tumors, or extensive previous abdominal surgery. In another large series from the Netherlands, the procedure was described in 111 consecutive cases and showed comparative results with the transabdominal approach.I'' These authors recommended the procedure for benign adrenal tumors less than 6 em. Nevertheless, case history analysis has revealed no apparent difference in patient outcome, morbidity, or operative time for the two approaches. 14.15,44A5,8o Moreover, in our experience and the experience of others," the transperitoneal approach has not caused bowel injury or other complications. Comparison between the two techniques has in fact indicated no real difference for small tumors, although for lesions larger than 5 to 6 cm, the transabdominal route is considered preferable." Disadvantages of the retroperitoneal approach include a lack of anatomic landmarks and a restricted working space. This combination of technical difficulties renders the retroperitoneal approach unsuitable for tumors larger than 6 em. On the other hand, a major advantage of the transperitoneal approach is that the abdominal cavity, and particularly the liver, can be explored. In patients with pheochromocytoma, the liver can be examined by inspection and ultrasound and suspicious lesions may be biopsied. Moreover, in our personal experience with the retroperitoneal approach, the exposure was inferior to that obtained via the transperitoneal approach.

Contraindications to Laparoscopic Adrenalectomy MALIGNANCY

The available data suggest that there are few absolute contraindications for laparoscopic adrenalectomy. We consider invasive adrenal carcinoma to be the only absolute contraindication for the laparoscopic approach owing to the possible extent and complexity of the operation required. An open technique also may be more desirable for patients with malignant pheochromocytoma when metastatic nodes are present in the periaortic chain or close to the bladder. Several authors differentiate between the biologic behavior of adrenal metastasis and primary adrenal cancer as to their suitability for the laparoscopic procedure.l':" Because solitary adrenal metastasis from an extra-adrenal primary is usually small and confined within the adrenal, the laparoscopic approach has considerable appeal for this specific indication.>' Conversely, adrenal cancer is usually larger and often locally invasive. An important limitation in this regard is that adrenal imaging and even fine-needle aspiration are often inaccurate to diagnose or exclude adrenal malignancy." Since no reliable and accurate preoperative diagnostic test to diagnose adrenal malignancy exists, it is difficult to determine when an open approach should be used. An initial

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laparoscopic approach can be used to establish the diagnosis with low morbidity and allows curative resection in most instances." Laparoscopic ultrasound is a simple and effective intraoperative technical adjunct that may be used to evaluate the nature and invasiveness of the suspected adrenal mass. Obviously, in patients who prove to have local invasion during surgery, the laparoscopic approach should be converted to an open procedure to allow curative, wide, radical resection. The limited experience to date with laparoscopic adrenalectomy in malignant disease is promising, with short-term results comparable with those of conventional surgery.69,71 Thus, it appears that a laparoscopic approach is reasonable for metastatic adrenal disease, provided the primary cancer is controlled and there is no evidence of extra-adrenal disease. Similarly, for primary neoplasms, if complete resection is technically feasible and there is no evidence of local invasion, an initial laparoscopic approach is an acceptable option in experienced hands at selected centers. 51,69,71 SIZE

The maximal acceptable size of a lesion appropriate for laparoscopic adrenalectomy is another unsettled issue. Although size per se is not a definite contraindication, laparoscopy is not advisable for masses larger than 12 to 14 em because of the increased incidence of malignancy and the technical difficulties associated with their removal. The largest lesion that we have resected was 14 em, but such a mass makes the dissection difficult and time consuming. The exposure also is problematic because of the limited space available in this area, Large masses frequently have unusual and numerous retroperitoneal feeding vessels that require tedious and lengthy dissection. Only surgeons with extensive laparoscopic experience should attempt resection of larger adrenal masses. Generally, the indications and contraindications for laparoscopic adrenalectomy, including the maximal size limit and other issues, are dictated largely by the experience of the individual surgeon.

Incidentaloma Management of incidentally discovered adrenal masses is still controversial. Although adrenocortical carcinomas are usually larger than 6 em, incidentally detected cancers 3 to 5 em or even smaller have been reported.51.82 Another confounding factor is that CT scanning underestimates by 20% to 40% adrenal tumor size compared with actual size on histopathology, 82 Definite indications for adrenalectomy include sizes larger than 4 cm, hormonally active lesions, suspicious characteristics on imaging studies, and documented increase in size. Because of the excellent results of the laparoscopic procedure, we and others" prefer laparoscopic adrenalectomy instead of observation for the young and low operative risk patients with 3- to 5-cm adrenal masses. Another argument against the watchful conservative policy in such cases is that most adrenal nodules increase in size with age" and the need for imaging and biochemical testing continues throughout the patient's life, Moreover, the patient is spared the anxiety, expense, and time lost from repeated follow-up appointments and the associated studies needed.

The New Gold Standard The accumulated evidence indicates that laparoscopic adrenalectomy in patients with hormonally active tumors is the new gold standard. This minimally invasive technique has become the procedure of choice for hyperaldosteronism,37,63,64 Cushing's syndrome and disease,3,21,22,25,26,62,67 and pheochromocytoma. 20,28,48,50,53,54.58 Bilateral laparoscopic adrenalectomy appears to be safe and effective in patients with pituitary-dependent Cushing's syndrome after failed transsphenoidal surgery and in cases with ectopic ACTH syndrome when the primary tumor cannot be identified or rernoved.S After initial reluctance and skepticism, it is now obvious that laparoscopic resection of pheochromocytomas can be accomplished safely despite frequent episodes of hemodynamic variability equal to those of historical open control subjects. The earlier recovery, fewer complications, and lack of endocrine recurrence make this approach the procedure of choice for the management of pheochromocytoma.W? In addition, a recent publication by Brunt and colleagues'? has reported favorable results in cases of unilateral and bilateral familial pheochromocytoma (patients with MEN 2A, MEN 2B, von Hippel-Lindau disease, and neurofibromatosis type 1). Another large series from Germany" has documented the successful outcome of endoscopic approach in 61 chromaffin neoplasms (52 pheochromocytomas and 9 paragangliomas), The patient population included a wide spectrum of this disease: unilateral, hereditary, bilateral, recurrent, and multiple tumors. In patients with bilateral disease, partial bilateral adrenalectomy was performed and achieved preservation of adrenocortical function in 86% of cases, without evidence of recurrence after 3 years of follow-up. Thus, in patients with hormonally active tumors of the adrenal, the procedure has proved feasible and safe and offered all the advantages of minimally invasive surgery. Additionally, it resulted in an excellent functional outcome and was associated with clinical and biochemical cure rates comparable with those of open surgery during long-term follow_up.3,52,53,55,57,62-64

Recent Advances Recent advances and innovations in laparoscopic adrenalectomy have been introduced. Outpatient laparoscopic adrenalectomy has been performed in selected low-risk patients with small adrenal tumors (mainly hyperaldosteronism, excluding pheochromocytoma) with satisfactory results. 65,83 To further minimize the morbidity of conventional laparoscopic procedures, needlescopic technique, using smaller ports, was reported by several groupS.84-86 The limited experience to date with a small number of patients showed that the procedure was feasible and resulted in improved wound cosmesis. It decreased postoperative pain and hospital stay without prolonging operative time." The continued technologic advances, offering more effective 2-mrn instruments, may convince more surgeons to try this new technique. Nevertheless, randomized, prospective trials comparing needlescopic with conventional laparoscopy are still needed to validate these favorable initial results. Laparoscopic cortical-sparing surgery in selected patients with bilateral pheochromocytoma and well-circumscribed

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bilateral cortisol or aldosterone-producing adenomas 29,59,87-91 has been reported. This approach may be valuable in those who would otherwise require life-long adrenal replacement therapy after complete adrenal gland extirpation. It was also used in patients with unilateral aldosterone-producing adenomas." Our limited experience" and that of others 87 -91 confirms the technical feasibility and safety of laparoscopic partial adrenalectomy. The recurrence rate after bilateral pheochromocytomas in patients with MEN syndromes approaches 20%.29,90 For this reason, some authors advise against adrenal-saving surgery in these instances. Intraoperative ultrasound is useful since one cannot rely solely on the direct laparoscopic view. Whenever tumor and normal parenchyma cannot be differentiated intraoperatively, total adrenalectomy becomes unavoidable. Total adrenalectomy is also undisputed in cases of suspected malignancy. There have been no studies showing failed adrenal function because of adrenal vein ligation; however, one should attempt to preserve the main vein during adrenal-sparing surgery. In case of severe hypertension during surgery for pheochromocytoma, it has been suggested to temporarily occlude the vein with a laparoscopic bulldog clamp." To preserve cortical response to stress, adrenal-sparing surgery may be valuable in selected patients. However, large prospective series with long-term follow-up are required before drawing definite conclusions. Other technical advances include the thoracoscopic transdiaphragmatic approach to the adrenal gland." adrenal cryoablation," and robotic laparoscopic adrenalectomy.'<" Finally, has the widespread introduction of laparoscopic adrenalectomy broadened the indications of adrenalectomy and changed the pattern of referral? Two recent publications 99•100 found that the introduction of laparoscopic adrenalectomy has resulted in an increase in the number of patients referred and, consequently, more adrenalectomies are performed. One study showed that the criteria for patient selection did not change but more patients with adrenal metastasis and incidentalomas were operated on laparoscopically.?? However, the other study indicated that this was due to an increased number of cases with hyperaldosteronism and pheochromocytoma, with no change in the number of operations for incidentalomas and metastasis. 100

Conclusions After a decade of worldwide experience, laparoscopic adrenalectomy has successfully passed its "definition" phase and achieved maturation. Based on our experience, and that of others, laparoscopic adrenalectomy is a well-established technique and is currently the treatment of choice for benign functioning and nonfunctioning neoplasms of the adrenal gland. Although other laparoscopic approaches are feasible, they have their limitations and offer no clear advantage over the lateral transabdominal approach, the preferred technique practiced by most surgeons performing laparoscopic adrenalectomy. The limited experience with the procedure in malignancy shows some promise, but its role is yet to be clarified. Currently, invasive adrenocortical carcinoma and metastatic pheochromocytoma to periaortic nodes are the only absolute contraindications. Only experienced laparoscopic surgeons

should attempt laparoscopic resection of large masses and, generally, the minimally invasive technique is not advisable for lesions greater than 12 to 14 em.

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55. Walz MK, Peitgen K, Neumann H, et al. Endoscopic treatment of solitary, bilateral, multiple, and recurrent pheochromocytomas and paragangliomas. World 1 Surg 2002;26:1005. 56. Tanaka M, Tokuda N, Koga H, et al. Laparoscopic adrenalectomy for pheochromocytoma: Comparison with open adrenalectomy and comparison of laparoscopic surgery for pheochromocytoma versus other adrenal tumors. 1 Endourol 2000; 14:427. 57. Cheah WK, Clark OH, Hom lK, et al. Laparoscopic adrenalectomy for pheochromocytoma. World 1 Surg 2002;26: 1048. 58. Salomon L, Rabii R, Soulie M, et al. Experience with retroperitoneal laparoscopic adrenalectomy for pheochromocytoma. 1 Urol 2001;165:1882. 59. lanetschek G, Finkenstedt G, Gasser R, et al. Laparoscopic surgery for pheochromocytoma: Adrenalectomy, partial resection, excision of paragangliomas. 1 UroI1998;160:330. 60. Mobius E, Nies C, Ruthmond M. Surgical treatment of pheochromocytomas: Laparoscopic or conventional? Surg Endosc 1999;13:35. 61. Col V, de Canniere L, Collard E, et a1.Laparoscopic adrenalectomy for pheochromocytoma: Endocrinological and surgical aspects of a new therapeutic approach. Clin EndocrinoI1999;50:121. 62. Vella A, Thompson GB, Grant CS, et al. Laparoscopic adrenalectomy for adrenocorticotropin-dependent Cushing's syndrome. 1 Clin Endocrinol Metab 2001 ;86: 1596. 63. Rossi H, Kim A, Prinz RA. Primary hyperaldosteronism in the era of laparoscopic adrenalectomy. Am Surg 2002;68:253. 64. Miyaki, Okuyama A. Surgical management of primary aldosteronism. Biomed Pharmacother 2000;54(Suppll):146. 65. Edwin B, Reader I, Trondsen E, et al. Outpatient laparoscopic adrenalectomy in patients with Conn's syndrome. Surg Endosc 2001;15:589. 66. Siren 1, Haglund C, Huikuri K, et al. Laparoscopic adrenalectomy for primary aldosteronism: Clinical experience with 12 patients. Surg Laparosc Endosc 1999;9:9. 67. Go H, Takeda M, Imai T, et a1. Laparoscopic surgery for Cushing's syndrome: Comparison with primary aldosteronism. Surgery 1995;117:11. 68. Heniford BT, Area Ml, Walsh RM, et al. Laparoscopic adrenalectomy for cancer. Sernin Surg Oncol 1999;16:293. 69. Henry IF, Sebag F, Iacobone M, et a1. Results of laparoscopic adrenalectomy for large and potentially malignant tumors. World 1 Surg 2002;26:1043. 70. MacGillivray DC, Whalen GF, Malchoff CD, et a1. Laparoscopic resection of large adrenal tumors. Ann Surg Oncol 2002;9:480. 71. Kebebew E, Siperstein AE, Clark OH, et a1. Results of laparoscopic adrenalectomy for suspected and unsuspected malignant adrenal neoplasms. Arch Surg 2002;137:948. 72. Vasilopoulou-Sellin R, Schultz PN. Adrenocortical carcinoma: Clinical outcome at the end of the 20th century. Cancer 2001 ;92: 1113. 73. Heniford BT, Iannitti DA, Hale 1, et a1. The role of intraoperative ultrasonography during laparoscopic adrenalectomy. Surgery 1997;122:1068. 74. Brunt LM, Bennett HF, Teefey SA, et a1. Laparoscopic ultrasound imaging of adrenal tumors during laparoscopic adrenalectomy. Am 1 Surg 1999;178:490. 75. Siperstein AE, Berber E. Laparoscopic ultrasonography of the adrenal glands. In: Gagner M, Inabnet B (eds), Minimally Invasive Endocrine Surgery. Lippincott Williams & Wilkins, 2002, p 175. 76. Gill IS, Schweizer D, Nelson D. Laparoscopic versus open adrenalectomy in 210 patients: Cleveland Clinic experience with 210 cases. 1 UroI1999;161(Suppl):21. 77. Brunt LM. The positive impact of laparoscopic adrenalectomy on complications of adrenal surgery. Endosc Surg 2002; 16:252. 78. Bonjer Hl, Sorm V, Berends Fl, et a1. Endoscopic retroperitoneal adrenalectomy: Lessons learned from 111 consecutive cases. Ann Surg 2000;232:796. 79. Ting AC, Lo CY, Lo CM. Posterior or laparoscopic approach for adrenalectomy. Am 1 Surg 1998; 175:488. 80. Salomon L, Soulie M, Mouly F, et a1. Experience with retroperitoneal laparoscopic adrenalectomy in 115 procedures. 1 UroI2001;166:38. 81. Guazzoni G, Cestari A, Montorsi F, et al. Eight-year experience with transperitoneallaparoscopic adrenal surgery. 1 Urol 2001;166:820. 82. Linos DA, Stylopoulos N. How accurate is computed tomography in predicting the real size of adrenal tumors? A retrospective study. Arch Surg 1997;132:740. 83. Gill IS, Hobart M, Schweizer D, et a1. Outpatient adrenalectomy. 1 Urol 2000;163:717.

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84. Gill IS, Soble 11, Sung GT, et al. Needlescopic adrenalectomy-the initial series: Comparison with conventionallaparoscopic adrenalectomy. Urology 1998;52:180. 85. Chueh SC, Chen J, Chen SC, et al. Clipless laparoscopic adrenalectomy with needlescopic instruments. J UroI2002;167:39. 86. Mamazza J, Schlachta CM, Seshadri PA, et al. Needlescopic surgery: A logical evolution from conventionallaparoscopic surgery. Surg Endosc 2001;15:1208. 87. Neumann HPH, Reincke M, Bender BU, et al. Preserved adrenocortical function after laparoscopic bilateral adrenal sparing surgery for hereditary pheochromocytoma. J Clin Endocrinol Metab 1999;84:2608. 88. Walz MK, Peitgen K, Saller B, et aI. Subtotal adrenalectomy by the posterior reroperitoneoscopic approach. World J Surg 1998;22:621. 89. Imai T, Tanaka Y, Kikumori T, et aI. Laparoscopic partial adrenalectomy. Surg Endosc 1999;13:343. 90. Baghai M, Thompson GB, Young WF, et al. Pheochromocytomas and paragangliomas in von Hippel-Lindau disease. Arch Surg 2002; 137:682. 91. Al-Sobhi S, Peschel R, Bartsch G, et al. Partiallaparoscopic adrenalectomy for aldosterone-producing adenoma: Short and long-term results. J Endourol 2000;14:497. 92. Gill IS, Meraney AM, Thomas JC, et aI. Thoracoscopic transdiaphragmatic adrenalectomy: The initial experience. J UroI2001;165: 1875.

93. Schulsinger DA, Sosa RE, Perlmutter AA, et aI. Acute and chronic interstitial cryotherapy of the adrenal gland as a treatment modality. J EndouroI1999;13:299. 94. Gill IS, Sung GT, Hsu TH, et aI. Robotic remote laparoscopic nephrectomy and adrenalectomy: The initial experience. J Urol 2000;164:2082. 95. Young JA, Chapman WHH, Kim VB, et aI. Robotic-assisted adrenalectomy for adrenal incidentaloma: Case and review of the literature. Surg Laparosc Endosc Percutan Tech 2002; 12:126. 96. Terachi T, Matsuda T, Terai A, et aI. Transperitoneal laparoscopic adrenalectomy: Experience in 100 cases. J Endourol 1997;fl:361. 97. Mancini F, Mutter D, Peix JL, et aI. Experiences with adrenalectomy in 1997, apropos of 247 cases: A multicenter prospective study of the French-speaking association of endocrine surgery. Chirurgie 1999;124:368. 98. Kebebew E, Siperstein AB, Dub QY. Laparoscopic adrenalectomy: The optimal surgical approach. J Laparoendosc Adv Surg Tech 2001; 11:409. 99. Miccoli P, Raffaelli M, Berti P, et al. Adrenal surgery before and after the introduction of laparoscopic adrenalectomy. Br J Surg 2002; 89:779. 100. Sidhu S, Bambach C, Pillinger S, et aI. Changing pattern of adrenalectomy at a tertiary referral center, 1970-2000. ANZ J Surg 2002;72:463.

Anatomy and Embryology of the Pancreas Christopher R. McHenry, MD

Embryology The pancreas is a derivative of the caudal part of the primitive foregut. It develops embryologically from dorsal and ventral pancreatic primordia, which appear at days 26 and 32 of fetal development, respectively. 1 The dorsal pancreatic bud originates as an endodermal outpouching from the dorsal aspect of the duodenum, and the smaller ventral pancreatic bud arises from the base of the hepatic diverticulum, closely related to the common bile duct (Fig. 75-1).2 As the descending duodenum rotates, the ventral pancreas migrates posteriorly and subsequently fuses with the dorsal pancreas at the end of the sixth week of fetal development' (see Fig. 75-1). The ventral anlage develops into the head and uncinate process of the pancreas. Malrotation of the ventral pancreas may result in an annular pancreas, a congenital malformation characterized by a ring of normal pancreatic tissue that surrounds the second portion of the duodenum and causes duodenal constriction and obstruction. With the fusion of the dorsal and ventral pancreatic primordia, the individual ductal systems coalesce with one another. The main pancreatic duct of Wirsung is formed from the anastomosis of the entire duct of the ventral pancreas, which forms the duodenal end of the main duct, with the distal portion of the duct of the dorsal pancreas (see Fig. 75-1). The duct of Wirsung is the main drainage conduit for pancreatic exocrine secretion and, together with the common bile duct, opens into the duodenum through the major papilla. The proximal portion of the dorsal pancreatic duct may involute or persist as the accessory duct of Santorini, which empties into the duodenum through the minor papilla. In approximately 5% to 10% of individuals, the ducts fail to join and persist as two separate ductal systems, a congenital anomaly known as pancreatic divisum.v' The cells of the pancreas appear during the third month of fetal development. They form as a result of the budding and rebudding of cells derived from the pancreatic primordia." The terminal portions of the budding cells develop a characteristic acinar arrangement, and the proximal portions form multiple short ductal tributaries that drain exocrine secretions from the acini into the main pancreatic duct. The endocrine

pancreas is composed of the islets of Langerhans, which develop from the parenchymal cells of the pancreas at the end of the third month of fetal life and are found as clusters of cells throughout the acini of the pancreas. The pancreatic islet cells produce peptide hormones, which, in contrast to exocrine secretions, are delivered directly into the bloodstream. Insulin and glucagon secretion from the islet cells begin as early as the fifth month of fetal development.v" Metaplasia of pluripotential endodermal cells of the primitive foregut has been postulated to be a source for ectopic or aberrant pancreatic tissue.? which has been reported to be present in 2% of all autopsies." Ectopic pancreatic tissue may manifest as a nodular submucosal mass in the gastrointestinal tract? and may be affected by the same pathologic conditions that affect the normal pancreas. Islet cells are found only in ectopic pancreas involving the stomach and duodenum and may be a source for extrapancreatic islet cell neoplasms. 10

Anatomy of the Pancreas The pancreas is a mixed endocrine and exocrine gland that is located in the retroperitoneum within the epigastric and the left hypochondriac regions of the abdomen. It extends transversely across the posterior abdominal wall from the medial aspect of the descending portion of the duodenum, where it is fixed, to the hilum of the spleen, where it is relatively mobile. The stomach overlies the pancreas anteriorly. The pancreas lies across the inferior vena cava, portal vein, aorta, superior mesenteric, and splenic vessels (Fig. 75-2). It measures 15 to 20 em in length and extends across the vertebral bodies of either the first or second lumbar vertebra. The adult pancreas weighs 80 to 90 g and has an average width and thickness of 3 em and 1 to 1.5 em, respectively." The exocrine pancreas is a compound acinar gland made up of secretory units that consist of individual acinar and centroacinar cells and ducts that penetrate the lumen of the acini. The exocrine pancreas constitutes the bulk of the parenchyma. Interspersed among the acinar cells are the islet cells of Langerhans. The islet cells are arranged in well-vascularized clusters throughout the exocrine pancreas.

665

666 - -

Endocrine Pancreas

Ventral pancreatic primordia

A

B

Accessory duct of---l_-1j.. Santorini Main pancreatic duct of Wirsung

c FIGURE 75-1. A, The dorsal and ventral pancreatic primordia at the end of the fifth week of fetal development. The arrow indicates the path of posterior migration of the ventral pancreatic primordia. B, Anatomic relationship of the pancreatic primordia and ductal systems following rotation of the duodenum and posterior migration of the ventral pancreatic primordia. C, Fusion of the dorsal and ventral pancreatic primordia and coalescence of the individual ductal systems.

They consist of four different cell types: alpha, beta, delta, and clear cells. The alpha cells produce glucagon and constitute 20% of the islet cell population. Beta cells account for approximately 70% of the islet cells and are responsible for insulin production. Delta cells account for 5% to 10% of the islet cells and function primarily as paracrine cells producing somatostatin for internal regulation of alpha- and beta-cell secretion. They are also known to produce gastrin and pancreatic polypeptide. Clear cells account for less than

5% of all islet cells, and their functional significance has yet to be delineated.

Divisions of the Pancreas Although there are no distinct anatomic demarcations, the pancreas is commonly divided into five parts: the head, uncinate process, neck, body, and tail (see Fig. 75-2). The head of the pancreas is adherent to the concavity of the descending

Anatomy and Embryology of the Pancreas - -

667

Left adrenal Right adrenal

Splenic artery Gallbladder

Accessory duct of Santorini

Left kidney

Superior mesenteric vessels

., Pancreatic duct of Wirsung

Uncinate

Inferior vena cava

FIGURE 75-2. Topographic anatomy of the pancreas.

duodenum, with which it shares a common blood supply from the superior mesenteric and gastroduodenal arteries. As a result, total resection of the head of the pancreas requires removal of the second and most of the first and third portions of the duodenum. The anterior surface of the head of the pancreas is adjacent to the pylorus and the first portion of the duodenum. Its posterior surface lies in close proximity to the medial border of the right kidney and in contact with the right renal vessels, inferior vena cava, and left renal vein. The terminal portion of the common bile duct is embedded within the posterior surface of the head of the pancreas in 85% of individuals. 12 The uncinate process projects medially from the left lower aspect of the head of the pancreas. In most cases, it extends behind the portal vein and the superior mesenteric vessels and anterior to the aorta and the inferior vena cava. The uncinate process is characterized by considerable variation in the extent of projection from the head of the pancreas and may occasionally be absent. The neck of the pancreas is a 2-cm segment that overlies the confluence of the superior mesenteric and splenic veins, forming the portal vein. There are usually no venous branches that empty into the portal or superior mesenteric veins anteriorly. A cleavage plane between the pancreas and the underlying veins is usually present and can be delineated by simple blunt dissection. This is clinically important for assessment of the resectability of pancreatic malignancy. The body of the pancreas overlies the aorta and the superior mesenteric artery and extends upward and to the left,

usually crossing the second lumbar vertebra. It is intimately associated with the left adrenal gland, left kidney, and splenic artery and vein, which course along its superior aspect. Because of its relationship to the vertebral bodies, the body of the pancreas is the segment where transection secondary to blunt trauma most commonly occurs. Small venous tributaries from the body of the pancreas empty into the splenic vein and are a potential source of troublesome bleeding when preservation of the spleen is attempted in patients undergoing distal pancreatectomy. Anteriorly, the body of the pancreas is covered by peritoneum separating the stomach from the pancreas. It is also the site for attachment of the transverse mesocolon. The middle colic artery originates from the superior mesenteric artery from beneath the body of the pancreas and emerges from between the peritoneal leaves of the transverse mesocolon. The tail of the pancreas is the narrow, mobile segment found within the lienorenal ligament along with the splenic vessels. It lies anterior to the left kidney and renal vessels at the level of the 12th thoracic or first lumbar vertebra. The tail of the pancreas terminates near or within the hilum of the spleen and, therefore, is also the region of the pancreas most at risk for injury during splenectomy.

Arterial Supply and Venous Drainage of the Pancreas The blood supply of the pancreas is predominantly derived from the pancreaticoduodenal and the splenic arteries

668 - - Endocrine Pancreas

Common hepatic a.

Posterosuperior pancreaticoduodenal a. _--,'--_ _--=~

Splenic nodes

Anterosuperior pancreaticoduodenal a.

Caudal pancreatic artery Inferior pancreaticosplenic nodes

Pancreaticoduodenal nodes

Transverse pancreatic a.

Duodenum Anterior and posterior inferior pancreaticoduodenal a.

Superior mesenteric a.

FIGURE 75-3. Arterial blood supply and lymph nodes of the pancreas.

(Fig. 75-3). All of the main arterial and venous channels of the pancreas are posterior to the main pancreatic duct. The head of the pancreas and the duodenum receive their blood supply from an arcade of vessels formed by the anastomosis of the anterosuperior and posterosuperior pancreaticoduodenal arteries with the anteroinferior and posteroinferior pancreaticoduodenal arteries (see Fig. 75-3). The superior pancreaticoduodenal arteries are branches of the gastroduodenal artery, and the inferior pancreaticoduodenal arteries are branches of the superior mesenteric artery. The uncinate process receives its blood supply primarily from collateral vessels arising from the inferior pancreaticoduodenal arteries. The uncinate process may also be supplied by small perforating branches that arise directly from the superior mesenteric artery. The neck, body, and tail of the pancreas receive their blood supply from the transverse pancreatic artery, which courses inferiorly and posteriorly through the gland, and multiple small branches from the splenic artery that anastomose with the transverse pancreatic artery (see Fig. 75-3). The transverse pancreatic artery is the principal blood supply for the main pancreatic duct. It is a branch of the dorsal pancreatic artery, which arises from the splenic artery in 37%, celiac artery in 33%, superior mesenteric artery in 21%, and hepatic artery in 8% of the population." A right branch of the dorsal pancreatic artery provides additional blood supply to the head and uncinate process of the pancreas, anastomosing with the posterosuperior pancreaticoduodenal arcade. A caudal pancreatic artery, which may arise from the splenic artery or the left gastroepiploic artery at the hilum of

the spleen, is a variable source of blood supply for the tail of the pancreas. The veins draining the pancreas are parallel and superficial to the arterial blood supply. Four pancreaticoduodenal veins form the venous arcade, which drains the head and uncinate process of the pancreas.' The anterosuperior pancreaticoduodenal and both inferior pancreaticoduodenal veins empty into the superior mesenteric vein. The posterosuperior pancreaticoduodenal vein empties into the portal vein above the superior margin of the pancreas. These veins and other smaller tributaries from the head of the pancreas terminate in the lateral or posterior aspect of the superior mesenteric and portal veins and may be injured with traction on the head of the pancreas. The neck, body, and tail of the pancreas are drained by multiple small venous tributaries that empty into either the splenic vein superiorly or the transverse pancreatic vein inferiorly. The transverse pancreatic vein eventually empties into the inferior mesenteric vein. Ligation of the splenic vein during distal pancreatectomy requires splenectomy, whereas ligation of the splenic artery does not require resection of the spleen because the spleen still receives blood from the left gastroepiploic artery through the short gastric arteries.

Anomalous Arterial Supply There are a number of important arterial anomalies that the endocrine surgeon should be able to recognize to avoid injury during pancreatic resection. The most common anomaly is an aberrant right hepatic artery arising from the superior

Anatomy and Embryologyof the Pancreas - - 669 mesenteric artery, which was reported by Michels to be present in 26% of cadavers." The aberrant right hepatic artery may course behind the head of the pancreas and be at risk for injury during pancreaticoduodenectomy. In 2% to 4.5% of individuals, the common hepatic artery may arise from the superior mesenteric artery and course posterior to the pancreatic head before dividing into right and left hepatic arteries. I Injury to this aberrant common hepatic artery may result in both hepatic and duodenal ischemia and necrosis. An anomalous middle colic artery, originating from the superior mesenteric artery, has also been reported, and it may course directly through the head of the pancreas and be at risk for injury during pancreaticoduodenectomy. I All of the anomalous pancreatic arteries arising from the superior mesenteric artery have been reported to pass anterior or posterior to or directly through the head of the pancreas."

Ducts of the Pancreas The pancreas has a main pancreatic duct of Wirsung and an accessory duct of Santorini (see Fig. 75-2). The main pancreatic duct courses from the tail of the pancreas through the pancreatic parenchyma close to its posterior surface and midway between the superior and inferior margins of the pancreas. It receives multiple small ductal tributaries throughout the body and tail of the pancreas and then courses caudally through the head of the pancreas, where it receives ductal tributaries from the uncinate process. The main pancreatic duct usually joins with the common bile duct in the head of the pancreas to form a short, dilated common channel known as the ampulla of Vater.The ampulla of Vater enters the duodenum through the major papilla, which is located on the posteromedial wall of the second portion of the duodenum, an average of 10.6 em from the pylorus. IS Rarely, the major papilla may be in the third portion of the duodenum. I The ampulla of Vater varies in length from 1 to 14 mm and is 5 mm or smaller in size in 75% of the population. 16 Michels reviewed the collective experience of 25 investigators who examined 2500 autopsy specimens and determined that a true ampulla of Vater was present in 64%, and the common bile duct and main pancreatic duct entered the duodenum through separate orifices in 14% of this population. 14 The ampulla of Vater, when present, or the intramural portion of the common bile duct and pancreatic duct is surrounded by smooth muscle fibers that form a sphincter complex known as either as the sphincter of Oddi or the sphincter of Boyden. The sphincter mechanism ranges in length from 6 to 30 mm and is responsible for controlling the release of exocrine secretions from the pancreatic and common bile ducts. I The diameters of the different segments of the main pancreatic duct have been determined by endoscopic retrograde cholangiopancreatography, and they vary from 0.9 to 2.4 mm in the tail, 2 to 4 mm in the body, and 3.1 to 5.3 mm in the head of the pancreas.' Duct dilation has been defined as a diameter of 8 mm or greater.i-" In patients with intractable pain secondary to chronic pancreatitis, longitudinal Roux-en-Y pancreaticojejunostomy is usually reserved for patients with a pancreatic duct diameter of 8 mm or greater. 17 The length of the pancreatic duct, determined from autopsy specimens, is generally between 20 and 25 em."

The accessory duct of Santorini is usually smaller than the main pancreatic duct. It is formed from the persistence of the proximal portion of the duct from the embryologic dorsal pancreas. It usually drains the anterosuperior portion of the pancreatic head, communicates with the main pancreatic duct, and in 70% of the population opens into the duodenum through the minor papilla, which is 2 em cranial and slightly anterior to the major papilla. The minor papilla is most often directly posterior to the gastroduodenal artery and thus is at risk for injury during surgery for peptic ulcer disease. Variations in the pancreatic ductal anatomy are common and include absence of a minor papilla in 30%, no connection between the accessory and main pancreatic ducts in 10%, and variable degrees of suppression in the development of the accessory or main pancreatic ducts." To avoid injury to the accessory pancreatic duct in patients undergoing gastrectomy or peptic ulcer surgery, duodenal dissection should end proximal to the gastroduodenal artery. This is especially important in the rare patients in whom the accessory duct constitutes the major drainage of the pancreas.

Lymphatic Drainage The lymphatic drainage of the pancreas follows the course of the blood vessels (see Fig. 75-3). There is no standard terminology for the lymph nodes of the pancreas. I The head and uncinate process of the pancreas are drained by pyloric and pancreaticoduodenal lymph nodes. The neck, body, and tail of the pancreas are drained by pancreaticosplenic lymph nodes. The pyloric, pancreaticoduodenal, and superior pancreaticosplenic lymph nodes drain to the celiac nodes, whereas the inferior pancreaticosplenic nodes drain to the superior mesenteric and periaortic nodal basins. Pansky described five pancreatic lymph node groups on the basis of studies of metastatic drainage: superior, inferior, anterior, posterior, and splenic. 13 From these five lymph node basins, lymphatic drainage proceeds centrally by two major pathways. The anterior, superior, and splenic lymphatic channels drain to the celiac nodes with progression to the hepatic nodes, whereas the posterior and the inferior nodes drain to the superior mesenteric and periaortic nodal chains. Both pathways subsequently drain through the thoracic duct and serve as a potential source for supraclavicular nodal metastasis.

Nerves of the Pancreas The pancreas is innervated by both sympathetic and parasympathetic nerve fibers through the splanchnic and vagus nerves, respectively. In general, the nerves innervating the pancreas follow the course of the pancreatic blood vessels. Both the splanchnic and vagus nerves carry visceral efferent (motor) and visceral afferent (sensory) fibers. The splanchnic nerves carry preganglionic efferent fibers to their cell bodies located in the celiac ganglion. Postganglionic fibers arising from the celiac ganglion form an extensive celiac nerve plexus, which follows the arteries to reach the pancreas. The celiac division of the posterior trunk of the vagus nerve supplies preganglionic parasympathetic fibers to the pancreas, which pass through the celiac ganglion without synapsing. The fibers end in the cell bodies within the parenchyma of

670 - - Endocrine Pancreas

Surgical Exposure of the Pancreas

FIGURE 75-4. The gastrinoma triangle.

the pancreas, which then give rise to the postganglionic parasympathetic fibers innervating the pancreas. The functions of the sympathetic and parasympathetic innervation are to regulate pancreatic blood flow, influence acinar and centroacinar cell secretion, and contribute pain fibers to the pancreas. In patients with pancreatic cancer, effective pain relief may be obtained by interruption of painful stimuli at the level of the celiac plexus or splanchnic nerves. This seems to be best accomplished by chemical splanchnicectomy performed at the time of laparotomy.P-" Intraoperatively, 20 mL of 50% alcohol is injected under direct vision along both sides of the celiac axis." This has been associated with pain relief in more than 80% of patients, the majority of whom obtain permanent pain relief."

Exposure of the pancreas in patients with islet cell neoplasms is preferably obtained through an upper midline or a bilateral subcostal incision. Intraoperative evaluation of patients with pancreatic islet cell neoplasms requires a meticulous examination of the entire pancreas for tumor masses that are frequently small (less than 2 em) and multiple. The duodenum and peripancreatic lymph nodes are also carefully examined because they may be sites of extrapancreatic islet cell tumors. The liver is examined for evidence of metastatic disease. In patients with gastrinoma, 90% of all tumors and virtually all occult tumors have been found in the gastrinoma triangle." The gastrinoma triangle is defined as the anatomic region bound by the junction of the cystic duct and common bile duct superiorly, the second and third portions of the duodenum inferiorly, and the junction of the neck and body of the pancreas medially (Fig. 75-4).23 Insulinomas and nonfunctional islet cell tumors are evenly distributed throughout the head, body, and tail of the pancreas, whereas glucagonomas are primarily situated in the tail of the pancreas.i" The pancreas is exposed by retracting the stomach upward and the transverse colon downward and dividing the gastrocolic omentum (Fig. 75-5). The body and tail of the pancreas are mobilized by incising the peritoneum along its inferior border (Fig. 75-6), allowing access to the avascular plane posteriorly for bidigital palpation (Fig. 75-7), which is important for detection and assessment of tumor size and determination of proximity to the main pancreatic duct. Complete evaluation of the head of the pancreas requires incision of the lateral attachments of the duodenum (Fig. 75-8). To facilitate duodenal mobilization, the hepatic flexure of the colon is mobilized, and then the lateral

,

FIGURE 75-6. Incision of the peritoneum along the inferior edge of the pancreas using a right-angle clamp and the electrocautery. (From McHenry CR. Pancreatic islet cell tumors. In: Baker RJ, Fischer IE reds], Mastery of Surgery, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2001, p 557.)

Anatomy and Embryology of the Pancreas - -

671

« I

FIGURE 75-7. Bidigital palpation of the pancreas after the peritoneum along the inferior edge of the pancreas has been incised from the left of the superior mesenteric vein to the spleen. The spleen has been mobilized. (From McHenry CR. Pancreatic islet cell tumors. In: Baker RJ, Fischer JE reds], Mastery of Surgery, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2001, p 557.)

peritoneal attachments of the second portion of the duodenum are incised. Mobilization is continued proximally and superiorly, dividing the avascular portion of the hepatoduodenal ligament, which allows visualization and palpation of the common bile duct. The duodenum is further mobilized distally and inferiorly so that the inferior vena cava and the aorta can be visualized. This allows the surgeon to perform

FIGURE 75-9. Palpation of the head and uncinate process of the pancreas after an extended Kocher maneuver has been completed. (From McHenry CR. Pancreatic islet cell tumors. In: Baker RJ, Fischer JE reds], Mastery of Surgery, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2001, p 556.)

bidigital palpation of the head and uncinate process of the pancreas (Fig. 75-9). Intraoperative assessment of the size, location, and proximity of islet cell tumors to the main pancreatic duct is important for deciding the best operative management. Enucleation remains the procedure of choice for small benign islet cell tumors (less than 2 em) not in proximity to the main pancreatic duct." Enucleation is also recommended for malignant islet cell tumors of the head or uncinate process of the pancreas when feasible. Intraoperative ultrasonography, the single best study for localizing tumors of the endocrine pancreas, may help facilitate enucleation by defining the relationship of the islet cell tumor to the pancreatic duct. Distal pancreatectomy and pancreaticoduodenectomy are appropriate for treatment of larger islet cell neoplasms, neoplasms in close proximity to the main pancreatic duct, and tumors deep in the pancreatic parenchyma where tumor enucleation is not possible.i" With successful preoperative localization of a solitary, benign insulinoma, enucleation may be accomplished laparoscopically with the use of laparoscopic ultrasonography.P

Summary

FIGURE 75-8. A Kocher maneuver is performed by dividing the lateral peritoneal attachments of the duodenum with a Metzenbaum scissors and reflecting the duodenum medially. (From McHenry CR. Pancreatic islet cell tumors. In: Baker RJ, Fischer JE reds], Mastery of Surgery, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2001, p 556.)

The management of islet cell tumors requires a thorough knowledge of pancreatic anatomy and embryology. Optimal surgical exposure and meticulous intraoperative evaluation of the pancreas are necessary to identify tumor masses, which are frequently less than 2 em in size. The surgeon should understand the anatomy of the pancreatic duct and be able to determine its proximity to the tumor. Intraoperative ultrasonography is a useful study for localizing tumors of the endocrine pancreas and may help define the relationship of an islet cell tumor to the pancreatic duct. The gastrinoma

672 - - Endocrine Pancreas triangle, duodenum, and peripancreatic lymph nodes are other potential sites for extra pancreatic islet cell tumors. In most patients, resection of an islet cell tumor can be accomplished by enucleation. When pancreatic resection is necessary, the surgeon should be aware of the potential anomalous arterial supply and be able to recognize the arterial anomalies when they occur in order to avoid injury.

REFERENCES 1. Skandalakis U, Rowe JS, Gray SW, Skandalakis JE. Surgical embryology and anatomy of the pancreas. Surg Clin North Am 1993;73:661. 2. Streeter JL. Developmental horizons in human embryos. Descriptions of age groups XV, XVI, XVII and XVIII. Contrib Embryol 1948; 32:133. 3. Caudal part of the foregut. In: Langman J (ed), Medical Embryology, 3rd ed. Baltimore, Williams & Wilkins, 1975, p 282. 4. Development of the digestive and respiratory systems and the body cavities. In: Patten BM, Carlson BM (eds), Foundations of Embryology, 3rd ed. New York, McGraw-Hill, 1974, p 459. 5. Dawson W, Langman 1. An anatomical-radiological study on the pancreatic duct pattern in man. Anat Rec 1961;139. 6. Fallin LT. The development and cytodifferentiation of the islets of Langerhans in human embryos and foetuses. Acta Anat 1967; 68:147. 7. Skandalakis JE, Gray SW, Rowe JS, Skandalakis L1. Anatomic complications of pancreatic surgery. Contemp Surg 1979; 15:17. 8. Pearson S. Aberrant pancreas: Review of the literature and report of three cases, one of which produced common and pancreatic duct obstruction. Arch Surg 1951;63:168. 9. Keeley 11. Intussusception associated with aberrant pancreatic tissue. Report of a case and review of the literature. Arch Surg 1950; 60:691.

10. Howard JM, Moss HN, Rhoads JE. Collective review, hyperinsulinism and islet cell tumors of pancreas with 398 recorded tumors. Int Abstr Surg Surg Gynecol Obstet 1950;90:417. II. Quinlan RM. Anatomy and embryology of the pancreas. In: Zuidema GO (ed), Shackelford's Surgery of the Alimentary Tract. Philadelphia, WB Saunders, 1991. 12. Baldwin WM. The pancreatic ducts in man, together with a study of the microscopical structure of the minor duodenal papilla. Anat Rec 1911; 5:197. 13. Pansky B. Anatomy of the pancreas. Emphasis on blood supply and lymphatic drainage. lnt J PancreatoI1990;7:101. 14. Michels MA: Blood Supply and Anatomy of the Upper Abdominal Organs. Philadelphia, JB Lippincott, 1955. 15. Flati G, Flati 0, Porowska B, et al. Surgical anatomy of the papilla of Vater and biliopancreatic ducts. Am Surg 1994;60:712. 16. RienhoffWF Jr, Pickerell KL. Pancreatitis: An anatomic study of pancreatic and extrahepatic biliary systems. Arch Surg 1945;51 :205. 17. Prinz RA, Greenlee HB. Pancreatic duct drainage in 100 patients with chronic pancreatitis. Ann Surg 1981;194:313. 18. Gray SW, Skandalakis JS, Rowe JS, Skandalakis JE. Surgical anatomy of the pancreas. In: Nyhus LM, Baker RJ (eds), Mastery of Surgery. Boston, Little, Brown, 1984. 19. Sarr MG, Cameron JL. Surgical management of unresectable carcinoma of the pancreas. Surgery 1982;91: 123. 20. Lillemoe KD. Current management of pancreatic carcinoma. Ann Surg 1995;221: 133. 21. Flanigan DP, Kraft RO. Continuing experience with palliative chemical splanchnicectomy. Arch Surg 1978;113:509. 22. Stabile BE, Morrow OJ, Passaro E Jr. The gastrinoma triangle: Operative implications. Am J Surg 1984;147:25. 23. Howard TJ, Zinner MJ, Stabile BE, Passaro E. Gastrinoma excision for cure. Ann Surg 1990;211:9. 24. Yeo CJ, Want BH, Anthone GHJ, Cameron 11. Surgical experience with pancreatic islet-cell tumors. Arch Surg 1993;128:1143. 25. Iihara M, Kanbe M, Okamoto T, et al. Laparoscopic ultrasonography for resection of insulinomas. Surgery 2001; 130:1086.

Multiple Endocrine Neoplasia Type 1 Geoffrey B. Thompson, MD • William F. Young, Jr., MD

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant-inherited disorder affecting tumorigenesis in at least eight endocrine and nonendocrine tissues whose components were first recognized in the early 20th century. In 1903, Erdheim' described a patient with a pituitary adenoma and parathyroid hyperplasia discovered at autopsy. Gerstel? reported on a patient with acromegaly and a severe peptic ulcer diathesis in 1938. Wenner;' in 1954, identified the autosomal dominant nature of the disease that bears his name (Wenner's syndrome, now referred to as MEN 1). Children of an affected parent have a 50% chance of inheriting the disease predisposition that is noted to be highly penetrant. Larsson and associates," in 1988, mapped the gene associated with MEN 1 (MEN1) to the long arm of chromosome 11 (llq13). MEN1 is a tumor suppressor and encodes a widely expressed protein called menin. Clinical expression of the genotype requires not only inheritance of an MEN1 gerrnline mutation but also inactivation of the wild-type MEN1 allele derived from the unaffected parent.>? Mutations in the gene lead to widespread endocrine tumorigenesis. Approximately 90% of affected kindred members have mutations detectable by genetic testing, and the phenotype develops in virtually all individuals with gerrnline mutations.

Epidemiology and Clinical Presentation The true prevalence of MEN 1 is likely underestimated; data suggest a prevalence of 0.2 to 2/100,000. 8 Major clinical manifestations in MEN 1 include the "3Ps": primary hyperparathyroidism (HPT) (95%), pancreatic endocrine tumors (PETs) (50% to 75%), and pituitary tumors (30% to 55%). Expression of the disease rarely occurs before 10 years of age and most often presents between 20 and 40 years of age. 9. 10 Two of the three major lesions must be present for the clinical diagnosis in probands. In family members of known MEN 1 kindreds, the presence of one major lesion is diagnostic (Table 76-1).11 Clinical diagnosis is confirmed by genetic testing.

All three major clinical manifestations arise in less than 12% of affected patients.'! Any of these three clinical manifestations may be the first component precipitating a diagnosis, but in most patients, primary HPT appears by the 3rd or 4th decades of life. Biochemical abnormalities can be detected decades before clinically overt symptoms become manifest. 13 For example, biochemical abnormalities may be noted in affected adolescents in their mid to late teens when careful, regular screening is performed. 14 Studies have shown that delaying screening until clinical symptoms develop can be associated with locally advanced disease or distant metastatic disease in as many as 50% of patients with PETs. 13 Less common, but overrepresented, manifestations in MEN 1 include adrenocortical tumors.P"? foregut carcinoid tumors,18-23 nonmedullary thyroid neoplasms (mostly follicular),24.25 and a host of unusual cutaneous/mucosal or visceral abnormalities, including multiple subcutaneous and visceral lipomas, multiple facial angiofibromas, hypomelanotic macules, gingival papules, and collagenomas.P'F Rare associations with MEN 1 also include meningiomas, ependymomas, pinealomas, renal cancers, rhabdomyosarcoma, leiomyosarcoma, and pancreatic ductal adenocarcinoma.A"

The Molecular Biology of MEN 1 The gene responsible for MEN 1 was identified in 199729 and is located on chromosome llq13. MEN1 spans 9 kb of genomic DNA and consists of 10 exons containing an 1830-base pair coding region. MEN1 encodes a 610-amino acid nuclear protein, referred to as menin.4.29-32 Menin is localized to the nucleus and interacts with the activating protein 1 transcription factor JunD and other proteins involved in transcription and cell growth regulation.Y" MEN1 mutations are spread over the entire coding region (exons 2 to 10); approximately 50% are frameshift, 24% are missense, 20% are nonsense, and 7% are deletion or in-frame insertion mutations." MEN1 acts as a tumor suppressor gene, and tumor development follows Knudson's "two-hit" hypothesis.'? Hence, individuals affected with MEN 1 inherit one MEN1

673

674 - - Endocrine Pancreas

Who Should Be Considered for Genetic Counseling and Testing?

allele with a gerrnline mutation (the "first hit"), and tumorigenesis in specific tissues then occurs after a second deleterious mutation (the "second hit") is acquired in the remaining wildtype allele in a single cell." Such homozygous-inactivating MEN] mutations result in menin protein absence or truncation, and neoplastic clonal expansion from that cell is then initiated. Thus, the mechanism for tumor formation in MEN 1 involves loss of menin function in a tumor precursor cell. Unlike the RETprotooncogene (associated with MEN 2), mutations in MEN] do not clearly demonstrate significant genotype-phenotype correlations. 36,38-4o Recent studies have found preliminary data suggesting that mutation type or location within MEN] may be associated with clinical presentation." However, the limited data available regarding genotype-phenotype correlations do not currently warrant modification of clinical management. Several analytic approaches to identifying MEN] mutations have been used, but most laboratories currently use direct DNA sequencing. The first step in the analysis of a sporadic case or a patient in a kindred with suspected or proven MEN 1 is to identify the specific MEN] mutation in germline DNA. Germline testing requires peripheral blood from an affected index case. In most probands, a disease-causing mutation is identified. Because MEN] somatic mutations are commonly found in endocrine tumors, tumor DNA is rarely useful in distinguishing germline mutations.t'r'" It is estimated that more than 10% of gerrnline MEN] mutations arise de novo and can subsequently be passed to future generations.Pr" Mutations in MEN] are highly penetrant; approximately 50% of mutation carriers are symptomatic by 20 years of age, and nearly 100% are symptomatic by 60 years of age. Most large series have failed to find MEN] gerrnline mutations in 10% to 20% of index cases,31.38.44-46 likely reflecting undetected mutations, such as large deletions that are transparent to DNA sequence analysis or mutations in another unknown gene. MEN1 mutational analysis is clinically available in at least four molecular genetics laboratories in North America.

In general, genetic screening of presymptomatic individuals is appropriate when early therapeutic interventions are available for the tumors diagnosed, particularly when diagnosed at a preclinical stage. Although this has not been proven in randomized, prospective studies of MEN 1 patients and remains somewhat controversial, there is an increasing body of evidence to support this contention, particularly with regard to MEN 1 pancreatic neuroendocrine tumors. 13,47.52 Although early recognition and intervention with regard to parathyroid and pituitary neoplasia does not prolong survival, it can reduce or prevent morbidity associated with hormonal overactivity and mass effect. Clinical screening of at-risk family members belonging to known MEN 1 kindreds should begin in adolescence, a time when biochemical abnormalities can begin to be detected long before overt clinical manifestations and metastases occur. 13 If a familial mutation has been identified, a negative genetic test in an at-risk family member precludes the need for routine, lifelong biochemical screening and imaging. However, if a mutation is not detected in a proband, further testing for MEN] mutations in at-risk family members is not indicated, and presymptomatic testing is not possible by direct DNA testing. In these cases, at-risk family members must continue to be clinically monitored throughout their lifetimes. Such families in which a mutation cannot be identified may consider pursuing linkage analysis, a less direct method of tracking the disease allele through the family. Because the process of genetic testing can be complicated, genetic counseling is recommended for all families considering this option. Presymptomatic testing of at-risk family members can be emotional, and families may benefit from a session with a genetic counselor. The genetic counselor acts as a guide, explaining the pros and cons of testing as well as aiding with interpretation of the results should the family choose to proceed. Regarding testing of apparently sporadic MEN 1 patients, mutation screening should be considered in young patients «50 years of age) with HPT, particularly in those with multi gland disease or recurrent HPT in the absence of renal disease. Consideration should also be given to testing patients with prolactinomas because up to 14% of such patients may actually have MEN 1. Testing is also appropriate for patients with multiple pancreatic neuroendocrine tumors (calcium levels should be checked in all patients with solitary PETs), patients with any MEN 1 lesion and an adrenal lesion, and patients with bronchial and thymic carcinoids (Table 76-2).13

Pituitary Tumors In MEN 1 kindreds, pituitary tumors are found less frequently than primary HPT or PETs.4o Signs and symptoms related to a pituitary adenoma are the initial clinical presentation of MEN 1 in up to 25% of "first in the kindred" cases but in less than 10% of familial cases that are

Multiple Endocrine Neoplasia Type 1 - - 675 successful pharmacologic or surgical treatment of the pituitary tumor, MEN 1 patients should continue to be evaluated with periodic pituitary tumor screening since a second pituitary adenoma may arise from the remaining pituitary tissue.

Primary Hyperparathyroidism

diagnosed prospectively.53 The estimated prevalence of pituitary tumors in MEN 1 patients ranges from 10% to 60%.53-55 For example, in a series of 324 patients with MEN 1, pituitary adenomas occurred in 197 (42%); mean age at diagnosis was 38 years (range, 12 to 83 yearsj." In most MEN I patients, the pituitary tumors are macroadenomas (>10 mm) (Fig. 76-1).56 All subtypes of pituitary adenoma have been reported in MEN 1, but most frequently they are prolactinomas (""60%). Patients may present with amenorrhea/galactorrhea in women, symptoms related to hypogonadism in men, and/or sellar mass effect symptoms. 53,56,5? Less common pituitary tumor subtypes in MEN 1 include somatotroph adenoma (acromegaly; ",,25%), corticotroph adenoma (Cushing's syndrome; ",,5%), and clinically nonfunctioning pituitary tumors (",,10%). Monitoring for pituitary tumor development in the MEN 1 patient should include measurement of serum prolactin and insulin-like growth factor 1 as well as imaging of the pituitary by magnetic resonance imaging (MRI) every 2 to 3 years." In patients with an abnormal pituitary MRI, hypothalamic-pituitary testing should be completed to characterize the type of the pituitary adenoma and its effects on the secretion of other pituitary hormones. Treatment of pituitary tumors in MEN 1 is guided by the adenoma subtype and is identical to that in patients with sporadic pituitary tumors (Fig. 76-2). In addition, after

Most MEN 1 patients develop hypercalcemia and primary HPT by the 4th decade of life. 58 Shepherd described elevated ionized serum calcium levels in 66% of patients younger than 25 years of age, 85% of patients between 25 and 55, and 87% of patients older than 55 in a large cohort of MEN 1 family members.58 Skogseid and colleagues described a mean age of onset of HPT at less than 19 years." This is in sharp contrast to patients with sporadic primary HPT who typically present in their 50s and 60s. Primary HPT is the initial clinicallbiochemical manifestation of MEN 1 in 60% to 90% of patients, but the percentage may be as low as 30% in young at-risk patients who are screened. 53 A serum factor mitogenic for parathyroid cells has been isolated in MEN 1 patients at levels 20 times those of normal subjects. Parathyroid mitogenic factor has far greater activity than any other measurable growth factor, and its activity has been quantified by in-vitro studies."

Diagnosis The diagnosis of primary HPT (Table 76-3) is dependent on demonstrating an inappropriate immunometric parathyroid hormone (PTH) level in the face of an elevated ionized serum calcium level. Hypocalciuria due to benign familial hypocalciuric hypercalcemia (BFHH) should be ruled out by calculating the calcium-creatinine clearance ratio: (24-hour urine calcium x serum creatinine) + (24-hour urine creatinine x serum calcium)

FIGURE 76-1. Head MRI showing coronal (A) and sagittal (B) views of a prolactin-secreting pituitary macroadenoma (arrows) in an 18-year-old young man with multiple endocrine neoplasia type 1. The patient presented with a 5-year history of daily headaches, vision

loss, and delayed sexual maturation. The serumprolactin level was 6309 ng/mL(normal, I to 15 ng/mL).

676 - - Endocrine Pancreas

FIGURE 76-2. Endonasal transsphenoidal pituitary surgery. (©Mayo. 2001.)

and by obtaining a detailed family history. Calcium-creatinine clearance ratios lower than 0.01 are indicative of BFHH.

Localization Studies Imaging clearly has a role in the evaluation and management of patients with sporadic HPT, of whom 85% have a solitary

adenoma, rendering many of these patients candidates for a directed surgical approach.60-62 The benefits of minimally invasive parathyroidectomy in this subgroup of sporadic patients appear real. In MEN 1 patients, however, the pathology is that of asymmetrical hyperplasia involving all parathyroid glands. Therefore, regardless of imaging, all glands must be explored and a transcervical thymectomy performed to rule out a supernumerary or ectopic gland, which is seen in as many as 20% of MEN I patients. Imaging in the setting of multigland disease is often misleading and frequently demonstrates only the dominant gland or glands.v' Sestamibi parathyroid scanning (SPS) 64 and percutaneous neck ultrasound'" typically demonstrate only the dominant gland or glands in MEN 1 patients, that if treated as such, will lead to persistent HPT for the unknowing and inexperienced surgeon.f SPS may, on occasion, demonstrate an ectopic or supernumerary gland that may be easier to find with preoperative knowledge of its whereabouts. These include hyperplasticglands located in the low anterior,middle, and deep posterior mediastinum; the undescended and intrathyroidal glands; and the rare intrapharyngeal gland. Imaging does, however, become essential in MEN 1 patients with recurrent disease (discussed later). 65-73

Management of MEN 1 lIY1Pe~arathyroidism

The timing of parathyroidectomy is an important issue. MEN 1 HPT involves all parathyroid tissue; thus, any treatment surgeons provide is considered palliative.Y" Attempts at eradicating all parathyroid tissue can result in a treatment

Multiple Endocrine Neoplasia Type 1 - - 677

that is far worse than the disease itself (permanent hypoparathyroidism). In the past, 40% to 50% of MEN 1 patients presented with nephrolithiasis; however, more recently, patients are being explored for mild or relatively asymptomatic disease. In patients with mild disease, it is appropriate to delay surgery until the serum calcium level is ~l mg/dl, above the upper limit of normal." Other indications include nephrolithiasis/nephrocalcinosis, hypercalciuria, glomerular filtration rate decreased by ~30% for ageand gender-matched controls, worsening bone (hip, radius, or spine) mineral density, especially when the T-score is less than -2.5 (2 SD from normal controls)," and pancreatitis." Vague neuropsychiatric disturbances and muscle weakness are less specific indicators. MEN 1 patients with hypergastrinemia and hypercalcemia should undergo early parathyroidectomy.Y'" Hypercalcemia is a potent stimulus for gastrin secretion. Control of hypercalcemia can lower or even normalize serum gastrin levels, often alleviating symptoms in MEN 1 patients with Zollinger-Ellison syndrome (ZES),79,80

Operative Approach A Kocher collar incision is made. The incision is deepened down through the platysma, and superior and inferior subplatysmal flaps are developed. The median raphe is divided and the strap muscles are retracted laterally without division. The thyroid lobes are sequentially elevated, and all four parathyroid glands and any supernumerary glands are exposed. Most supernumerary glands are located in proximity to the other glands or less often in ectopic locations. Transcervical thymectomy should be performed to rule out a supernumerary gland and to evaluate the thymus for a carcinoid tumor. Failure to identify a superior gland necessitates mobilization of the superior thyroid pole by individually ligating the superior thyroid artery and vein or their branches on the thyroid capsule. This helps avoid injury to the external branch of the superior laryngeal nerve. Rotation of the upper pole upward and outward often brings the superior gland into view. Larger superior glands can migrate along the tracheoesophageal groove, into the retroesophageal space, and down into the posterior mediastinum. These can usually be elevated into the wound with adequate exposure and gentle traction. Missing inferior glands should be sought within the thymus, the carotid sheath, in an undescended location in front of the carotid bifurcation, and just beneath the thyroid capsule, typically along its inferior pole. The rare undescended superior parathyroid gland can be located within the pharyngeal musculature. Intraoperative ultrasonography (IOUS) may be of aid in locating ectopic glands within the neck.81 Once four glands have been identified and the transcervical thymectomy has been performed, the surgeon then proceeds with a subtotal parathyroidectorny.P It is our preference to leave behind an inferior gland or a portion thereof, depending on its size. Leaving an inferior gland or remnant makes reoperation safer because of the inferior gland's distance from the recurrent laryngeal nerve. If a superior gland is much smaller or grossly normal compared to the rest, we would consider leaving this as the remnant. The vascularized remnant should be approximately 50 to 60 mg in weight.83-85 The remnant should be prepared prior to excising the other glands so as to ensure its viability prior to completing the

subtotal parathyroidectomy. If the remnant becomes devascularized, it should be removed and the other inferior gland trimmed. The remnant or remaining gland should be tagged with a nonabsorbable suture or preferably a metal clip. Additional parathyroid tissue should be cryopreserved or immediately autotransplanted (multiple small pieces totaling 50 to 60 mg) into a small, infraclavicular, subcutaneous pocket. Despite earlier reports regarding the efficacy of cryopreservation'f" and the viability of cryopreserved tissue in vitro studies/" we have used few of the hundreds of cryopreserved specimens stored at Mayo Clinic. When used, rarely have these delayed autotransplants resulted in meaningful restoration of normal parathyroid function. It is now this surgeon's (GBT) practice, when performing a subtotal parathyroidectomy, to transplant 50 to 60 mg of nonmalignant parathyroid tissue into a chest wall subcutaneous pocket just below the clavicle. If the immunometric PTH level is ~l pmollL (normal, 1 to 5 pmollL) 24 hours postoperatively, the transplant is removed at the bedside. If the postoperative immunometric PTH is below the level of detection, the transplant is left in place. Time will tell whether graft-dependent recurrences will be easier to detect and manage in this location, but it is thought to be the case. By placing the graft close to the deltopectoral groove, below the clavicle, selective venous sampling (SVS) (subclavian vein) can be used along with SPS and ultrasound to evaluate for graft-dependent recurrence. Another option for managing MEN 1 primary HPT is total parathyroidectomy, transcervical thymectomy, and immediate forearm autotransplantation. 86,87,9O Autotransplantation is classically carried out by implanting 10 to 15 (l-mm) pieces of fresh tissue into multiple pockets of the nondominant, brachioradialis forearm muscle. Each site is marked with a fine, monofilament nonabsorbable suture for future reference. The forearm skin incision should be made in a longitudinal fashion so as to avoid confusion with regard to a self-inflicted wound. Recurrence rates are extremely low following total parathyroidectomy, but permanent hypoparathyroidism rates can be unacceptably high.91.93 Later explantation is also more formidable with regard to intramuscular implants.

Persistent/Recurrent Hyperparathyroidism in MEN 1 Patients Permanent hypoparathyroidism occurs in less than 10% of patients undergoing subtotal parathyroidectomy, and most series describe rates in the range of 1% to 2%.92-95 The rates of permanent hypoparathyroidism range from 10% to 30% for patients undergoing total parathyroidectomy with immediate autografting. 85.92 Total parathyroidectomy, however, has been associated with recurrence rates as low as 0 (range, o to 60%), whereas recurrence rates for subtotal parathyroidectomy have never been reported less than 4% (range, 4% to 20%).83,85,91-97 Persistent HPT is generally less than 5% with both procedures.v-'? Malmaeus and coworkers found that when 1 to 2.5 glands were removed, persistent HPT occurred in 24% and recurrent disease in 62%. The recurrence and persistence rate was 0 in 18 patients undergoing total parathyroidectomy (Table 76-4).92 Persistent HPT occurs because of misdiagnosis of hyperplasia and incomplete resection. Recurrent HPT is generally

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the result of failure to locate one or more supernumerary glands or is due to hyperfunction of the cervical remnant or (forearm) autograft. When evaluating a MEN 1 patient for persistent/recurrent disease, it is essential to first re-establish the diagnosis. Elevated ionized calcium, a detectable and inappropriate immunometric PTH level, and a calcium-creatinine clearance ratio higher than 0.01 confirm and re-establish the diagnosis. Review of previous operative records and prior pathology slides is essential to the understanding of what was and was not accomplished at past exploration.A direct fiberoptic laryngoscopy should be performed to evaluate cord function prior to re-exploration. In addition, an assessment of HPT-associated morbidity should be ascertained (kidney, ureter, bladder films with tomograms, creatinine clearance, and bone mineral density) to evaluate the risk-benefit ratio for reoperation. Imaging is essential in the reoperative setting,64-73 and operative success appears to correlate with an increasing number of concordant tests.64 Preoperative localization is critical because of scarring, loss of normal tissue planes, and the increased likelihood of ectopic/supernumerary glands in the reoperative setting. Percutaneous ultrasonography, SPS, computed tomography (CT), MRl, SVS, and angiography all have been used with varying degrees of success in reoperative MEN 1 HPT patients (Table 76-5). Today, our test of choice remains sestamibi parathyroid subtraction scanning with 1231. 98-100 Subtraction scanning with either 1231 or 99mTc pertechnetate is superior to nonsubtraction studies (delayed imaging or washout studies). Subtraction with 1231 appears to provide sharper images and may be superior in the setting of multigland disease.I?'

The combination of oblique planar images and singlephoton emission CT yields the most sensitive information (Figs. 76-3A and 76-4A).102 Sensitivities in the range of 70% to 85% have been reported.98-102 SPS falls short in patients with multigland disease (but less so when only one or two glands remain) and in patients with nodular thyroid disease. It is particularly helpful in patients with mediastinal and ectopic glands/" Cervical ultrasonography is the second most frequently used imaging study. It is very observer dependent, with reported sensitivity rates varying between 25% and 90%.60.65-68 The Mayo Clinic and the University of California-San Francisco have reported sensitivities of 48% to 55% with large numbers of patients.P'" Ultrasound is hampered by thyroid nodules, enlarged lymph nodes, and tumors directly adjacent to the trachea and bony structures. Using ultrasound guidance, a fine-gauge needle can be inserted into the gland in question. Cells can then be sent for cytology and the aspirated effluent for immunometric PTH levels.F" Marked elevation in immunometric PTH levels (several thousands) is pathognomonic for abnormal parathyroid tissue, and rarely are the results equivocal. MRl provides less scatter artifact from previously placed metal clips. It is particularly helpful for imaging ectopic glands. Parathyroids demonstrate high signal intensity on T2-weighted MR images (~fat). Sensitivity ranges from 60% to 80% have been reported in more recent studies. 72,73,104-1l0 Today, it is also possible to perform computed fusion studies correlating findings on MRI/CT with those seen on nuclear scintigraphy.'!' CT is most useful for identifying ectopic glands within the mediastinum. It requires the use of intravenous ionized contrast material and carries with it true-positive rates of only 24% to 52%.65,69,70.71 CT is particularly hampered by the presence of previously placed metal clips. If two of the tests discussed earlier (sestarnibi/ultrasound, ultrasound/fine-needle aspiration, sestamibi/MRl or CT) are concordant, then surgery is the next step. If only one test is positive, or if there is equivocation or marked discordance among the tests, then consideration should be given to SVS.ll2 Immunometric PTH gradients are sought by selectively catheterizing and sampling various cervical and mediastinal veins, comparing the immunometric PTH levels to those of a peripheral vein. If a forearm autograft is present, gradients can be determined by sampling veins from both arms. 112 Peripheral forearm samples can be measured before and after inducing temporary limb ischemia with a tourniquet to check for graft-dependent recurrence (Casanova test).lI3 The National Institutes of Health reported that SVS

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FIGURE 76-3. A, Sestamibi parathyroid scintigraphy demonstrating an abnormal left superior parathyroid gland on oblique image. B, "Lateral approach" to superior parathyroid during reoperation for recurrent hyperparathyroidism. (©Mayo, 1999.)

localized (or regionalized) 76% of previously missed adenomas with a 4% false-positive rate.'? The true-positive rate for SVS at University of California-San Francisco was 69% with a false-positive rate of 15%.71 Selective angiography has been used as a last resort because of anecdotal reports regarding cerebrovascularevents. Selective arterial catheterization of the common carotid, thyrocervical, and internal mammary arteries has been reported to demonstrate a vascular blush in 60% to 80% of patients.69.114-116 The hypocalcemic stimulus of selective intra-arterial injection of nonionic contrast material has also been used to augment immunometric PTH levels during venous sampling of the superior vena cava.116 Angiography has also been used for ablation of mediastinal glands supplied by branches of the bronchial and internal mammary arteries.114 The decision to operate on patients without localization or with only one positive test must be individualized based on the degree of disease-related morbidity and sound clinical judgment. In patients with minimal or no overt complications and calcium levels lower than 11 to 11.5 mg/dL, an argument can be made for waiting 3 to 6 months and then reimaging. IOUS and radioguided surgery following a preoperative injection of sestamibi may serve as useful adjuncts to the surgeon, particularly in some of the more challenging cases. 82,117-119

Intraoperative PTH monitoring may be useful in determining the completeness of resection in both first-time and reoperations for MEN 1 HPT.120.121 Although the 50% rule (>50% drop in serum PTH levels from baseline within 10 minutes of parathyroid resection) is thought to apply in all cases, we have had false-positive results in patients with multigland disease when the immunometric PTH level fell between 50% and 70%.64 Our preference following subtotal, total, or completion parathyroidectomy is to see the intraoperative PTH level fall to normal or undetectable levels at 15 minutes following excision of the presumptive last gland. False-negative and positive studies do occur.122

Operative Approach in Persistent/Recurrent Hyperparathyroid MEN 1 Patients The operative plan is generally that of a directed approach based on preoperative imaging and the number of glands previously removed. The previous collar scar is excised for an optimal cosmetic result. Subplatysmal flaps are created, and the parathyroids are approached from lateral to medial via the "lateral approach" (see Fig. 76-3B). This provides an unscarred path to the tracheoesophageal groove. A plane is developed between the sternocleidomastoidand strap muscles. The omohyoid tendon is divided along with branches of the

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7~. A, Sestarnibi parathyroid scintigraphy demonstrating intrathymic mediastinal parathyroid gland. B, Transcervical thymectomy during reoperation for persistent hyperparathyroidism. (©Mayo,

FIGURE

1999.)

ansa cervicalis to the strap muscles. The contents of the carotid sheath are carefully retracted laterally, and the tracheoesophageal groove is exposed low in the neck to visualize the recurrent laryngeal nerve in an unviolated plane. Once the nerve is exposed, the direction of the operation is determined by the findings on the preoperative imaging studies. An inferior gland within the thyrothymic ligament can be reached by grasping the ligament anterior to the trachea and beneath the strap muscles. The thymus is then teased into the wound with gentle traction, dividing lateral venous tributaries to the innominate vein between fine metal clips. Dividing the strap muscles at the level of the clavicle can facilitate exposure. Our preferred alternative is to incise the median raphe low in the neck and expose the thymus

anteriorly (see Fig. 76-4B). The thymus is extracted until the enlarged parathyroid gland is fully exposed. Upward retraction of the manubrium facilitates the dissection. The feathered end of the thymus is transected between right-angled clamps and removed. If the gland is within the tracheoesophageal groove (superior gland), it is often apparent as the groove is approached from lateral to medial. Once the nerve is exposed low in the neck, its entire course throughout the neck should be carefully exposed. This is facilitated by dividing the superior thyroid vessels and mobilizing the superior pole of the thyroid lobe up and out of the wound. The retroesophageal space and upper posterior mediastinum can be reached from the lateral approach, as can the carotid sheath, carotid bifurcation, thyroid, and pharyngeal musculature. IOUS can

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be used to visualize nonpalpable intrathyroid and intrapharyngeal tumors, as well as carotid sheath and undescended glands. Once the offending gland has been removed, it is kept sterile on iced saline. Intraoperative PTH monitoring is performed. If the PTH falls to low-normal or undetectable levels or at least to below 70% of baseline within 15 minutes of excision, one can safely terminate the exploration after transplanting 50 to 60 mg of parathyroid tissue into the nondominant brachioradialis muscle (or infraclavicular subcutaneous region). If levels do not fall, unilateral or bilateral re-exploration should proceed via lateral and anterior (for thymic glands) approaches until all offending tissue is removed and confirmed by intraoperative PTH. The goal of reoperative parathyroid surgery in MEN 1 should be to eliminate all parathyroid tissue and autotransplant 50 to 60 mg of tissue into an extracervical site. There is an exception, however, to this rule. In the era of minimally invasive parathyroidectomy, unsuspecting surgeons may perform excision of a dominant gland based on SPS. If such a patient turns out to be an MEN 1 proband or kindred member, the limited dissection still allows one to go back and perform a subtotal parathyroidectomy. Given the risk of permanent hypoparathyroidism following total parathyroidectomy, this seems appropriate if a 50- to 60-mg inferior remnant can be left on the contralateral or ipsilateral side to the prior minimally invasive procedure. Deep-seated mediastinal glands pose a special challenge. Less than 2% of all parathyroid operations require a noncervical approach. Most thymic glands can be reached via a cervical approach, but when this is not possible, options include a partial or full median sternotomy, a limited left anterior thoracotomy (Chamberlain procedure), video-assisted endoscopic/thoracoscopic approaches, and conventional posterolateral thoracotomy.123,124 Abnormal glands in the aorticopulmonary window require left thoracotomy or full median sternotomy, taking care to avoid injury to the left recurrent laryngeal nerve as it courses along the ligamentum arteriosum. Tumors in the right middle mediastinum (adjacent to the right pulmonary artery and tracheal bifurcation) are best accessed via a right posterolateral thoracotomy. Angiographic ablation has been used successfully for elimination of select tumors whose blood supply is derived from branches of the internal mammary or bronchial arteries. I 14,125 Graft-dependent recurrences can be managed with surgical excision under local anesthesia. Intramuscular grafts can be challenging to explant and debulk.P' giving rise to consideration for infraclavicular subcutaneous implants. Another management option for graft-dependent and remnant-dependent recurrences is ultrasound-guided percutaneous ethanol ablation.P? This is not curative and will require future retreatment. However, given the palliative nature of surgery for MEN 1 HPT, this offers a nonoperative approach for normalizing calcium and PTH levels, albeit for short periods. Recurrent laryngeal nerve injury can occur when alcohol ablation is used for remnant-related recurrences.

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occurs in 10% to 30% of reoperations, with a permanent recurrent laryngeal nerve injury rate of 1% to 5%.83,90.93.128

Pancreatic/Duodenal Neuroendocrine Tumors Background Pancreatic and duodenal neuroendocrine tumors represent the second most frequent classic manifestation in MEN 1P These neoplasms become clinically apparent in 50% to 75% of kindred mernbers.P Autopsy studies have demonstrated histologic changes in more than 80% of MEN 1 patients. 129- 131 The MEN 1 pancreas is characterized by multiple microadenomas and macroadenomas (Fig. 76-5), islet hypertrophy, hyperplasia, and dysplasia, as well as islet cell carcinomas; nesidioblastosis occurs rarely.132,133 PETs may arise from precursor cells within the pancreatic ducts. Neoplastic cells are argyrophilic and contain secretory granules. Most tumors stain positive for chromogranin A, synaptophysin, and neuronspecific enolase with immunohistochemistry.Pt!" The tumors are generally solid, but large cystic variants have been reported (Fig. 76_6).136,137 Cellular pleomorphism is common even in adenomas, and the diagnosis of malignancy can be made with certainty only in the presence of metastatic

Results of Reoperative Surgery Normocalcemia is achieved in the reoperative setting in 20% to 65% of cases, with subsequent recurrences occurring in 30% to 60% (Table 76_6).83.90,93.128 Permanent hypoparathyroidism

FIGURE 76-5. Multiple islet tumors in a patient with multiple endocrine neoplasia type I with endogenous hyperinsulinism.

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FIGURE 76-6. CT scan (A) and distal pancreatectomy/splenectomy specimen (B) in a patient with multiple endocrine neoplasia type 1 with large cystic islet cell carcinoma.

disease or by demonstrating direct invasion of contiguous structures. Elevation of biochemical serum markers is frequent, even in the absence of an overt clinical syndrome.P These markers include pancreatic polypeptide (PP), insulin, glucagon, gastrin, proinsulin, somatostatin, vasoactive intestinal polypeptide (VIP), parathyroid hormone-related peptide (PTHrp), and neurotensin.13.138.139 Approximately 50% of MEN 1 patients with PETs have duodenal carcinoids.PThese are typically small «5 to 10 mm), submucosal, and multiple. Duodenal carcinoids in MEN I typically secrete gastrin but may also produce serotonin and somatostatin.l-P More than 90% of MEN I gastrinomas are duodenal in origin; the remainder are pancreatic. Although most duodenal carcinoids can be found in the first and second portions of the duodenum, they can be found throughout the duodenum.I'" This has important implications when planning an exploratory duodenotomy. When discovered, nearly 50% of pancreatic and duodenal endocrine tumors have metastasized to regional lymph nodes or the liver.130-135.141 All pancreatic/duodenal endocrine tumors are capable of malignant transformation, and this is especially true for nonfunctioning tumors. Size does not necessarily correlate with malignant behavior. 136.137 Although there is a correlation between primary tumor size greater than 3 em and the presence of liver metastases.I" even the smallest tumor is capable of spreading to regional lymph nodes. Pancreatic and duodenal endocrine tumors are the number one causes of tumor-related death in MEN 1 patients. 135.141.142 Although genotype-phenotype correlations are not well understood in MEN I, genetic testing is now available that is capable of identifying MEN1 mutations in up to 90% of probands" An increasing body of evidence suggests that morbidity can be reduced and survival prolonged with early detection of PETs in at-risk MEN 1 family members, hence highlighting the potential importance of presymptomatic

testing. 12,47.50.140 No data exist, however, from randomized, controlled, prospective studies, and it is unlikely that there will ever be such trials given the small number of patients, the safety of proposed therapeutic interventions, and the evidence available from noncontrolled prospective and retrospective studies.

Biochemical Screening Skogseid and associates'V" have recommended an annual biochemical screening program beginning in adolescence that consists of measuring glucose, insulin (proinsulin), gastrin, PP, glucagon, and chromogranin A (sensitivity, 35% to 70%) (Table 76-7). PP is a nonspecific islet cell tumor marker whose levels must be adjusted for age. High levels correlate with large, radiographically detectable tumors.If Chromogranin A is the most sensitive of the markers mentioned but generally requires a larger tumor burden for easy detection. I44,145 False-positive results have been reported in the setting of hypertension, renal disease, stress, and inflammatory bowel disease. Gastrin levels are rarely elevated in young patients. When basal gastrin levels are increased, it is usually an indicator of multiple duodenal carcinoids or a larger pancreatic primary. 13 A standardized meal test with measurement of serum PP and serum gastrin responses enhances the specificities of both of these latter two markers in predicting the presence of pancreatic and duodenal endocrine tumors.l'" An abnormal response for serum PP is a value that is greater than 2 SDs above the mean for healthy controls. 146 Similarly, a doubling of postprandial gastrin levels to twice the upper limit of normal is considered a positive test. 146 Antral G-cell hyperplasia, however, can give a similar gastrin response. To improve the specificity of the screening program, Skogseid and associates have insisted that two independent serum markers be elevated and increasing over a

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FIGURE 76-7. Endoscopic ultrasonography of a hypoechoic islet cell tumor in the pancreatic body (arrow).

Imaging

6-month interval.l-!" Insulin and proinsulin are dependent serum markers, as is an abnormal response for PP and gastrin following a standardized meal stimulation test.13.146 When the basic biochemical screening program is positive, it is reasonable to extend the investigations to other less common markers including VIP, calcitonin, PTHrp, and 24-hour urinary 5-hydroxyindoleacetic acid. If elevated, these may serve as useful markers in future follow-up. Hormonal profiles may change with time, may be polyhormonal, and may differ from primary tumor to metastases.P Elevations in the beta and alpha subunits of human chorionic gonadotropin may be indicators of malignant transformation.P Formal 72-hour fasts for insulinoma and provocative testing for gastrin are applied selectively.

Conventional imaging (percutaneous ultrasound, CT, MRI) modalities for the early detection of pancreatic duodenal endocrine tumors is fraught with hazard; both low sensitivities and specificities have rendered the earlier mentioned biochemical screening protocol even more important.F'{" The sensitivity for endoscopic ultrasonography, however, may be as high as 90% (Fig. 76_7).149.151 Diagnostic accuracy increases when somatostatin receptor scintigraphy (Fig. 76-8) correlates with endoscopic ultrasonographic findings.ISO.ISI Endoscopic ultrasonography also offers the opportunity for directed fine-needle aspiration cytology. We discourage this for tumors in the pancreatic head because efforts at enucleation may be thwarted by even the slightest amount of bleeding and inflammation. If this does occur, surgery should be delayed for several weeks to allow resolution to take place. The efficacy of PET scanning for pancreatic duodenal endocrine tumors remains to be determined. 152

Who Should Undergo Surgery? Patients with two rising independent serum markers, regardless of negative imaging, should be explored (Table 76_8).13

FIGURE 76-8. Somatostatin receptor scintigraphy (left [anterior] and right [posterior]) demonstrating a gastrinoma in the region of the duodenum with multiple hepatic metastases.

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FIGURE 76-9. Enucleation of an islet cell tumor in the pancreatic head. Dissection of the pancreas "away from tumor" using an endarterectomy spatula and minimal bipolar cautery is illustrated. (From Thompson GB. Islet cell tumors. In: Mayo Clinic Gastrointestinal Surgery. Philadelphia, WB Saunders, 2003.)

Other Pancreatic Endocrine Tumors An elevated biochemical marker and an unequivocal imaging study (endoscopic ultrasonography plus fine-needle aspiration) or concordant endoscopic ultrasonography and somatostatin receptor scintigraphy in the absence of biochemical markers would be the other indications, in the absence of distant metastatic disease.'! In carriers of germline mutations who have a single positive biochemical marker, imaging should be carried out yearly (but every 3 years for those with negative biochemistryj.P Some centers now rely exclusively on endoscopic ultrasonography for screening, but further validation is warranted.

Hypoglycemic Syndrome Insulinoma associated with endogenous hyperinsulinism is the most common functioning PET in MEN I patients younger than 25 years of age." Although these patients often have multiple pancreatic tumors, typically only one is the source of insulin excess.P This raises the question of whether selective arterial calcium stimulation testing with hepatic vein sampling for insulin should be considered. 139,153 Although insulinomas are most often benign, there is no effective medical therapy. Without surgery, hormonal sequelae remain debilitating and lifethreatening. Surgery involves an 80% distal pancreatectomy to the right of the superior mesenteric vein with enucleation (Fig. 76-9) of any remaining pancreatic head tumors, using IOUS.154 This removes the insulinoma(s) as well as many of the nonfunctioning tumors capable of malignant transformation. Splenic preservation may be possible in young, thin patients by carefully separating the splenic vein from the underside of the gland using fine metal clips and an ultrasonic dissector. Small spleens can be preserved on the short gastric vessels alone. Recurrence rates in patients with MEN I are higher than in sporadic cases but nonetheless are acceptable. 13 Leaving behind 20% of the pancreas generally limits recurrences and avoids endocrine insufficiency in most cases.

MEN 1 patients with malignant islet cell tumors (glucagonomas, VIP tumors, PTHrp tumors, and some insulinomas) deserve an equally, if not more aggressive approach, including an 80% distal pancreatectomy, splenectomy, and lymphadenectomy, along with enucleation of any residual tumors. Isolated liver metastases or a finite number of multiple hepatic metastases can be successfully managed, with excellent control of hormonal sequelae, using a combination of hepatic resection and radiofrequency thermal ablation. 155,156

Zollinger-Ellison Syndrome Gastrinomas represent the most common functioning pancreatic/duodenal endocrine tumors in MEN 1 patients. 157 Nearly one third of ZES patients are MEN I kindred members, and more than 50% of MEN 1 patients have hypergastrinemia. In the past, surgery for MEN I ZES was carried out with reluctance, if at all. 158-160 Cure rates were low, based on normalization of gastrin levels, and medical therapy in the form of proton pump inhibitors (PPIs) has been extremely effective at eliminating peptic acid sequelae. Medical therapy does not, however, prevent malignant transformation, nor does it prevent the development of metastatic disease.P? Presently, 30% to 50% of patients undergoing surgical exploration have at least regional nodal metastases, many of which are amenable to resection, often providing excellent palliation. 125,161 More than 80% of gastrinomas in MEN 1 patients are duodenal in origin.50.140.157 In addition, ZES patients appear at greater risk for malignant transformation of nonfunctioning tumors when compared to other MEN I patients. 13,162,163 Norton and colleagues have shown that patients with nodal metastases can achieve similar survival benefits with operative intervention compared to those without lymph node involvemenr"! Gastrin levels often rise late in MEN 1 patients. Once the gastrin level is elevated, 30% to 50% of patients already harbor nodal metastases even in the face of negative imaging studies. Resection of larger (>3-cm) PETs does not appear to reduce the risk of developing liver metastases, once again making a strong argument for screening, early detection, and early surgical intervention. 164

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The procedure most often performed has been popularized by Dr. Norman Thompson at the University of Michigan at Ann Arbor (Fig. 76_10).125,157,162,165 The surgery is carried out after adequate treatment with PPIs to heal active ulcers. Antibiotics and deep venous thrombosis prophylaxis are provided. The abdomen is thoroughly explored through a transverse epigastric or chevron incision. Careful attention is paid to the liver, which is explored both by palpation and IOUS. The gastrocolic omentum is completely mobilized off the transverse colon from left to right, entering the lesser sac. Both colonic flexures are mobilized and retracted caudally. The duodenum is widely kocherized out to the ligament of Treitz. The avascular plane along the inferior border of the pancreas is incised and the pancreatic body is freed to its superior border, The lienorenal and lienophrenic ligaments are divided using electrocautery, and the spleen, body, and tail of the pancreas are mobilized to the splenic veinsuperior mesenteric vein junction. The inferior mesenteric vein may require division to further facilitate exposure. The superior mesenteric vein is then isolated from the neck of the pancreas. Division of the anteroinferior pancreaticoduodenal vein, as well as the right gastroepiploic vessels, augments exposure of the uncinate and pancreatic head and reduces the risk of avulsing these delicate veins as the operation proceeds. At this point, careful bidigital palpation of the entire gland is carried out along with IOUS in anteroposterior planes and transverse-longitudinal directions. Special attention is paid to the location of the pancreatic and bile ducts and their relationship to nearby islet cell tumors. Lymph nodes are removed from along the posterior aspect of the pancreatic head, the hepatoduodenalligament, the subpyloric region, branches of the celiac artery, and the proximal superior mesenteric artery. In patients with hypergastrinemia, a longitudinal duodenotomy is made along the free wall of the second portion of the duodenum. The duodenal wall is

FIGURE 76-10. Eighty percent distal pancreatectomy (splenic preserving), enucleations (pancreatic head), exploratory duodenotomy, and lymphadenectomy for a patient with multiple endocrine neoplasia (MEN) type I and Zollinger-Ellison syndrome. (Courtesy of Dr. Norman Thompson, University of Michigan, Ann Arbor, Michigan.)

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carefully palpated between thumb and index finger proximally across the pylorus and distally beyond the ligament of Treitz. The duodenal mucosa is intussuscepted into the duodenotomy for further inspection and palpation. Smaller carcinoids are excised submucosally; larger tumors may require full-thickness excision. The duodenotomy is then closed longitudinally with interrupted, 3-0 absorbable suture to avoid luminal narrowing. An 80%distal resection is performed to the right of the superior mesenteric vein. Splenic preservation is carried out in the absence of large malignant tumors, as previously described. Any remaining tumors are enucleated using an endarterectomy spatula, bipolar cautery, and fine metal clips, carefully dissecting the pancreas away from the tumor so as to avoid pancreatic ductal injury (see Fig. 76-9). Enucleation sites are left open, and closed-suction drainage catheters are left in place. When available, intraoperative gastrin and insulin assays can be confirmatory. IOUS can help determine the integrity of the pancreatic duct following completion of the enucleation(s). The abdomen is closed in a standard fashion, and intravenous PPIs are continued in the postoperative period. A fasting basal serum gastrin level should be obtained prior to dismissing the patient; slight elevations may be due to PPIs. Oral PPIs are continued for 1 month while the duodenotomy heals. Failure to achieve eugastrinemia mandates continuation of medical therapy. Pancreatic pseudocysts and fistulas are the most common complications, affecting 10% to 20% of patients. Conservative management with closed-suction drainage and time usually results in the resolution of most of these problems. Thompson has the largest series (over 40 patients) of MEN l/ZES patients having undergone this procedure. One half remain eugastrinemic. Distant metastases and death have rarely occurred with follow-up as long as 4 decades. Clearly, this surgery has had a profound impact on the natural history of the disease in this surgeon's hands (personal communication). 157,162 Other operative approaches include total pancreatectomy, pancreatoduodenectomy, and pancreas-sparing duodenectomy.166 Total pancreatectomy may leave the patient with a treatment that is far worse than the disease itself, but it does play a role in patients with large malignant tumors throughout the gland and in patients with a strong family history of highly lethal pancreatic and duodenal endocrine tumors. Pancreatoduodenectomy is reserved for patients with extensive duodenal and pancreatic head disease, whereas pancreas-sparing duodenectomy with enucleations is an option for patients with a large tumor burden in the duodenum but few tumors in the pancreas. This can be combined with a distal pancreatectomy. Locoregional recurrences can be safely re-resected in selected cases. In other situations, completion pancreatectomy may be a good option in the absence of distant metastases. The management of advanced disease may involve hepatic resection and radiofrequency ablation (open or percutaneous) of liver metastases. 155.156 This can provide excellent palliation with regard to both hormonal sequelae and survival. When surgery is no longer an option, stabilization and hormonal control can also be achieved with the longacting form of octreotide (Sandostatin LAR).167 Combination chemotherapy,168-170 most often with streptozotocin and doxorubicin or 5-fluorouracil, has demonstrated temporary

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responses in as many as two thirds of patients treated. a-InterferonI67.171 has also been employed in select cases, providing effective palliation. Rarely has liver transplantation been considered for disease confined to the liver.

Adrenal Neoplasia and Hyperplasia Thirty-five percent to 40% of MEN 1 patients harbor adrenocortical lesions, and these are clearly overrepresented in the MEN 1 syndrome.P"? Most lesions are hyperplastic, bilateral, and nonfunctioning. Aldosterone- and cortisolsecreting adenomas, however, have been reported.P"? Hypercortisolism in MEN 1 can be the result of an ACTHsecreting pituitary process, a cortisol-secreting adenoma! carcinoma or, rarely, due to an adrenocorticotropic hormone (ACTH)- or corticotropin-releasing factor-producing islet cell tumor or thymic carcinoid.P Adrenocortical carcinomas have also been described in MEN 1 patients, most often in association with insulin-producing islet cell tumors.17.25.172 This raises the possibility of a shared underlying genetic cause or a trophic effect of insulin on adrenocortical cells.

Carcinoid Tumors Carcinoid tumors (particularly foregut) are also overrepresented in MEN 1 patients. 18-22 They are all capable of behaving in a malignant fashion and as a group represent the second most common cause of tumor-related deaths in MEN 1 patients after pancreatic neuroendocrine tumors. Thymic carcinoids are highly aggressive. Management of such foregut tumors is by appropriate surgical resection. Transcervical thymectomy performed as part of HPT operations is not a guarantee against future development of thymic carcinoids.F'<" Gastroduodenal carcinoid tumors can be nonfunctioning or associated with gastrin or serotonin production.s-!" Duodenal carcinoids are the principle cause of ZES in MEN 1 patients.22.5o.14o They are often multiple and frequently metastasize to regional lymph nodes and subsequently to the liver. Gastric carcinoids can be gastrin producing (highly malignant) or can evolve secondary to the hypergastrinemia from gastrin-producing duodenal carcinoids (enterochromaffin cell hyperplasiaj.i-!" Treatment requires excision and lymphadenectomy and, less often, gastrectomy or pancreatoduodenectomy, depending on the extent of foregut involvement.

Summary MEN 1 syndrome is an autosomal dominant-inherited tumor disorder caused by mutations in the MEN] tumor suppressor gene (chromosome llqB). The diagnosis is made in probands by documenting two of the three major manifestations (multigland primary HPT [>95%], pancreatic neuroendocrine tumors [50% to 75%], or pituitary tumors [30% to 55%]) or by demonstrating one major manifestation in an at-risk family member of a known MEN 1 kindred. Genetic testing

identifies a mutation in up to 90% of MEN 1 kindreds. Other overrepresented tumors include adrenal neoplasia, foregut carcinoid tumors, and a number of unusual cutaneous abnormalities. Primary HPT is the most common manifestation and is seen in more than 95% of MEN I patients. Palliation of HPT is best achieved with subtotal parathyroidectomy and transcervical thymectomy. Prolactinomas are most often managed with dopamine agonists. Failures of medical therapy and large (compressive) macroadenomas, both functioning or nonfunctioning, are best managed with endonasal trans sphenoidal adenomectomy. Pancreatic and duodenal neuroendocrine tumors are the most frequent cause of tumorrelated deaths in MEN 1. Nonfunctioning islet cell tumors are most frequent in screened patients, and duodenal gastrinomas are the most frequent cause of a functioning syndrome (ZES). This is followed by hyperinsulinism and, less often, the glucagonoma or VIP tumor syndromes. Pancreatic resection is clearly indicated and beneficial for patients with hyperinsulinism, glucagonomas, VIP tumors, and larger nonfunctioning tumors. There is increasing evidence suggesting that early surgical intervention for MEN l/ZES patients and patients with subclinical pancreatic neuroendocrine tumors does result in prolonged palliation and a reduction in the rate of malignant transformation. Since biochemical abnormalities can be detected decades prior to the development of overt clinical symptoms, genetic testing, biochemical screening, and imaging of appropriately selected patients appear warranted.

Acknowledgments The authors thank Abbie L. Young, MS, and Dr. Britt Skogseid for their critique of this chapter.

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138. Oberg K, Skogseid B. The ultimate biochemical diagnosis of endocrine pancreatic tumours in MEN I. J Intern Med 1998;243:471. 139. Skogseid B, Oberg K, Akerstrom G, et al. Limited tumor involvement found at multiple endocrine neoplasia type I pancreatic exploration: Can it be predicted by preoperative tumor localization? World J Surg 1998;22:673. 140. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas of the duodenum of patients with multiple endocrine neoplasia type I and the Zollinger-Ellison syndrome. N Engl J Med 1990;322:723. 141. Dean PG, van Heerden JA, Farley DR, et at. Are patients with multiple endocrine neoplasia type I prone to premature death? World J Surg 2000;24:1437. 142. Doherty GM, Olson JA, Frisella MM, et at. Lethality of multiple endocrine neoplasia type 1. World J Surg 1998;22:581. 143. Mucht MG, Frisella MM, DeBenedetti MK, et al. Pancreatic polypeptide is a useful plasma marker for radiographically evident pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1. Surgery 1997; 122: 1012. 144. Granberg D, Stridsberg M, Seensallu R, et al. Plasma chromogranin A in patients with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 1999;84:2712. 145. Goebel SU, Serrano J, Gibril F, et al. Prospective study of the value of serum chromogranin A or serum gastrin levels in the assessment of the presence, extent, and growth of gastrinomas. Cancer 1999; 85:1470. 146. Skogseid B, Oberg K, Benson L, et al. A standardized meal stimulation test of the endocrine pancreas for early detection of pancreatic endocrine tumors in multiple endocrine neoplasia type I syndrome: Five years' experience. J Clin Endocrinol Metab 1987;64:1233. 147. Grama D, Skogseid B, Wilander E, et al, Pancreatic tumors in multiple endocrine neoplasia type I: Clinical presentation and surgical treatment. Worldl J Surg 1992;16:611. 148. Kisker 0, Rothmund M. Localization of endocrine pancreatic tumors. In: Clark OH, Duh QY (eds), Textbook of Endocrine Surgery. Philadelphia, WB Saunders, 1997, p 593. 149. Thompson NW, Czako PF, Fritts LL, et at. Role of endoscopic ultrasonography in the localization of insulinomas and gastrinomas. Surgery 1994;116: 1131. 150. Zimmer T, Stolze1 U, Bader M, et al. Endoscopic ultrasonography and somatostatin receptor scintigraphy in preoperative localization of insulinomas and gastrinomas. Gut 1996;39:562. 151. Proye C, Malvaux P, Pattou F, et al, Noninvasive imaging of insulinomas and gastrinomas with endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery 1998;124:1134. 152. Ahlstrom H, Eriksson B, Bergstrom M, et at. Pancreatic neuroendocrine tumors: Diagnosis with PET. Radiology 1995;195:333. 153. Doppman JL. Insulinoma localization studies: Questions and answers. AJR Am J Roentgenol 1997;168: 1376. 154. Rasbach DA, van Heerden JA, Telander RL, et al. Surgical management of hyperinsulinism in the multiple endocrine neoplasia type I syndrome. Arch Surg 1985;120:584. 155. Siperstein AB, Rogers SJ, Hansen PD, Gitomirsky A. Laparoscopic thermal ablation of hepatic neuroendocrine tumor metastases. Surgery 1997;122:1147. 156. Que FG, Nagomey DM, Batts KP, et al. Hepatic resection for metastatic neuroendocrine carcinomas. Am J Surg 1997;169:36. 157. Thompson NW. Current concept in the surgical management of multiple endocrine neoplasia type I pancreatico-duodenal disease: Results in the treatment of 40 patients with Zollinger-Ellison syndrome. hypoglycaemia, or both. J Intern Med 1998;243:495. 158. Yu F, Venzon DJ, Serrano J, et at. Prospective study of the clinical course, prognostic factors, causes of death, and survival in patients with long-standing Zollinger-Ellison syndrome. J Clin OncoI1999;17:615. 159. Cadio G, Vaugnar A, Doukhan I, et al. Prognostic factors in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1. Gastroenterology 1999;116:286. 160. Norton JA, Fraker DL, Alexander HR, et al, Surgery to cure the Zollinger-Ellison syndrome. N Engl J Med 1999;341:635. 161. Norton JA, Alexander HR, Fraker DL, et al. Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type I and Zollinger-Ellison syndrome. Ann Surg 2001 ;234:495. 162. Thompson NW. Management of pancreatic endocrine tumors in patients with multiple endocrine neoplasia type 1. Surg Oncol Clin North Am 1998;7:881.

690 - - Endocrine Pancreas 163. Burgess JR, Greenaway TM, Parameswaran V, et al. Enteropancreatic malignancy associated with multiple endocrine neoplasia type I: Risk factors and pathogenesis. Cancer 1998;83:428. 164. Mignon M, Cadiot G. Diagnostic and therapeutic criteria in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1. J Intern Med 1998;243:489. 165. Mullan MH, Gauger PG, Thompson NW. Endocrine tumours of the pancreas: Review and recent advances. ANZ J Surg 2001;71:475. 166. Lairmore TC, Chen VY, DeBenedetti MK, et al. Duodenopancreatic resections in patients with multiple endocrine neoplasia type 1. Ann Surg 2000;231:909. 167. Frank F, Klose K, Wied M, et aJ. Combination therapy with octreotide and alpha interferon: Effect on tumor growth in metastatic endocrine gastroenteropancreatic tumors. Am J Gastroentero1 1999;94:1381. 168. Moerte1 CG, Lefkopoulo M, Lipsitz M, et al. Streptozotocindoxorubicin, streptozocin-fluorouracilor chlorozotocin in the treatment of advanced islet cell carcinoma. N Eng1J Med 1992;326:519. 169. Moertel CG, Kvols LK, O'Connell MJ, et al. Treatment of neuroendocrine carcinoma with combined etoposide and cisplatin: Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 1991;68:227.

170. Eriksson B, Oberg K. An update of the medical treatment of malignant endocrine pancreatic tumors. Acta Oncol 1993;32:203. 171. Grieco A, Bianco A, Alfei B, et al. Liver metastases of endocrine tumor associated with multiple endocrine neoplasia type I: A sustained response to interferon therapy or a peculiar benign course? Hepatogastroenterology 2000;47: 1269. 172. Dotzenrath C, Goretzki PE, Cupisti K, et al. Malignant endocrine tumors in patients with MEN I disease. Surgery 2001;129:91. 173. Burgess JR, Giles N, Shepherd J1. Malignant thymic carcinoid is not prevented by transcervical thymectomy in multiple endocrine neoplasia type 1. Clin Endocrinol 2001;55:689. 174. Sugiura H, Morikawa T, Itoh K, et al. Thymic carcinoid in a patient with multiple endocrine neoplasia type I: Report of a case. Surg Today 2001;31:428. 175. Teh BT. Thymic carcinoids in multiple endocrine neoplasia type 1. J Intern Med 1998;243:501. 176. Jensen RT. Management of Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type 1. J Intern Med 1998;243:477.

Transplantation of Endocrine Cells and Tissues Alan P. B. Dackiw, MD, PhD • Martha Zeiger, MD

Hormone replacement therapy for endocrine deficiency may not completely achieve the physiologic independence of a normally functioning system, because the complex metbolic interactions of hormones and their targets often cannot be wholly reproduced. Investigators have explored transplantation of endocrine tissues and cells with varying degrees of clinical success. Although autotransplantation (the movement of tissue or cells from one location to another in the same individual) as evidenced by the success of parathyroid autotransplantation has found clinical applicability, allotransplantation (transplantation of tissue or cells from one individual to another in the same species) has been limited by rejection. Xenotransplantation (transplantation with another species' tissue) has remained investigational. Table 77-1 shows a number of endocrine deficiency states that might be amenable to transplantation of endocrine cells or tissues. However, advances have been made in the field of pancreatic islet cell transplantation that, in addition to thyroid transplantation, parathyroid transplantation, and adrenal transplantation, are discussed in this chapter.

Thyroid Clinical transplantation of thyroid tissue has not been widely utilized as thyroid hormone replacement therapy is safe, effective, and cost-effective in treating postoperative or disease-induced hypothyroidism in most patients. Autotransplantation of thyroid tissue has been performed mainly in two clinical scenarios, following resection of lingual thyroid and following thyroidectomy for multinodular goiter or Graves' disease. Numerous case reports documenting these transplants have appeared in the literature dating back to more than 50 years ago. I - 13 Long-term follow-up of autotransplanted thyroid tissue has been reported. Sheverdin reported the results of a 15-year observational study of autotransplanted thyroid gland fragments in 1992. 12 Mild hypothyroidism was noted in 3.2% of the transplant recipients during the first 6 months after operation. In the nontransplantation group, postoperative hypothyroidism developed in 6.6% of the patients during the same period of time. The author's conclusion was that autotransplantation of part of

the resected thyrotoxic thyroid gland was an effective method of preventing postoperative hypothyroidism. Successful autotransplantation of thyroid has also been reported by other groups" with follow-up of up to 37 years." Transplanted thyroid fragments have been placed in both the abdominal wall" and neck.'! Steinwald, Neinase, and their colleagues have also reported successful cases of autotransplantation of lingual thyroid into muscle with long-term follow-up of 16 and 5 years, respectively.P-'? Cryopreserved thyroid tissue has also been autotransplanted." Follow-up studies have reported optimal freezing conditions for cryopreservation." Specifically, l-rnm thyroid pieces are placed into the freezing medium, which consists of culture medium supplemented with 10% fetal bovine serum and 10% dimethyl sulfoxide. The tissue is cooled slowly to -80 0 C with prefreezing incubation at 4 0 C for 1 hour and subsequently kept in liquid nitrogen for preservation. The number of surviving cells in this study under optimal conditions was 1.24 to 2.03 (1.71 ± 0.40) x 106 per 0.1 g of tissue, and recovery was 25.2% to 58.0% (45.5% ± 14.6%). As a follow-up to this work, Shimizu and coworkers reported a trial of autotransplantation of cryopreserved thyroid tissue for postoperative hypothyroidism in patients with Graves' disease.P At the time of subtotal thyroidectomy, the surgical specimen was partially cryopreserved until it was subsequently used for autotransplantation. Four patients with postoperative hypothyroidism underwent autotransplantation of cryopreserved thyroid tissues. These patients had previously required 50 to 150 ug/day of thyroxine at 1.8, 3.4, 3.5, and 2.8 years after operation. For the transplantation procedure, 2.5 to 3.5 g of cryopreserved thyroid tissue was autotransplanted into the forearm muscle of each patient (Fig. 77-1). In three of the patients, thyroxine administration could be discontinued and the clinical symptoms of hypothyroidism disappeared because of a decreased serum thyroid-stimulating hormone (TSH) level. Pathologic and immunohistochemical examinations of the thawed cryopreserved tissue demonstrated well-preserved thyroid structure and thyroglobulin-positive follicular cells with colloid, suggesting that the transplanted material was functional. In addition, 1231 scintiscanning in two patients showed an

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accumulation of radioactive iodine at the transplantation sites. One patient, who was able to discontinue thyroid hormone for 6 months, subsequently required supplementation because of recurrent hypothyroidism. The importance of close follow-up of patients with residual native thyroid tissue or autotransplanted tissue is emphasized because of the potential for recurrent hyperthyroidism and even thyroid storm."

FIGURE 77-1. Transplantation of cryopreserved thyroid tissue into the brachioradialis muscle. Defrosted thyroid tissue (2.5 g) is transplanted into several pockets that are created in the brachioradialis muscle. (From Shimizu K, Kumita S, Kitamura Y,et aI. Trial of autotransplantation of cryopreserved thyroid tissue for postoperative hypothyroidism in patients with Graves' disease. JAm Coll Surg 2002;194:14.)

Others have also had success with thyroid autotransplants and autotransplantation of cryopreserved tissue in the abdominal wall and forearm. 22•23 Roy and coauthors reported 15 patients with benign thyroid disorders (7 with Graves' disease and 8 with multinodular goiter) who underwent modified subtotal thyroidectomy and autotransplantation of 3 to 5 g of thyroid tissue in the sternocleidomastoid muscle. The transplanted tissue was functional in six of the eight patients with multinodular goiter and four of the seven patients with Graves' disease. All of the patients with multinodular goiter and a functional transplant became euthyroid within 6 months postoperatively. Although the transplanted tissue was functional in four patients with Graves' disease, only one became euthyroid; the other three required supplemental hormone therapy for postoperative hypothyroidism. This study demonstrated the ability of autotransplanted thyroid tissue to survive, function, and grow in muscle; however, long-term functional studies from these reports are pending. In addition to thyroid autotransplantation, studies have evaluated the feasibility of thyroid allografts and xenografts. Raaf and colleagues evaluated isogeneic and allogeneic thyroid grafts in thyroidectomized recipient rats." Grafts, either fresh or cultured, were placed in hamstring muscle pockets or under the renal capsule. Survival and function of the grafts were evaluated by restoration of normal levels of serum thyroxine, weight gain, kidney transarnidinase (a thyroxine-induced enzyme), and the histologic appearance of re-excised implants. Isografts, fresh and cultured, functioned well as ectopic thyroid glands, although restoration of normal serum thyroxine levels was more rapid for the fresh implants. Fresh allografts functioned transiently but ultimately failed because of rejection. No function was detected for cultured allografts, and rejection was seen histologically. The rat thyroid allograft therefore differs from the rat parathyroid allograft, which can often function for several months despite histologic evidence of rejection. Thus, in this study, maintenance of thyroid cells in tissue culture prior to implantation did not appear to alter the long-term immunogenicity of the graft. Methods designed to overcome rejection include immunosuppression, immunomodulation, and immunoisolation.P Attempts have been made to reduce the immunogenicity by immunomodulation of the thyroid allograft. Iwai and coworkers pretreated thyroid cells with anti-Ia antibody or antidendritic cell antibody." Initially, thyroids of C67BU6J mice were treated with collagenase, and the follicles were isolated using a Percoll density gradient technique. These follicles were treated with anti-Ia antibody (Ab) or antidendritic cell antibody plus complement in order to eliminate dendritic cells. The follicles were then mixed with agarose and transplanted under the left renal capsule of BALB/c mice. One hundred days after transplantation, acceptance of the grafts was verified by both histologic study and the incorporation of 1251 into the grafts. Allografts treated with complement were rejected, whereas allografts treated with antibody plus complement were accepted. When nontreated thyroids of C57BU6J mice were grafted under the right renal capsule of BALBIc mice that had accepted dendritic cell-depleted thyroids of C57BU6J mice, the nontreated thyroids were rejected. These findings indicate that the

Transplantationof EndocrineCells and Tissues - - 693 dendritic cells play an important role in the rejection of mouse thyroid allografts, and that the depletion of dendritic cells permits allografts to be accepted without inducing donor-specific tolerance and might be developed as a viable strategy for the treatment of patients with congenital or acquired hypothyroidism. Yoshizaki and colleagues also examined the efficacy of thyroid allotransplantation for the therapy of hypothyroidism in the rat model. 27 Transplanted thyroid function was determined by the 1251 uptake ratio and evaluated by immunohistochemical and microautoradiographic assessments. Fully allogeneic thyroid glands cultured for 8 to 24 hours in Hanks' balanced salt solution at pH 6.3 or 7.2 were transplanted into rats under the kidney capsule. Five weeks after allotransplantation, thyroid glands cultured for 16 hours at pH 6.3 demonstrated prolonged survival. The authors concluded that this procedure could be used as an initial therapy not only for patients who have undergone total thyroidectomy but also for patients with primary hypothyroidism. Other techniques to protect allogeneic thyroid tissue have also been examined. A technique of encapsulating thyroid tissue (immunoisolation) with an artificial membrane to protect against rejection has been reported.P The membrane is constructed of calcium alginate and a poly-r.-lysine coating; it prevents the diffusion of large molecules such as hemoglobin but freely permits the passage of smaller molecules such as thyroxine and culture medium. Because larger molecules are excluded, the contents of the microcapsules are protected from rejection. In this study, in vitro cultured, microencapsulated rabbit thyroid tissue secreted triiodothyronine (T3) and thyroxine (T4 ) and achieved concentrations of 8.68 ± 2.93 and 245.23 ± 124.87 nmollL after 3 days. These levels remained stable for 6 to 9 days of incubation. The authors concluded that these microcapsules showed promise as a treatment modality and as a possible solution to the problem of immune isolation. Braun and colleagues also reported a method of encapsulating thyroid tissue." These investigators used an encapsulation method involving the precipitation of a polyelectrolyte complex membrane of cellulose sulfate and polydimethyldiallylammonium chloride in syngeneic thyroid transplantation. Half a thyroid gland was placed beneath the kidney capsule, either after being encapsulated or as a nonencapsulated control graft. In euthyroid as well as hypothyroid recipients, the grafted tissue was viable for up to 12 weeks. Furthermore, the hypothyroid state, which was characterized by markedly diminished 1251 incorporation in the thyroid, no body weight gain, and undetectable serum T4 concentrations, was compensated by the grafted tissue. However, the encapsulated grafts were associated with lower iodine incorporation, T4 secretion, and body weight gain compared with nonencapsulated control grafts. It was thought that this might be due to a partial restriction of TSH by the capsule membrane. The authors concluded, however, that the cellulose sulfate membrane is biocompatible and enables the functional survival of syngeneic grafted tissue. A new method for thyroid transplantation across major histocompatibility complex (MHC) barriers using allogeneic bone marrow transplantation has been reported." Previously, it was demonstrated that allogeneic bone marrow transplantation

after lethal irradiation elicits donor-specific tolerance for organ or tissue transplantation across MHC barriers and that portal venous administration of donor bone marrow cells elicits donor-specific tolerance across MHC barriers with two administrations of an immunosuppressant (cyclosporine or FK-506).31 Lee and coworkers used this central and intrahepatic tolerance-inducing system to establish a method for thyroid transplantation. In addition to sublethal (6 to 5 Gy) irradiation, recipient B6 (H-2 b) mice received intraperitoneal injections with the myeloablative drug busulfan on day -2 to provide sufficient space for the donor hematopoietic cells to expand in the recipients. To induce intrahepatic tolerance, donor BALB/c (H-2 d) bone marrow cells were treated with neuraminidase, which enhances the trapping of intravenously injected bone marrow cells in the liver. After the injection of the neuraminidase-treated bone marrow cells, the thyroid organs from the BALB/c mice were engrafted under the renal capsules. A 90% graft survival rate was obtained over 100 days with a combination of busulfan administration, 6-Gy irradiation, and intravenous injection of neuraminidasetreated bone marrow cells. T cells collected from the tolerant recipients suppressed the proliferative responses to donor alloantigens. The authors concluded that this regimen prevented the rejection of thyroid allografts. Further studies have examined the mechanism of thyroid allograft rejection. Niimi and colleagues found that the overexpression of heme oxygenase-l correlated with the protection of fully allogeneic thyroid grafts from rejection. 32,33 In these studies, one lobe of the thyroid was transplanted under the kidney capsule. C57BL/l0 (H-2 b) thyroids were rejected in naive CBA (H-2 k) mice within 14 days after transplantation. However, when mice were treated with anti-CD4 monoclonal antibodies, all grafts survived for more than 60 days. The first grafts still survived after second C57BLlI0 or BALB/c (H-2 d) thyroid grafts that were transplanted into the same recipients were rejected acutely, which suggests that the primary grafts were modified under anti-CD4 antibody treatment. To confirm this hypothesis, C57BL/l0 thyroid grafts from anti-CD4 antibody-treated mice were retransplanted. All grafts survived in naive mice, which correlated with the overexpression of heme oxygenase-l in the grafts. An inhibitor of heme oxygenase-l (zinc protoporphyrin) or control compound (copper protoporphyrin) was injected intraperitoneally after transplantation of C57BLllO thyroid grafts into the primary CBA recipients that had been treated with anti-CD4 antibody. The grafts in mice that had been treated with zinc protoporphyrin, but not copper protoporphyrin, were rejected when retransplanted to naive recipients, suggesting that overexpression of heme oxygenase-l correlated with the protection of fully allogeneic thyroid grafts from rejection when retransplanted into naive recipients. Human thyroid xenografts have also been transplanted into immunodeficient mice in models to study Graves' disease, and these studies have demonstrated functioning human thyroid tissue that remains responsive to TSH stimulation.t'-" Thus, although thyroid autotransplantation is feasible, currently the applicability of thyroid allotransplantation or xenotransplantation in humans remains investigational as thyroid hormone replacement therapy has generally been satisfactory in treating both disease-induced and postoperative hypothyroidism and avoids immunosuppression.

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3.0

Parathyroid The treatment of surgically acquired and idiopathic hypoparathyroidism requires life-long treatment with vitamin D and oral calcium supplementation. This is not, however, a perfect physiologic replacement because, although it sufficiently regulates blood calcium and phosphate levels, it does not reverse the lowered urinary calcium reabsorption and excessive urinary calcium excretion, which may result in renal stones." Owing to the complexity of parathyroid hormone's metabolic interactions, clinical hypoparathyroidism is one of the most difficult of all endocrine disorders to treat. Autotransplantation of parathyroid tissue in humans is well established and widely practlced.P:" Although parathyroid allotransplantation is well established in animal models, it is rarely performed in humans and has rarely been used clinically because its advantages have been outweighed by the need for immunosuppression. Allotransplantation of parathyroid tissue in humans may be desirable, however, for treating long-term hypoparathyroidism (e.g., after inadvertent removal of parathyroid glands during thyroid surgery). Studies have attempted to reduce the immunogenicity of parathyroid tissue similarly to thyroid tissue. Microencapsulation, as noted before, is a technique that was first attempted in islet cell transplantation. Hasse and colleagues have been able to achieve long-term success in a rat model.f After isolation and tissue culture, tissue pieces from parathyroid glands of 280 Lewis rats were encapsulated in barium alginate and grafted into hypocalcemic DA rats. From the 7th to the 90th day after transplantation, the recipient rats (DA rats) showed a normal serum calcium concentration, demonstrating the successful long-term survival and function of microencapsulated allotransplanted parathyroid tissue. This group subsequently evaluated the feasibility of parathyroid xenotransplantation.P In this study, human parathyroid tissue was microencapsulated and transplanted into the rat and the effect of this microencapsulation on xenotransplanted human parathyroid tissue was evaluated over a 30-week course. Functionally human parathyroid tissue was able to replace that of the rat. All animals that had received the microencapsulated parathyroid tissue were normocalcemic for 16 weeks and 27 of 40 animals were normocalcemic at the end of the study. In contrast, serum calcium concentrations dropped to postparathyroidectomy levels within 4 weeks in the animals that had received native tissue only. Histologic evaluation of the explanted, functionally successful xenografts showed vital parathyroid tissue inside intact microcapsules surrounded by a small rim of fibroblasts. Fibrotic nonfunctioning parathyroid remnants were demonstrated in animals with nonencapsulated parathyroid tissue. These authors established the feasibility of microencapsulation of human parathyroid tissue and ability to preserve its viability over long periods in vivo, even with xenotransplanted tissue. Thus, transplantation of human parathyroid tissue and maintenance of its physiologic function were achieved without postoperative systemic immunosuppression in a xenotransplant model. 44,45 The group validated this model with an amitogenic alginate, and this technique has now been used clinically where parathyroid transplantation was performed without immunosuppression (Fig. 77_2).46

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FIGURE 77-2. Calcium and intact parathyroid hormone (iPTH) concentrations before and after parathyroid allotransplantation. Hasse and colleagues'" succeeded in parathyroid allotransplantation in two human subjects without immunosuppression. The donor for the patients was an ABO-compatible, human leukocyte antigen (HLA)-mismatched patient with parathyroid hyperplasia caused by secondary hyperparathyroidism.After parathyroidectomy, the tissue was cut into l-mm! pieces and immersed in amitogenic 2% sodium alginate. The suspension was passed through a spray nozzle for encapsulation with a constant flow of 6.5 Llmin. The microencapsulated parathyroid cells were cultured and 20 microcapsules were transplanted into the brachioradialis muscle of the nondominant forearm of the patients. After transplantation, the recipients had normal levels of calcium and iPTH without immunosuppression. (From Lee MK, Bae YH. Cell transplantation for endocrine disorders. Adv Drug Deliv Rev 2000;42: 103.)

Prior to these techniques utilizing immunoisolation, other investigators also studied parathyroid allotransplantation using other techniquesv'? leading to attempts at parathyroid allotransplants in humans.P Duarte and coauthors reported on a 25-year-old woman with idiopathic hypoparathyroidism that had been diagnosed when the patient was 4 years of age.!' Long-term medical management with vitamin D and oral calcium supplementation was complicated by multiorgan calcinosis and renal failure. At the age of 21 years, the patient received a successful cadaveric renal allograft; however, 4 years later, she developed calcinosis cutis with widespread skin necrosis. Medical control of calcium and phosphate metabolism was unsatisfactory, and the skin necrosis became progressive and life threatening. A parathyroid allograft that was performed with tissue from a parathyroid adenoma resulted in normalization of the serum calcium and phosphorus levels with arrest and subsequent healing of the skin necrosis. Later failure of the parathyroid allograft was followed by successful retransplantation of normal parathyroid tissue from a cadaveric organ donor.5 I In addition, Tolloczko and colleagues reported on patients with postoperative hypoparathyroidism (after thyroid operations) who were treated with cultured, hormonally active, living and ABO-compatible parathyroid cells. 52. 54 Tissue was harvested from two patients with secondary hyperparathyroidism. In these studies, hormonal activity of the graft was variable but lasted up to 14 months. Others have also attempted

Transplantationof EndocrineCells and Tissues - - 695 parathyroid allotransplantation to treat intractable hypoparathyroidism.P-" Similar to the immunoisolation provided by encapsulation, other methods to avoid long-term immunosuppression such as immunomodulation have been employed in order that parathyroid allotransplantation be feasible. Pretransplantation treatment of the graft to eliminate passenger cells is one such method. An alternative approach is short-term treatment of the recipients with cyclosporine. Bloom and associates cultured parathyroid glands from Lewis X Brown Norway rats for 1 week and treated them with antiserum directed against class II MHC antigens. 57 Treated glands were then transplanted into hypocalcemic Wistar-Furth recipients that previously received 30 mg/kg cyclosporine once a day for 3 days before transplantation. At 280 days after transplantation, 67% of the recipients had functional parathyroid allografts. Control rats (no cyclosporine; fresh, untreated glands) rejected these grafts within 28 days. Control rats given 3 days of cyclosporine and transplanted with fresh, untreated glands had functional grafts for greater than 56 days (median survival, 80.5 days). The authors concluded that prolongation of allograft survival with short-term, preoperative cyclosporine demonstrates the efficacy of immunosuppression given at the time of antigen presentation. This course of cyclosporine was even more effective when the recipient received a graft whose passenger cells were eliminated. Some sites in the body may also be immunoprivileged. The lateral ventricle of the brain has been investigated as a potential immunoprivileged site for viable parathyroid allograftS. 58,59 Yao and colleagues allotransplanted parathyroid tissue from histoincompatible rats that survived and remained functional for more than 3 months in the cerebral ventricles of recipient F344 rats. Microscopic examination proved that the allotransplanted parathyroid tissues retained normal histologic features. In contrast, when the parathyroid was placed beneath the renal capsule, the allografted parathyroid tissue uniformly lost its capacity to liberate parathyroid hormone within 1 month, and only residual scar tissue remained at the transplantation site. After allotransplantation of parathyroid tissue into the cerebroventricle, the serum concentrations of both Ca 2+ and parathyroid hormone were maintained at levels similar to those before parathyroidectomy, until the time of sacrifice. The thymus has also been reported as an immunoprivileged site for parathyroid autotransplants.s" As noted, parathyroid autotransplantation is a well-defined clinical entity with an interesting history37.39 and is most often performed for a parathyroid inadvertently removed during thyroid surgery or when it cannot be preserved on its vascular supply. Autotransplantation may also be performed in the management of the patient with parathyroid hyperplasia or secondary hyperparathyroidism. As this is the technique most commonly performed by the endocrine surgeon, the technique of autotransplantation is reviewed here. Parathyroid tissue to be autotransplanted is temporarily stored in iced saline solution. A muscle pocket is created (generally in the sternocleidomastoid or the forearm, although the subcutaneous space has also been used). It is important to avoid bleeding in the pocket as hematoma formation prevents subsequent vascularization of the autograft; thus, packing the pocket for several minutes to ensure hemostasis

is advised. Multiple pockets may also be created, and we do so to maximize subsequent autotransplant success and decrease the risk of loss related to hematoma. The parathyroid tissue (approximately 1- x l-mm pieces) is placed into the pocket(s). The pocket may be closed with a Prolene suture, clip, or both, to mark the transplant site as hyperparathyroidism may develop after autotransplantation of histologically normal parathyroid tissue. For this reason, it is important to mark the site of the parathyroid autotransplant." In addition to the immediate transplantation of fresh tissue, cryopreserved tissue may be autotransplanted in this manner. The specific techniques of cryopreservation have been described in detail and are widely used. 62,63 Thus, although parathyroid autotransplantation is well established clinically, allotransplantation may hold promise for the future. Cultured fetal parathyroid gland cells have been used in treating patients with hypoparathyroidism.v' Whether these techniques or stem cell technology will have utility in the treatment of hypoparathyroid patients will require further elucidation.

Adrenal Adrenal cortical insufficiency (Addison's disease) occurs with a prevalence of 93 to 110 per million population.P Etiologies of Addison's disease include bilateral adrenal dysfunction induced by autoimmune reactions and tuberculosis, carcinoma, hemorrhage, and infarction. In addition, patients with multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and familial pheochromocytoma who have had bilateral adrenalectomy for pheochromocytoma are another population who require life-long steroid replacement therapy. Life-long steroid hormone replacement (cortisone and mineralocorticoid) is the only available therapy for acquired or congenital adrenal cortical insufficiency. In contrast to exogenous thyroid hormone replacement therapy, adrenal hormone replacement therapy is less physiologic and more difficult to regulate. More important, it does not adequately or autonomously substitute the hormone peaks required in physiologic stress situations or replace the physiologic circadian secretion of corticosteroids. Inappropriate replacement in adrenal insufficiency can result in persistent metabolic abnormalities in an overtreated patient (hypertension, glucose intolerance, osteoporosis) or persistence of the addisonian state in an undertreated patient (hypotension, electrolyte abnormalities). A more physiologic strategy to replace adrenal cell function in patients with adrenal insufficiency would be to transplant autologous or allogeneic adrenal cortical cells into addisonian patients. This approach has been evaluated by a number of investigators. As early as 1951, Patino and Fenn reported the successful transplantation of a human embryonic adrenal gland in a patient with Addison's disease/" Rodent models of adrenal cell transplantation have been studied more recently. Ricordi and colleagues found that culture of donor tissue followed by short-term recipient treatment with cyclosporine allowed 30-day survival of adrenal cortical tissue in a rat model.f They also reported that parathyroid and adrenal medulla

696 - - Endocrine Pancreas transplants were often infiltrated by mononuclear cells; however, adrenal cortical tissue was well preserved after transplantation. A potential mechanism for this is discussed subsequently. Scheumann and colleagues conducted similar experiments in which adrenal cortex from rats was isolated from the medulla by collagenase digestion and implanted under the kidney capsule of recipient rats.68 The recipient rats' native adrenals were subsequently removed. The corticosterone levels of the transplanted animals were close to normal and the animals survived for 8 weeks. Surviving adrenal cortical cells could be demonstrated in the explanted grafts by immunohistochemistry. An interesting subsequent finding by these investigators was that isolated, purified zona glomerulosa cells (usually responsible for aldosterone synthesis), when transplanted, had the ability subsequently to express the enzyme cytochrome P-4S0 11~, which is necessary for corticosterone synthesis/" These results suggest that glomerulosa cells are able to take over and maintain the physiologic function of the entire adrenal cortex. Hornsby and colleagues developed a mouse model in which xenotransplanted adrenal cortical tissue was formed in immunodeficient mice by using techniques of cell transplantation. In this model, cells of bovine and of adult and fetal human origin can be transplanted subcutaneously in severe combined immunodeficient (SCID) mice after being embedded in collagen gel. At this site the cells survived, became vascularized by host endothelial cells, secreted steroid into the circulation, and replaced adrenal function in adrenalectomized animals.P:" Additional review of these studies examined some of the potential mechanisms of growth of the xenotransplanted cells." In these experiments, bovine adrenal cortical cells in a small cylinder were introduced beneath the kidney capsule in rats (Fig. 77-3). In this model, the extent to which the transplanted cells became lined by host endothelial cells was correlated with higher degrees of proliferation and nuclear p21, suggesting that vascularization is the critical step for the survival of the transplanted cells." The immune response to transplanted adrenal cortical cells has also been evaluated. Ellerkamp and coworkers cultured allogeneic adrenal cortical cells in mixed lymphocyte cultures to examine the alloimmune response." In this

model, the presence of adrenal cortical cells potently suppressed the allogeneic immune response. Interestingly, this effect was only in part due to the secretion of corticosteroids as demonstrated in experiments using the steroid receptor antagonist mifepristone (RU 486). These data thus suggested an immunomodulatory property of adrenal cortical cells in addition to the effect of the secreted corticosteroid. Seeliger and colleagues also studied a model of cellular adrenal cortical transplantation." They demonstrated that syngeneic transplantation resulted in physiologic corticosterone levels early after transplantation, whereas fully MHC-incompatible grafts were rejected. Recipients of Kb-transgenic grafts (expression of the transgenic MHC class I molecule showed unimpaired adrenocortical function but did not tolerize toward Kb-transgenic skin grafts. Possible mechanisms suggested included a local immunomodulatory effect of glucocorticoids secreted by the graft and low immunogenicity of the relatively small numbers of transplanted cells in this model, in which a single cell suspension of adrenocortical cells was grafted under the kidney capsule. Interestingly, an adrenal cell transplantation model has also suggested the mechanism of adrenal cortex zonation." In this model, purified cell suspensions of glomerulosa and fasciculata cells were obtained by density gradient separation and were transplanted under the kidney capsule either immediately or after a 29-day culture period. Cells derived from the zona glomerulosa maintained viability, produced both aldosterone and corticosterone, and regenerated a neocortex with cells that histologically resemble both zona glomerulosa and zona fasciculata cells and thus are suitable for adrenocortical transplantation. In contrast, cells derived from the zona fasciculata maintained viability but did not regenerate zona glomerulosa and did not produce aldosterone. These results suggest that the cell migration model, in which zona glomerulosa cells can acquire the phenotype of zona fasciculata cells as they can migrate centripetally,is more likely the correct explanation of adrenocortical zonation. Other studies have evaluated the role of intercellular adhesion molecule I (ICAM-I) in adrenal transplantation." Fragmented adrenal glands of wild-type B lO.BR (H-2k) and wild-type or ICAM-I-deficient BALB/c (H-2d) mice were transplanted beneath the kidney capsule of adrenalectomized BI0.BR mice (complete MHC haplotype disparity

FIGURE 77-3. Experimental transplantation of adrenal cortical cells. The host is a scm mouse. A small polycarbonate filter is inserted beneath the capsule of the kidney. The cylinder creates a space beneath the capsule into which the cells are introduced. Tissue becomes visible within the cylinder with evidence of new blood vessel formation from the capsule and surrounding connective tissue. (From Hornsby Pl. Transplantation of adrenocortical cells. Rev Endocr Metab Disord 2001;2:313.)

Transplantation of Endocrine Cells and Tissues - -

in the latter). In this model, ICAM-l deficiency significantly prolonged the survival of adrenal grafts. Although markedly reduced reserve capacity was observed, the authors concluded that fragmented adrenal grafts were able to maintain physiologic basal corticosterone levels and that autologous or MHC-compatible allogeneic transplantation of adrenal grafts may replace oral hormone substitution in humans. Thomas and colleagues evaluated the transplantation of human adrenal cells into SCID mice." Human adrenocortical cells from postnatal donors were transplanted beneath the kidney capsule of adrenalectomized scm mice together with mitomycin C-treated 3T3 cells that secrete fibroblast growth factor. Adrenocortical cells from seven donors, male and female, ranging from 6 to 50 years of age, were used. Vascularized adrenocortical tissue formed at the site of transplantation. Cortisol, the normal human glucocorticoid, was present in the plasma of animals, replacing corticosterone, the mouse glucocorticoid. Some animals also had measurable aldosterone. The tissue formed from the transplanted cells showed histologic and ultrastructural features of normal adrenal cortex. This study demonstrated that tissue formed from transplanted human adrenocortical cells is able to replace the essential functions of the adrenal gland in scm mice and that transplanted human endocrine cells can functionally replace a surgically removed endocrine organ in a host animal. Further studies from this group investigated the role of the animal's host adrenal glands in adrenal cortical cell transplantation." Classic organ and tissue transplantation studies have suggested that the success of transplantation depends on the activity of the pituitary gland and other endocrine systems and is therefore influenced by the host animals' own adrenal glands. These cell transplantation experiments, involving the introduction of bovine adrenocortical cells into scm mice, did produce transplant tissues in the presence of the host animals' adrenal glands. However, the tissue that formed was small and its cells also smaller than usual. When the adrenals of such animals were removed in a second surgical procedure, the transplants showed a rapid increase in steroidogenic function and a slower increase in size over several weeks. The conclusions from these studies were that the initial process by which transplanted adrenocortical cells organize into a tissue structure is not affected by the presence of the host animals' adrenal glands but the growth of the transplants is limited until the adrenal glands are removed. Perhaps, in the future, adrenal regeneration may be feasible by engineering embryonic stem cells to express an adrenal cell phenotype. Studies have found that stable expression of steroidogenic factor I (SF-I) is sufficient to alter embryonic stem cell morphology, permit cyclic adenosine monophosphate- and retinoic acid-induced expression of the endogenous side chain cleavage enzyme gene, and consequently promote steroidogenesis in embryonic stem cells.s? The clinical applicability of adrenal cell transplantation requires further investigation.

697

history of medicine. Beta-cell replacement therapy is the only treatment that reestablishes and maintains long-term physiologic normoglycernia." because intensive subcutaneous insulin regimens cannot completely mimic the physiologic fluctuations of in vivo insulin secretion.f The two options for replacement of beta-cell function in patients are whole-organ pancreas transplantation and islet cell transplantation. Although diabetes mellitus is not generally managed by the endocrine surgeon, whole-organ pancreas transplantation and islet cell transplantation are addressed briefly here for completeness. These topics have been expertly reviewed,81-83 and the reader is referred to these and the referenced studies for further detail.

Pancreas Transplantation Whole-organ pancreas transplantation is a major surgical procedure with a significant rate of morbidity and the need for immunosuppression. However, it improves the patient's quality of life and reverses some diabetic complications, and up to 82% insulin independence at I year is reported.f Pancreas transplantation can be performed simultaneously with kidney transplantation (SPK), as occurs in approximately 90% of patients, or after kidney transplantation (4%) and in specialized enters in nonuremic patients as pancreas transplantation alone (6%).82 Survival rates are better for SPK because acute rejection can be treated earlier, coinciding with the simultaneous rise in serum creatinine that is indicative of acute rejection of the kidney. Pancreas transplantation in a nonuremic patient is performed more rarely. These patients have "brittle" (labile) diabetes or hypoglycemic unawareness that is regarded as potentially more harmful than the combined risk of the immunosuppression and surgical risks. The University of Minnesota has the largest experience (n = 225), with acceptable rates of graft survival (80% at 1 year) and survival of patients (90% at 1 year).84 A combination of long waiting lists and restrictions dictated by organ allocation policies has prompted many pancreas transplantation centers to encourage initial kidney transplantation using a living donor kidney and follow-up with a cadaver pancreas as a separate procedure.P The University of Maryland has taken this option one step further by offering simultaneous living kidney (using laparoscopic nephrectomy for the donor nephrectomy) and cadaver pancreas transplantation (SPLK) when a donor pancreas becomes available." With this single recipient surgical procedure, they reported 1-year actuarial survival of 94% and 86% for the kidney and pancreas, respectively. As a result, they noted that the waiting time for SPK at their center has been reduced by 45%. The group in Minneapolis also continues to promote living donation of both pancreas and kidney (SLPK) and have reported 115 procedures." However, there is a long learning curve and the need for meticulous donor evaluation to minimize the metabolic and surgical complications for the donor.

Islet Cell Transplantation

Pancreas The introduction of insulin therapy for the management of diabetes mellitus is one of the greatest milestones in the

The main advantages of islet cell transplantation are that it is generally a minor radiologic procedure with low morbidity and mortality and can be performed before the onset of debilitating diabetic complications (Fig. 77-4). The history

698 - - Endocrine Pancreas

FIGURE 77-4. Pancreas transplantation is associated with insulin independence in more than 80% of patients but is a complicated procedure with significant perioperative morbidity. Islet cell transplantation with its reduced antigen load, technical simplicity, and low morbidity has the potential to restore glucose homeostasis and prevent long-term complications. (From Lakey JR, Burridge PW, Shapiro AM. Technical aspects of islet preparation and transplantation. Transpl Int 2003;16:613.)

of islet cell transplantation has been reviewed." In the past, however, results have been poor because of the variability of the multiple steps in the islet cell isolation process, the need for diabetogenic immunosuppression agents, and the challenges with rejection monitoring." The islet isolation procedure is challenging as the pancreas requires donor retrieval in the same manner as whole-organ pancreas transplantation, a short cold ischemic time, digestion with collagenase, cell separation and centrifugation, resuspension, and then intraportal injection.f Perhaps as a result of this prolonged, difficult islet isolation process, the l-year insulin-independent graft survival was only 14% in 37 patients in the international islet transplant registry from 1998 to 1999. A landmark study at the University of Alberta in Edmonton, Canada, reported 100% success in seven patients using a new immunosuppression protocol, a milestone achievement that reinvigorated the enthusiasm for and interest in islet transplantation worldwide.f? The success of the Edmonton protocol includes careful recipient selection, transplantation of an appropriate islet cell mass, avoidance of steroids, and use of sirolimus, low-dose tacrolimus, and daclizumab.P Generally, more than one donor has been required to achieve sufficient islet cell numbers, with the second and subsequent donor islets transplanted freshly as they became available. Selection of patients included a history of at least 5 years of type I diabetes; failure of optimal insulin therapy, usually with life-threatening hypoglycemia; and the benefits of transplantation must outweigh the risk of life-long immunosuppression. An update of the Edmonton results was presented by Shapiro at "200 I: A Transplant Odyssey Congress" in Istanbul with reported I-year insulin-independent graft survival of 80% for 20 patients. The results of the Edmonton group have been validated in other institutions (Minneapolis, Miami, Milan, Geneva, Giessenj.f

Although pancreas allotransplantation is more advanced clinically than that of the other endocrine organs discussed, both whole-organ pancreas transplantation and islet cell transplantation are dependent on cadaveric organs, and thus only a small number of diabetic patients can be treated in this manner. Whether islet cells will ultimately be generated from stem cells or precursor cells to expand the number of cells available for transplantation requires further study. The future and potential transplantation therapies available both for the management of patients with diabetes and the care of other patients with the endocrine deficiencies discussed in this chapter are indeed exciting and challenging. In the future, the endocrine surgeon may not only resect abnormal thyroid, parathyroid, adrenal, and pancreatic tissue but also routinely transplant normal cells or tissues to replace lost endocrine function.

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35. Martin A, Valentine M, Unger P, et al. Preservation of functioning human thyroid organoids in the scid mouse: I. System characterization. J Clin Endocrinol Metab 1993;77:305. 36. Matsuoka N. Martin A, Concepcion ES, et al. Preservation of functioning human thyroid organoids in the scid mouse: II. Biased use of intrathyroidal T cell receptor V genes. J Clin Endocrinol Metab 1993;77:311. 37. Lo CY. Parathyroid autotransplantation during thyroidectomy. ANZ J Surg 2002;72:902. 38. Olson JA Jr, DeBenedelli MK, Baumann DS, Wells SA Jr. Parathyroid autotransplantation during thyroidectomy. Results of long-term follow-up. Ann Surg 1996;223:472; discussion 478. 39. Saxe A. Parathyroid transplantation: A review. Surgery 1984; 95:507. 40. Caccitolo JA, Farley DR, van Heerden JA, et al. The current role of parathyroid cryopreservation and autotransplantation in parathyroid surgery: An institutional experience. Surgery 1997;122:1062. 41. Brunt LM, Sicard GA. Current status of parathyroid autotransplantation. Semin Surg OncoI1990;6:115. 42. Hasse C, Schrezenmeir J, Stinner B, et al. Successful allotransplantation of microencapsulated parathyroids in rats. World J Surg 1994;18:630. 43. Hasse C, Zielke A, Klock G, et al. First successful xenotransplantation of microencapsulated human parathyroid tissue in experimental hypoparathyroidism: Long-term function without immunosuppression. J Microencapsul 1997;14:617. 44. Hasse C, Zielke A, Klock G, et al. Amitogenic alginates: Key to first clinical application of microencapsulation technology. World J Surg 1998;22:659. 45. Hasse C, BohrerT, Barth P, et al. Parathyroid xenotransplantation without immunosuppression in experimental hypoparathyroidism: Longterm in vivo function following microencapsulation with a clinically suitable alginate. World J Surg 2000;24: 1361. 46. Hasse C, Klock G, Schlosser A, et al. Parathyroid allotransplantation without immunosuppression. Lancet 1997;350:1296. 47. Feind CR, Weber CJ, Derenoncourt F, et al. Survival and allotransplantation of cultured human parathyroids. Transplant Proc 1979; 11:1011. 48. Kukreja SC, Johnson PA, Ayala G, et al. Allotransplantation of rat parathyroid glands: Effects of organ culture and transplantation into the adrenal gland. Experientia 1979;35:559. 49. Chen GR. [Allotransplantation of parathyroid glands with vascular anastomosis: Report of 6 cases (author's transl).] Zhonghua Wai Ke Za Zhi 1981;19:470. 50. Sollinger HW, Mack E, Cook K, Belzer FO. Allotransplantation of human parathyroid tissue without immunosuppression. Transplantation 1983;36:599. 51. Duarte B, Mozes MF, John E, et al. Parathyroid allotransplantation in the treatment of complicated idiopathic primary hypoparathyroidism. Surgery 1985;98: 1072. 52. Tolllloczko T. Sawicki A, Wozniewicz B, et al. [Allotransplantation of the parathyroid in patients without immunosuppression.] Pol Tyg Lek 1995;50:10. 53. Tolloczko T, Woniewicz B, Sawicki A, et al. Clinical results of human cultured parathyroid cell allotransplantation in the treatment of surgical hypoparathyroidism. Transplant Proc 1996;28:3545. 54. Tolloczko T, Wozniewicz B, Gorski A. et al. Cultured parathyroid cells allotransplantation without immunosuppression for treatment of intractable hypoparathyroidism. Ann Transplant 1996;1:51. 55. Zeng Q. Allotransplantation of parathyroid glands to treat intractable hypoparathyroidism. Surgery 1986;99: 131. 56. Kunori T, Tsuchiya T, Itoh J, et al. Improvement of postoperative hypocalcemia by repeated allotransplantation of parathyroid tissue without anti-rejection therapy. Tohoku J Exp Med 1991;165:33. 57. Bloom AD, Economou sa, Gebel HM. Indefinite survival of rat parathyroid allografts without postoperative immunosuppression. Surgery 1986;100: 1032. 58. He X, Yao C, Zhu Y. Preliminary observation of the brain as a site for parathyroid gland allotransplantation in rats. Proc Chin Acad Med Sci Peking Union Med Coli 1990;5:226. 59. Yao CZ, Ishizuka J, Townsend CM Jr, Thompson JC. Successful intracerebroventricular allotransplantation of parathyroid tissue in rats without immunosuppression. Transplantation 1993;55:251. 60. Gao Z, Xing Z, Zhu Y. Preliminary observation of the thymus as a privileged site for parathyroid gland allotransplantation in rats. Chin Med Sci J 1993;8:246.

700 - - Endocrine Pancreas 61. D' Avanzo A, Parangi S, Morita E, et al. Hyperparathyroidism after thyroid surgery and autotransplantation of histologically normal parathyroid glands. J Am Coli Surg 2000;190:546. 62. Wells SA Jr, Christiansen C. The transplanted parathyroid gland: Evaluation of cryopreservation and other environmental factors which affect its function. Surgery 1974;75:49. 63. Wells SA Jr, Gunnells JC, Leslie JB, et al. Transplantation of the parathyroid glands in man. Transplant Proc 1977;9:241. 64. Song C, Song Y, Wu L, et al. [Allotransplantation of cultured fetal parathyroid gland cells in treating patients with hypoparathyroidism.] Zhonghua Wai Ke Za Zhi 2000;38:690. 65. Ellerkamp V, Musholt TJ, Klebs SH, et al. A murine model of allogeneic adrenocortical cell transplantation: Perspectives for the treatment of Addison's disease in humans. Surgery 2000;128:999. 66. Patino JF, Fenn JE. A successful transplant of embryonic adrenal tissue in a patient with Addison's disease. Yale J Bioi Med 1993;66:3. 67. Ricordi C, Santiago JV, Lacy PE. Use of culture and temporary immunosuppression to prolong adrenal cortical allograft survival. Endocrinology 1987;121:745. 68. Scheumann GF, Hiller WF, Schroder S, et al. Adrenal cortex transplantation after bilateral total adrenalectomy in the rat. Henry Ford Hosp Med J 1989;37: 154. 69. Scheumann GF, Heitmann P, Teebken OE, et al. Enzymatic properties of transplanted glomerulosa cells. World J Surg 1996;20:933; discussion, 938. 70. Thomas M, Northrup SR, Hornsby PJ. Adrenocortical tissue formed by transplantation of normal clones of bovine adrenocortical cells in scid mice replaces the essential functions of the animals' adrenal glands. Nat Med 1997;3:978. 71. Hornsby PJ, Thomas M, Northrup SR, et al. Cell transplantation: A tool to study adrenocortical cell biology, physiology, and senescence. Endocr Res 1998;24:909. 72. Popnikolov NK, Hornsby PI. Subcutaneous transplantation of bovine and human adrenocortical cells in collagen gel in scid mice. Cell Transplant 1999;8:617. 73. Hornsby PJ. Transplantation of adrenocortical cells. Rev Endocr Metab Disord 2001;2:313. 74. Tunstead JR, Thomas M, Hornsby PJ. Early events in the formation of a tissue structure from dispersed bovine adrenocortical cells following transplantation into scid mice. J Mol Med 1999;77:666. 75. Seeliger H, Hoffmann MW, Behrend M, et al. Transplantation of H-2Kb-transgenic adrenocortical cells in the mouse having undergone

76.

77. 78.

79. 80. 81. 82. 83. 84. 85. 86. 87. 88.

an adrenalectomy: Functional and morphological aspects. Transplantation 2000;69: 1561. Teebken OE, Scheumann GF. Differentiated corticosteroid production and regeneration after selective transplantation of cultured and noncultured adrenocortical cells in the adrenalectomized rat. Transplantation 2000;70:836. Musholt TJ, Klebs SH, Musholt PB, et al. Transplantation of adrenal tissue fragments in a murine model: Functional capacities of syngeneic and allogeneic grafts. World J Surg 2002;26:950. Thomas M, Wang X, Hornsby PJ. Human adrenocortical cell xenotransplantation: Model of cotransplantation of human adrenocortical cells and 3T3 cells in scid mice to form vascularized functional tissue and prevent adrenal insufficiency. Xenotransplantation 2002;9:58. Thomas M, Hawks CL, Hornsby PJ. Adrenocortical cell transplantation in scid mice: The role of the host animals' adrenal glands. J Steroid Biochem Mol Bioi 2003;85:285. Crawford P, Sadovsky Y, Milbrandt 1. Nuclear receptor steroidogenic factor I directs embryonic stem cells toward the steroidogenic lineage. Mol Cell BioI 1997;17:3997. Lakey JR, Burridge PW, Shapiro AM. Technical aspects of islet preparation and transplantation. Transpl Int 2003;16:613. White SA, Kimber R, Veitch PS, Nicholson ML. Surgical treatment of diabetes mellitus by islet cell and pancreas transplantation. Postgrad Med J 2001;77:383. Allen RDM, Nankivell BJ, Hawthorne WJ, et al. Pancreas and islet transplantation: An unfinished journey. Transplant Proc 200 1;33:3485. Gruessner RW, Sutherland DE, Najarian JS, et al. Solitary pancreas transplantation for nonuremic patients with labile insulin-dependent diabetes mellitus. Transplantation 1997;64: 1572. Farney AC, Cho E, Schweitzer EJ, et al. Simultaneous cadaver pancreas living-donor kidney transplantation: A new approach for the type I diabetic uremic patient. Ann Surg 2000;232:696. Gruessner RWG, Sutherland DER, Drangstveit MB, et al. Pancreas transplants from living donors: Short- and long-term outcome. Transplant Proc 2001;33:819. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type I diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230. Ryan EA, Lakey JR, Rajotte RV, et al. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 2001;50:710.

Pancreatic Endocrine Physiology Bo Ahren, MD, PhD • Maria Sorhede Winzell, PhD

Historical Introduction

Islet Function

In 1869, Paul Langerhans showed that islands of characteristic cells are distributed throughout the pancreas and that these islands are richly innervated. 1After the demonstration that diabetes evolves after pancreatectomy? it was suggested in 1901 that the disease is caused by lack of a factor produced by these islets of Langerhans.' Although several researchers were close to the discovery of insulin, the critical pieces of work in this area were performed by Banting, Best, MacLeod, and Collip in the early 1920s.4 The structure of insulin was established in the 1950s; insulin was the first protein ever to be structurally defined." Other landmark discoveries have been the radioimmunoassay determination of insulin in 19606 and the identification of the gene coding for insulin in 1977.7 The islets also produce other regulatorypeptides, apart from insulin, and four major hormones are known to be produced by the different islet endocrine cells. The idea that the islets also produce a factor that increases blood glucose was proposed by Murlin and colleagues in 1923,8although glucagon was not isolated until 1955.9 In 1968, pancreatic polypeptide (PP) was identified, 10 and in 1974, it was discovered that the islets also produce somatostatin.'! During the 1980s, the microanatomy of the islets with endocrine cells, nerves, and blood vessels was characterized (Fig. 78_1).12-16 Other contributions to our knowledge of the endocrine pancreas include characterization of the cell biologic processes underlying the exocytosis of the peptide-storing secretory granules (Fig. 78_2),17 the regulation of expression of the islet peptide genes, 18 and the understanding of the failure of the B cells as a key contributor to the development of type 2 diabetes."

A key role for the pancreatic islets is to deliver an optimal amount of peptide hormones into the bloodstream to optimize carbohydrate metabolism. Of most importance in this respect is insulin, which facilitates the transport of glucose into insulin-dependent cells for storage as glycogen and fat with a concomitant reduction in blood glucose and free fatty acid levels as a consequence. One of the most important target organs for insulin action is the liver, in which at least 50% of the insulin secreted from the endocrine pancreas is extracted before reaching the systemic circulation. Other important target organs are skeletal muscle and adipose tissue, which express the insulin receptor. Insulin reduces circulating levels of glucose by inhibiting glucose release from the liver and augmenting glucose uptake in skeletal muscle and adipocytes. Glucagon is also an important hormone regulating carbohydrate metabolism. Glucagon increases blood glucose levels mainly by increasing hepatic glucose delivery through stimulation of glycogenolysis. A thorough understanding of the regulation of carbohydrate metabolism therefore requires a detailed knowledge of the pancreatic islets and their anatomy and physiology as well as pathophysiologic importance for conditions of impaired glucose tolerance and diabetes.

The authors have been supported by Swedish Research Council Grant l4X-6834, the Albert Pablsson, Crafoord, and Novo Nordic Foundations, the Swedish Diabetes Association, and the Faculty of Medicine, Lund University.

Islet Anatomy The endocrine pancreas consists of the pancreatic islets, which are distributed throughout the pancreas and form, in adults, approximately 1% to 2% of the pancreatic mass. The individual islet is a well-organized microorgan (see Fig. 78-1). Each islet comprises a number of cells, and the islets vary in size from one or a few cells to a few thousand endocrine cells. The different islet cell types show a typical arrangement. In the center of each islet, a core of B cells exists,

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FIGURE 78-1. Functional anatomy of a typical islet of Langerhans. The insulin-producing B cells (gray) are located in the center of the islet with the glucagon-producing A cells, the somatostatin-producing D cells, and the pancreatic polypeptide-producing F cells (white) located in the periphery. The arterioles penetrate to the center of the islet structure, where permeable, fenestrated capillaries are formed. This organization of the blood supply suggests that artery-borne hormones such as GIP, GLP-l, and CCK and nutrients such as glucose first reach the B cells and that the B cells can affect the other cell types in an endocrine fashion. Sympathetic, parasympathetic, and afferent sensory nerves innervating the islet release various neurotransmitters involved in the regulation of insulin secretion. ACh = acetylcholine; CCK = cholecystokinin; CGRP = calcitonin gene-related peptide; GIP = gastric inhibitory polypeptide; GLP-l = glucagon-like peptide I; GRP =gastrin-releasing peptide; NE = norepinephrine; NPY = neuropeptide Y; PACAP =pituitary adenylate cyclase-activating polypeptide; PP = pancreatic polypeptide; VIP = vasoactive intestinal peptide.

constituting approximately 60% to 80% of all islet cells. Surrounding these B cells, there is a mantle zone consisting of the glucagon-producing A cells, the somatostatin-producing D cells, and the PP-producing F cells. The A and F cells show a characteristic mutual distribution; the tailor dorsal portion of the pancreas is rich in A cells but poor in F cells, with the reverse relation between these cell types in the head or ventral portion of the gland" Another characteristic of the islet cells is that they produce a number of different peptides besides the four major islet hormones (Table 78-1).

B Cells Insulin The main peptide produced by the B cells is insulin. In humans, the gene coding for insulin is located on the short arm of chromosome 11, in region p15. 21.22 The regulation of the gene expression has been shown to reside in a 350-bp Sf-flanking region. This region contains a proximal promoter region and a distal transcriptional enhancer region. The enhancer region, in tum, is composed of several different sequences to which nuclear regulatory proteins bind to stimulate or inhibit the promoter. The transcription of the insulin gene is subjected to regulation because, for example, it is stimulated by glucose through the formation of a substrate formed by the aerobic glycolysis of the hexose.P Also, cyclic adenosine monophosphate (cAMP) and phorbol esters

activate insulin gene transcription," and the amount of insulin messenger RNA (mRNA) is increased when the demand for insulin is enhanced (e.g., after partial pancreatectomyj.P Several transcription factors have been demonstrated to bind to cis-regulatory elements on the promoter region of the gene, such as Beta2, pdxl (also called ipfl), and MafA, and gene disruption studies have demonstrated critical roles of these factors in insulin gene expression.v-" Therefore, transcription factors, nutrients, and other regulators of B-cell function have the capability to alter the amount of available insulin by influencing the transcription of the gene message. After the transcription, the mRNA coding for insulin passes to the endoplasmic reticulum, where the message is translated. A signal peptide is removed, and proinsulin is formed. The translation of insulin mRNA to proinsulin, like the transcription of the insulin gene, has also been shown to be under the regulation of a variety of factors, for example, glucose.i? After its synthesis, proinsulin is packaged in the secretory granules; inside these, the peptide is cleaved to insulin and C peptide, which are extruded in equimolar amounts through an exocytotic process when the B cells are activated.P The final exocytosis of the secretory granules is regulated by a variety of factors, mainly nutrients, hormones, and nerves. This regulation has been extensively studied during the last 3 decades. I? Thus, through influences on at least three levels of regulation within the B cell (transcription, translation, exocytosis), the peripheral demand for insulin is tightly controlled to optimize carbohydrate metabolism.

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703

FIGURE 78-2. Schematic overview of cell biologic processes involved in the stimulation of insulin secretion from the pancreatic B cell. Glucose is transported into the B cell by facilitated transport by the glucose transporter (GLUT2). Within the B cell, glucose is metabolized and adenosine trisphosphate (ATP) is generated. ATP then inhibits K+ permeability by closing the ATP-regulated K+ channels. Accumulation of K+ inside the B cell leads to depolarization of the plasma membrane, which in turn transforms the voltage-dependent calcium (Caz+) channels into an open state. The influx of Caz+ leads to an increase in the concentration of free cytoplasmic Ca z+. Cytosolic Caz+ acts in several ways to increase the rate of exocytosis of insulin from the insulin-storing secretory granules. For example, Caz+ is required for the activation of protein kinase C (PKC), protein kinase A (PKA), and calmodulin, all of which phosphorylate specific proteins required for initiation of the exocytotic process. Caz+ is also a cofactor for the activation of the receptor-coupled enzyme phospholipase C (PLC). PLC activation can be initiated by activation of G-protein-coupled cholecystokinin (CCK) and acetylcholine (ACh) receptors. PLC activation leads to the hydrolysis of the plasma membrane phospholipid phosphatidylinositol bisphosphate (PIP z) into diacylglycerol (DAG) and inositol trisphosphate (lP 3) . DAG activates PKC and IP 3 liberates Caz+ from intracellular storage sites (i.e., the endoplasmic reticulum). Interaction of glucagon-like peptide I(GLP-I) or gastric inhibitory peptide (GIP), with their specific receptors on the B-cell plasma membrane, results in elevated intracellular levels of cyclic adenosine monophosphate (cAMP), which activates PKA. Activation of PKA affects the production of lipid signals by activation of hormone-sensitive lipase (HSL). HSL hydrolyzes stored triglycerides and increases the intracellular concentration of fatty acids (FAs), which are converted to acyl-CoA. Acyl-CoA has multiple effects on the B cell, functioning as a signaling molecule in potentiating glucose-stimulated insulin secretion. Extracellular fatty acids may also interact with a plasma membrane-bound receptor (GPR40) to stimulate insulin secretion directly by potentiating the increase in intracellular Ca z+ caused by glucose. Phospholipase A z (PLA z) activation yields arachidonic acid (AA), which has been proposed to liberate Ca z+ from intracellular stores. It should be noted that interactions and cross-talk between the different intracellular messenger systems as well as the action of substances inhibitory of insulin secretion have not been taken into consideration in this figure.

Islet Amyloid Polypeptide The islet B cells also produce islet amyloid polypeptide (lAPP, or amylin), which was initially purified from amyloid deposits in an insulinoma." lAPP was later demonstrated to be a normal constituent of the B cells." This peptide has been shown to contain 37 amino acids and shows a high degree of structural similarity to the neuropeptide calcitonin gene-related peptide (CGRP).33.34 The lAPP gene is localized to chromosome 12, and it codes for an 89-amino acid proIAPP.35 In the B cells, lAPP is stored in the secretory granules'" and is released from the cells together with and in parallel with insulin." Some studies, however, have suggested that insulin and lAPP are not released in absolute parallelism'" and the levels of insulin mRNA and lAPP mRNA seem to be regulated in a nonparallel fashion under certain conditions." The function of lAPP is poorly understood. A local regulatory role to restrain insulin secretion has been suggested

because the peptide inhibits insulin secretion.vv" The finding that an lAPP antagonist exaggerates insulin secretion in rats may suggest that under physiologic conditions lAPP restrains insulin secretion.F Therefore, lAPP secreted from the islet B cells seems to function as an inhibitor of the activity of the B cells. In addition to potential effects of lAPP to inhibit insulin secretion, the main interest in lAPP has been concentrated on its ability to form amyloid fibrils, which occurs in the islets during the development of type 2 diabetes. 34,43-45 Exaggerated release of lAPP with the subsequent formation of islet amyloid and deterioration of islet function has, therefore, been an intriguing speculation as a pathogenetic event for the development of diabetes.

Pancreastatin Another peptide that is produced by the islet B cells is pancreastatin, which is a carboxyterminal ami dated

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49-amino acid peptide initially purified from the pancreas and found to inhibit glucose-stimulated insulin secretion from the perfused rat pancreas." Pancreastatin is cleaved from chromogranin A before its storage in B-cell secretory granules.f The peptide is released from the pancreas in parallel with insulin.f inhibits insulin secretion, and stimulates glucagon secretion.i? The physiologic function of pancreastatin is not known.

A Cells Glucagon The most important peptide produced in the A cells is glucagon. The glucagon gene is composed of six exons and five introns, and the gene is expressed not only in the islet A cells but also in the intestinal L cells and the brain. The glucagon gene codes for a 160-amino acid proglucagon, which is posttranslationally cleaved to several different peptides." An important difference exists between the pancreatic A cells and intestinal L cells with regard to cleavage of proglucagon and the final formation of different glucagon-related peptides. Thus, in the pancreatic A cells, three different peptides are formed: glucagon, glicentinrelated polypeptide, and a larger peptide, called the major proglucagon fragment, which in its sequence contains the sequence of glucagon-like peptide I (GLP-I) and GLP-2. In contrast, in the intestinal L cells, GLP-l and GLP-2 are formed as separate peptides and, in addition, oxyntomodulin is formed. 50

It is known that glucagon gene expression, glucagon synthesis, and glucagon secretion are stimulated by various amino acids (e.g., arginine) and hormones that increase cAMP formation and inhibited by glucose and insulin. Often, the B and A cells are reciprocally regulated, which is illustrated by glucose stimulating the B cells but inhibiting the activity of the A cells. Because insulin and glucagon counteract the effects of each other on glucose metabolism, such a reciprocal regulation is functional. However, some stimuli activate both cell types (e.g., vagal nerve stimulation)." Such combined activation of both insulin and glucagon cells could be of importance for the rate of glucose turnover, which increases when glucagon activates hepatic glucose delivery concomitantly with insulin facilitating peripheral glucose uptake. This may be of physiologic importance after food intake, when facilitated transport of nutrients to target cells is required without an exaggerated increase in the circulating levels of the nutrients.

Peptide YY Besides glucagon, other peptides seem to be produced by the pancreatic A cells. One such peptide is peptide YY (PYY), which is a 36-amino acid peptide that shows structural similarities to neuropeptide Y (NPY) and pp.52 Thus, PYY has been confined to secretory granules of the islet A cells.P The function of PYY produced by the islet A cells is not known, although the peptide has been shown to inhibit the secretion of both insulin and glucagon.P>'

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D Cells

F Cells

Somatostatin

Pancreatic Polypeptide

In 1974, it was shown by immunocytochemistry that the islet D cells contain somatostatin, which was initially described the year before as a hypothalamic peptide inhibiting the secretion of growth hormone.'! It is now known that in the islet D cells, the somatostatin gene codes for prosomatostatin, which is a 92-amino acid peptide.P Prosomatostatin is processed to three different peptides: the 14-amino acid peptide somatostatin-14 (prosomatostatin [78-92]), which is the main product in the islet D cells; a fragment consisting of the 12 aminoterminal amino acids of somatostatin-28 (prosomatostatin [64-76]); and a larger fragment, corresponding to prosomatostatin (1-64).55 The secretion of somatostatin from the islet D cells seems to be regulated in parallel with that of insulin. For example, glucose, amino acids, and sulfonylureas'" as well as vagal nerve activation'? stimulate somatostatin secretion, whereas sympathetic nerve activation inhibits somatostatin secretion.P Somatostatin is, however, a widespread regulatory peptide and the contribution of the islet source of somatostatin to the circulating pool of somatostatin is negligible; hence it is not possible to study regulation of islet release of somatostatin by measuring circulating levels of the peptide. Somatostatin is a powerful inhibitor of both insulin and glucagon secretion.P However, the physiologic function of the islet somatostatin is not established, and the parallel activation of Band D cells, often in a reciprocal fashion with that of the A cells, is poorly understood. Previously, it was thought that somatostatin inhibits the secretion of both insulin and glucagon through a paracrine factor,'? but later studies have questioned whether the somatostatin released from the peripherally located D cells ever reaches the A and B cells in quantities sufficient to exert any effect. 13 Therefore, more studies are required to address the potential local role of somatostatin. Another hypothesis is that locally released somatostatin from the peripheral islet D cells functions to restrain exocrine pancreatic secretion because the microanatomy of islet vessels indicates that the effluent vessels from the islet periphery reach the exocrine tissue'? and somatostatin is a powerful inhibitory substance of exocrine secretion.59 However, this hypothesis needs direct experimental support before it gains general acceptance.

PP was first described as a contaminant of a chicken insulin extract. 10 It is known today that the PP is produced by the pancreatic F cells. PP consists of a 36-amino acid sequence and is produced by cleavage from a 95-amino acid precursor/" The F cells are particularly abundant in the ventral portion of the pancreas, where the F cells seem to replace the A cells in the mantle zone of the islet. Because PP secretion is stimulated by vagal activation, it has been suggested that plasma PP levels offer a good parameter for vagal activity.'" The peptide has been shown to inhibit the secretion of pancreatic juice and bile and to suppress insulin secretion,65.66 which might be of importance for interprandial homeostasis, although the physiologic role of PP is yet to be established.

Diazepam-Binding Inhibitor Another peptide that is produced by the human D cells is diazepam-binding inhibitor (DBI), which is an 86-amino acid peptide that binds to the benzodiazepine recognition site within the y-aminobutyric acid (GABA)-receptor complex. 6o Immunocytochemical studies have localized DBI to D cells in human islets, although in rat islets the peptide seems to be confined to the A cells." Because DBI inhibits glucose-stimulated insulin secretion,61,62 the two peptides produced by the D cells, somatostatin and DBI, both restrain insulin secretion, and a tempting speculation is that the role of the D cells is to inhibit B-cell activity, although, as previously stated, the islet paracrine concept has not been established.

Islet Blood Flow The pancreatic islets have a rich blood supply compared with the surrounding exocrine tissue. Approximately 10% of the pancreatic blood flow is directed to the islets, which make up only approximately 1% to 2% of the pancreatic mass. The microvasculature of the pancreatic islets exhibits a characteristic feature, which has been carefully studied in the rat." It has been shown that the arterioles nourishing an islet enter into the central B-cell mass, where fenestrated and highly permeable capillaries are formed (see Fig. 78-1). The capillaries then pass out from the central B-cell mass to the mantle zone, where they either empty into venules or anastomose with the capillaries of the exocrine parenchyma. Careful studies have also presented evidence that within the central B-cell mass, approximately 8 to 10 B cells are distributed around a central capillary/" This microvascular organization makes it likely that the nourishing blood passes first through the central B-cell mass before reaching the peripherally located A, D, and F cells. This anatomy of the islet vessels is probably of importance for the function of the islet because blood-borne substances first reach the B cells before they can affect the other cells. Also, insulin secreted from the B cells reaches the other cells in high concentrations and, therefore, affects the secretion of glucagon and somatostatin in an inhibitory direction. In contrast, because of the flow direction within the islet, the products from the A and D cells probably do not reach the B cells; therefore, it seems unlikely that the stimulatory action of glucagon and the inhibitory action of somatostatin with regard to insulin secretion are exerted by local endocrine effects within the islets. The islet microvasculature anatomy also suggests that anastomoses between the islet and exocrine capillaries result in an insular acinar portal system, which suggests that the peptides secreted from the islet cells reach the acinar cells in high concentrations. 14 The regulation of the islet blood flow has not been studied in such a great detail as that of islet hormone secretion. It seems, however, that the blood flow in the islets is controlled differently from that in the exocrine tissue. For example, glucose, vagal nerve activation, and lAPP all increase the relative fraction of islet blood flow versus total pancreatic blood flow.68.69

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Islet Nerves The pancreatic islets are richly innervated by the autonomic nerves (see Fig. 78-1).15,16 These nerves are postganglionic sympathetic nerves with their nerve cell bodies in the celiac ganglion, and postganglionic parasympathetic nerves with their nerve cell bodies in intrapancreatic ganglia. Preganglionically, the nerve impulses pass through the splanchnic and vagus nerves, respectively. The nerves primarily innervate the vessels, but some fibers also enter into the islets and terminate in close proximity to the islet endocrine cells. Electrical activation of the nerves has been shown to exert profound influences on insulin and glucagon secretion. Thus, activation of the sympathetic nerves inhibits insulin but stimulates glucagon secretion, whereas activation of the vagus nerves stimulates both insulin and glucagon secretion. Besides the classic neurotransmitters norepinephrine and acetylcholine, the islet nerves have also been shown to harbor various neuropeptides (see Table 78-1). A large number of studies have examined the role of these neurotransmitters in pancreatic islet physiology.

Islet Neurotransmitters: Sympathetic Effects It was initially thought that the neurotransmitter mediating the sympathetic effects is norepinephrine because this is the classic adrenergic neurotransmitter and is known to inhibit glucose stimulated insulin secretion." However, combined adrenergic blockade does not abolish the influences of sympathetic nerve stimulation on insulin and glucagon secretion and norepinephrine only partially reproduces the stimulation of glucagon secretion that accompanies sympathetic nerve activation.I'r? Therefore, the sympathetically induced influences on islet hormone secretion seem to be partially nonadrenergic. Such effects may be mediated by neuropeptides confined to sympathetic nerve terminals, such as NPy73 and galanin." This hypothesis is supported by the findings that both NPY and galanin are released from the pancreas during sympathetic nerve stimulation and that both of these neuropeptides inhibit insulin secretion and stimulate glucagon secretion.P:" In addition, NPY may be involved in the regulation of pancreatic blood flow because perivascular adrenergic nerves contain NPy73 and NPY has profound vasoconstrictor influences on the pancreas.I? Therefore, it is established that sympathetic nerve activation inhibits insulin but stimulates glucagon secretion, although the neurotransmitter involved on these actions has not been finally defined. It is tempting to speculate that different neurotransmitters are involved under different conditions in the sympathetic regulation of islet function. For example, the inhibition by sympathetic nerve activation of basal insulin secretion might be mediated by a neuropeptide (NPY, galanin, or both), whereas the inhibition of glucose-stimulated insulin secretion might be mediated by norepinephrine.

Catecholamine Effects The influence of catecholarnines on insulin secretion was initially thought to be inhibitory because norepinephrine and

epinephrine were demonstrated to reduce the insulin secretory response to glucose. 70,80,81 However, the influences of the catecholamines are dependent on the degree of expression of various adrenergic receptors. Thus, activation of postsynaptic a-adrenergic receptors, mainly of the lXz subtype on the islet B cells, inhibits insulin secretion.f whereas activation of the ~-adrenergic receptors, mainly of the ~2 subtype, stimulates insulin secretion." On the other hand, with regard to glucagon secretion, catecholarnines seem to be stimulatory through the activation of both a- and ~-adrenergic receptorS.84.85

Islet Neurotransmitters: Parasympathetic Effects Both acetylcholine and the cholinergic agonist carbamoyl choline stimulate insulin secretion.l" It has, therefore, been thought that acetylcholine is the mediator of vagal effects on islet function. However, results of studies on the possible involvement of acetylcholine as the neurotransmitter in vagally controlled islet hormone secretion have questioned this hypothesis. Thus, in the pig, vagally induced insulin and glucagon secretions are not totally inhibited by atropine," whereas in the dog, glucagon secretion during vagal nerve activation is not inhibited by atropine." This suggests that noncholinergic involvement exists after vagal nerve activation of islet hormone secretion, at least in some species. Studies of the nature of this noncholinergic involvement have proposed that vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), and gastrin-releasing polypeptide (GRP) may be involved. Nerves containing the 28-amino acid neuropeptide VIP have been demonstrated in the endocrine pancreas." Furthermore, VIP is released from the perfused pancreas during vagal nerve activation.f" and VIP potently stimulates insulin and glucagon secretion. 16 Moreover, islet nerves also contain the 38-amino acid neuropeptide PACAP, and PACAP is a powerful stimulator of insulin and glucagon secretion as demonstrated in several species, including humans.89-91 The physiologic importance of PACAP for normal islet function is also supported by studies in mice genetically deficient in one of the PACAP receptors, which show impaired glucose-stimulated insulin secretion.P? Similarly, nerves containing the 27-amino acid peptide GRP exist in the pancreas." GRP is released from the pancreas during vagal nerve activation." and GRP stimulates the secretion of insulin and glucagon." The influences of the parasympathetic nerves and their neurotransmitters, acetylcholine, VIP, PACAP, and GRP, are probably of main importance after food intake, when activation of these nerves contributes to the marked insulin response.

Cholecystokinin Nerves Cholecystokinin (CCK) immunoreactivity occurs in islet nerves, although the nature of these nerves is yet to be defined." Because it is known that CCK potently stimulates insulin secretion." the CCK nerves may be of importance for islet function. However, the physiologic importance of the islet CCK nerves remains to be established.

Pancreatic Endocrine Physiology - - 707

Sensory Nerves The endocrine pancreas is innervated by sensory afferent nerves as well as by the sympathetic and parasympathetic nerves." These sensory nerves seem to harbor CGRP and substance P as neurotransmitters.P'?' Both these neuropeptides inhibit insulin secretion." The role of these sensory nerves in the regulation of islet function has been examined with the use of the neurotoxin capsaicin, which destroys sensory nerves." Using a neonatal model with capsaicin treatment in mice, a sensory denervation was created, and it was demonstrated that CGRP and substance P were partially or completely depleted from islet nerves after such treatment, indicating that this is a suitable model for studying the function of the sensory nerves in the endocrine pancreas." Interestingly, it was demonstrated that such treatment potentiates insulin secretion and increases glucose tolerance." Thus, sensory nerves seem to restrain glucose tolerance.

The Gut and Insulin Secretion It has long been known that oral ingestion of glucose results in high levels of plasma insulin, although the increase in plasma glucose is only marginal. 100,101 This is due to the action of gut hormones, called incretins, that are released into the circulation during meal intake and stimulate insulin secretion. The most important incretins are glucose-dependent insulinotropic polypeptide (GIP; also called gastric inhibitory polypeptide) and GLP_1. IOZ,103 GLP-l is a 3Q-amino acid peptide produced in the L cells in the distal part of the small intestine, and GIP is a 42-amino acid peptide produced in the K cells in the duodenum and proximal portion of the small intestine. They are both released into the circulation during the first 15 minutes after initiation of food intake, and they both stimulate insulin secretion. Their importance as incretin hormones is illustrated by findings that insulin secretion and glucose tolerance are impaired in mice with genetic deletion of the GIP receptors'?' and the GLP-l receptors. 105 GLP-l is the most important incretin hormone. 103,106,107 This peptide is processed from proglucagon in the intestinal L cells and released into the blood during meal ingestion. GLP-l potently stimulates insulin secretion at concentrations that are produced by food intake. The peptide has, in addition, been of interest as a potential novel treatment modality in diabetes because of its combined effect to stimulate insulin secretion, inhibit glucagon secretion, and reduce blood glucose levels by a "peripheral" effect. 108,109 It should be recalled that GLP-l is not produced in the pancreatic A cells but only in the intestinal L cells because of the cell-specific posttranslational modification of proglucagon related to differential expression of proconvertases. A problem in developing GLP-l as a treatment for type 2 diabetes is that it is rapidly degraded by means of the enzyme dipeptidyl peptidase IV (DPPIV)."O This enzyme is expressed in several tissues, including endothelial cells, liver, gut, and kidney, and cleaves the two aminoterminal amino acids from GLP-l, making the truncated form inactive in stimulating insulin secretion. Because of this, the half-life of GLP-l is

only a few minutes. Attempts to overcome this drawback when developing GLP-l for treatment include production of DPPIV-resistant GLP-l analogs and development of agents that inhibit the activity of DPPIy'"O Both these approaches have been successful, and clinical trials have been undertaken with both of them. III,IIZ

Cell Biology of Islet B Cells The cell biology of the islet cells has been studied in great detail regarding the underlying mechanisms of secretion of insulin from the islet B cells (see Fig. 78-2). The most important regulator of insulin secretion is glucose, which enters the cells through a specific glucose-transporting protein, GLUT-2. 113,1l 4 GLUT-2 is insulin independent in its action, and its capacity for transporting glucose is high. Hence, the intracellular glucose concentration rapidly equilibrates with the extracellular concentration, indicating that GLUT-2 is not the rate-limiting step for B-cell function. When glucose has entered the B cells, it is phosphorylated by glucokinase to glucose 6-phosphate.1 15 The glycolytic activity in the glucose-exposed islet is basically regulated by glucokinase acting as the rate-limiting enzyme in the flux of substrates through the glycolysis. The glucokinase activity has therefore been recognized as the B-cell glucose sensor. I 16 After its phosphorylation, glucose is metabolized and adenosine triphosphate (ATP) is formed. 117 An increased intracellular content of ATP or rather an increased ratio of ATP to ADP (adenosine diphosphate) leads to closure of specific ATP-regulated potassium (K+) channels in the plasma membrane. I 18 This leads to a decreased outflow of K+ from the B cells, which, in turn, depolarizes the cells, resulting in the opening of L-type voltage-sensitive Ca z+ channels. 119 This causes a massive inflow of Caz+ from the extracellular space because the cytoplasmic free concentration of Ca z+ under resting conditions is only approximately 100 nmollL, whereas extracellularly it is approximately 1.2 mmollL (i.e., more than 10,000 times that of the cytoplasm). The massive inflow of Ca z+ raises the cytoplasmic Ca z+ concentration.P" which is necessary for exocytosis of the insulin secretory granules. 17 This chain of events is of importance for the first phase of glucose-stimulated insulin secretion. Interestingly, oral hypoglycemic agents, such as sulfonylureas, which are commonly used to treat patients with type 2 diabetes, also initiate insulin secretion by inducing closure of the ATPregulated K+ channels.'?' Furthermore, several inhibitors of insulin secretion act by opening these K+channels and thereby induce hyperpolarization and closure of the voltage-sensitive Ca z+ channels, for example, diazoxide.F' which is used in the treatment of insulinomas, and the neuropeptide galanin.F' Hence, the activity of the ATP-regulated K+channels and the degree of polarization of the B-cell plasma membrane are of great importance for insulin secretion. However, for the maintenance of a sustained elevation of the secretory rate of the islet B cells, mechanisms other than those initiated by depolarization and uptake of Ca" are of importance (see Fig. 78-2). One such mechanism is the formation of cAMP, which is stimulated by glucose through activation of adenylate cyclase.P' Cyclic AMP activates

708 - - Endocrine Pancreas protein kinase A, which stimulates the exocytosis of granules. 17 Several factors besides glucose that affect insulin secretion modulate the cellular content of cAMP. For example, the inhibitors of insulin secretion galanin and PYY reduce islet cAMP,54.123 whereas the insulin-promoting peptides glucagon and GLP-I increase the islet content of CAMP.125,126 The actions of cAMP and protein kinase A require a stimulatory level of glucose; hence, this pathway is regarded as a modifier of glucose-stimulated insulin secretion. It has been proposed that islet cAMP is under the influence of a variety of G proteins of both a stimulatory and an inhibitory nature.F' Besides the uptake of extracellular Ca 2+ and the formation of cAMP, insulin secretion may also be stimulated by factors that increase the hydrolysis of membranous phosphoinositides through the activation of phospholipase C,17.128 which causes the hydrolysis of phosphatidylinositol 4,5-bisphosphate, yielding inositol l,4,5-trisphosphate (IP 3) and diacylglycerol (DAG). IP 3 diffuses into the cytoplasm and activates specific IP 3 receptors on intracellular Ca 2+ storage sites, which further enhances the cytoplasmic concentration of Ca 2+ and potentiates insulin secretion. Furthermore, DAG and Ca 2+ activate protein kinase C (PKC), which through a direct action on the exocytotic machinery stimulates insulin secretion.!" Cholinergic agonists, CCK, and the neuropeptide GRP all stimulate insulin secretion mainly through this phospholipase C pathway.96,130,131 Glucose has also been shown to stimulate the formation of arachidonic acid in the endocrine pancreas through activation of phospholipase A 2 (PLA 2).132 Because an inhibitor of PLA 2, p-amylcinnamoylanthranilic acid, has been demonstrated to inhibit markedly both arachidonic acid formation and insulin secretion after glucose activation of isolated islets, it has been proposed that this pathway is of importance for insulin secretion. 133 A mediator of this pathway might be liberation of intracellular Ca 2+, which is induced by arachidonic acid. 133 However, it has also been suggested that the main function of PLA 2 is to maintain the intracellular stores of insulin rather than being required for the initiation of insulin secretion.P" Besides these signaling pathways, lipids are also involved in intracellular signaling and insulin secretion (see Fig. 78-2). During glucose metabolism in B cells, the cytosolic concentration of long-chain acyl coenzyme A (LC-CoA) increases.P' and a model for second-phase insulin secretion is based on the knowledge that when glucose is metabolized there is increased production of citrate in the Krebs cycle in the mitochondria. Citrate is transported into the cytosol, where it is converted to malonyl CoA, a potent inhibitor of carnitine palrnitoyltransferase I (CPT-I), which transports longchain fatty acids into the mitochondria, where they are oxidized. Thus, the transport of long-chain fatty acids is inhibited during glucose metabolism and the concentration of LC-CoA increases in the cytosol. LC-CoA has been found to have effects on the ATP-regulated K+ channels-" and on PKC activation137 and to influence directly the secretion of insulin by facilitating the fusion of secretory granules with the B-cell plasma membrane. 138 Lipid signaling molecules involved in insulin secretion may also be derived from the breakdown of intracellular triglyceride stores. Hormone-sensitive lipase, the enzyme known to hydrolyze stored triglycerides in adipose tissue, was

found to be expressed and also active in B cells.P? supporting a role for endogenous lipolysis in regulation of insulin secretion. It is thus possible that hydrolysis of B-cell triglyceride stores plays an important role in stimulus-secretion coupling by increasing the intracellular concentration of fatty acids, which are converted to acyl CoA by acyl CoA synthase, thereby contributing to increased LC-CoA concentration in the cytosol. Besides this mechanism mediating lipid-induced insulin secretion, it has also been suggested that fatty acids activate intracellular pathways through binding to receptors that are expressed on the surface of the cells.l'? GPR40 is a G-proteincoupled receptor that is highly expressed on B cells. By binding of long-chain fatty acids to GRP40, glucose-stimulated insulin secretion is potentiated. Fatty acid activation of GPR40 results in increased intracellular Ca 2+ and potentiation of glucose-stimulated insulin secretion. Therefore, both glucose and nonglucose stimuli are of importance for insulin secretion through perturbing intracellular pathways. Many of these have been characterized in detail through intense research work during the last 3 decades. Still, however, the complete nature of the cell biology of the B cells is not established.

Cell Biology of Islet Non-B Cells The mechanisms by which nutrients stimulate insulin secretion, including the signal transduction pathways of the B cells, have been extensively studied. Much less is known about the other islet cell types, including the mechanisms behind modulation of glucagon secretion. Glucagon is secreted from A cells in response to low blood glucose, and thus the secretion is decreased as glucose increases. It has been shown that pyruvate metabolism in the mitochondria is implicated in the initiation of glucagon secretion141 and that the mechanism of action seems to involve closure of ATPregulated K+ channels, which have been shown to be expressed on islet A cells together with voltage-dependent Ca 2+ channels.142.143 Furthermore, as in most exocytotic events, Ca 2+ and ATP are required in glucagon secretion. In B cells, glucose increases ATP production and elevates intracellular Ca 2+; however, in A cells, ATP production is much less increased and Ca 2+ is barely changed after glucose stimulation."" By contrast, A cells respond to pyruvate with both increased ATP production and Ca 2+ influx, whereas B cells do not, because of low expression of pyruvate transporters. Thus, the coupling ofATP generation and Ca 2+ elevation differs between A and B cells, and it has been suggested that the simultaneous activation of B cells inhibits glucagon secretion."! The insulin granules contain several substances that may be involved in the inhibition of glucagon secretion, including islet amyloid polypeptide, zinc, ATP, and possibly glutamate. Other data suggest that zinc is important in inhibiting glucagon secretion. 141

Pulsatility of Islet Hormone Secretion A characteristic of islet hormone secretion is its oscillatory or pulsatile pattern. For example, insulin secretion has been

Pancreatic Endocrine Physiology - - 709 shown to occur in a periodic manner, with a rapid periodicity of approximately 8 to 15 minutes and a slower oscillation at intervals of 80 to 150 minutes.I44-146 In vitro studies have demonstrated that the oscillation of insulin secretion is an intrinsic characteristic of the B cells."? The oscillation of insulin secretion is accompanied by similar oscillations in the concentration of the cytoplasmic free Ca 2+,148 and a model has been proposed suggesting that raising the glucose level initiates oscillations in glycolysis and an oscillatory nature of the formation of ATP, which, in tum, causes oscillatory patterns of changes in membrane depolarization and Ca 2+ influx.r'" The ATPIADP ratio has been shown to oscillate in normal B cells. ISO The reason for insulin secretion to oscillate is not completely known, but it could be to prevent the continuous elevation of stimulatory metabolites, which may lead to desensitization and downregulation of responses. The mechanism behind the metabolic oscillations is based on detailed studies of spontaneous oscillatory glycolysis in skeletal muscle extracts. In skeletal muscle, the oscillations are driven by autocatalytic activation of the muscle isoform of the key enzyme phosphofructokinase by its product fructose 1,6-bisphosphate, resulting in large oscillations in the ATPIADP ratio. 151 The time course of changes in metabolic and ionic parameters involves earlier changes in the ATP/ADP ratio and in metabolites such as malonyl-CoA, which occur before Ca 2+ or insulin secretion. ISO Besides the oscillation of the individual B cells, islets also oscillate together, suggesting that several islets function as a unit, which results in regular oscillation of circulating levels of insulin.P? The synchronization of the individual islets has been suggested to be governed by the pancreatic ganglia and therefore to be neural.F' which is supported by the finding that after islet transplantation, oscillation develops at the time when the transplanted graft is innervated.'> That this is of physiologic importance is illustrated by the fact that the characteristic of the oscillatory pattern is altered in type 2 diabetes. ISS In healthy subjects, almost all pulsatory phases of insulin secretion occur in association with an accompanying oscillatory change in plasma glucose levels, whereas this temporal association is weaker in diabetics. 155 It is tempting to speculate that this altered relation between glucose and insulin oscillations is of pathophysiologic importance for the development of type 2 diabetes.

Endocrine Pancreas and Type 2 Diabetes From the previous discussions, it is clear that the endocrine pancreas is a complexly regulated organ that integrates incoming impulses of nutrient, hormonal, and neural nature, The endocrine pancreas converts these impulses to an optimal secretion of the islet hormones mainly for the regulation of carbohydrate homeostasis. An example of the consequences that follow derangement of the endocrine pancreas is type 2 diabetes, A primary event during the development of this disease is a reduced action of insulin on the activation of peripheral insulin receptors.P" This results in a compensatory increase in insulin secretion, which explains the hyperinsulinemia that accompanies states with peripheral insulin insensitivity, such as obesity. The relation between

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Insulin sensitivity

FIGURE 78-3. Schematic illustration of the relation between insulin sensitivity and insulin secretion. During progression to insulin resistance (i.e., low insulin sensitivity), insulin secretion is increased in a compensatory manner, The relation between the two variables is nonlinear and best described by a hyperbolic function. If insulin secretion is adequate in relation to insulin sensitivity, normal glucose tolerance (NOT) remains. However, if the B cells fail to compensate insulin resistance adequately, impaired glucose tolerance or type 2 diabetes develops.

insulin sensitivity and insulin secretion is tightly regulated, and careful mathematic analyses have shown that the relation displays a curvilinear function that is best fit by a hyperbolic function (Fig.78_3),157,158 as first demonstrated by Bergman and collaborators in the early 1980s.157 Hence, when insulin resistance develops, normal islet function ensures adequate hyperinsulinemia. These patients thus have normoglycemia and hyperinsulinemia. This is, for example, seen in the many subjects with obesity, who have insulin resistance but have compensated with a sufficient increase in insulin secretion to avoid glucose intolerance. However, in patients who proceed to type 2 diabetes, there is a defect in glucose action on the B cells, leading to impaired glucose-stimulated insulin secretion, making it impossible for the B cells to compensate fully for the peripheral insulin insensitivity. This leads to hyperglycemia and diabetes,I9,I59 Hence, the main defect in type 2 diabetes is defective beta cells; insulin resistance can be regarded as a risk factor because it may unmask the defective islet function. Also, the ability of the A cells to respond properly with inhibition of glucagon secretion when the glucose level is increased is impaired in diabetes.P? This leads to hyperglucagonemia, which, together with the insufficient hyperinsulinemia, increases the hepatic glucose output and reduces the glucose uptake in peripheral tissues, which are the metabolic signs of type 2 diabetes. Central to the disease is the inability of the B cells to respond normally to increased glucose levels. This may be due both to impaired function of the individual B cells and to reduced number of B cells, for example, through apoptosis. 160 The cellular biology basis for this defect is still poorly understood. For the development of type 2 diabetes, furthermore, it has been demonstrated that it is mainly the first, initial, phase of insulin secretion that is of importance. 161 Hence, appropriate early treatment of the disease is augmentation of the first or early phase of insulin secretion (the first 10 to 15 minutes) after meal ingestion, which is instituted by rapid secretagogues such as nateglinide and repaglinide-" together with improvement of insulin resistance by life style intervention and drugs such as metforrnin and thiazolidinediones.

710 - - Endocrine Pancreas

Endocrine Pancreas and Hypoglycemia An important physiologic role of the endocrine pancreas is protecting the body against hypoglycemia, which is undertaken by the release of glucagon to counteract the fall in glucose. A large number of studies have been directed at establishing the mechanisms underlying the glucagon response to hypoglycemia, and it has been demonstrated that it is caused by an increase in both parasympathetic and sympathetic neural activity and by elevated levels of epinephrine secreted by the adrenal medulla. 162 The importance of the neural effects for this response has been demonstrated in humans, in whom infusion of a ganglionic blocker has been found to inhibit the glucagon response to hypoglycemia.lf A similar response is that seen during neuroglycopenia, when a local reduction of glucose in the brain cells initiates activation of the autonomic nervous system to increase the . some species, . also secretion of glucagon and, m so imsu lin. 64.164 Neuroglycopenia is induced experimentally by an intravenous injection of the glucose analog 2-deoxyglucose, which competes with glucose and creates a state of intracellular glucose deprivation, stimulating the discharge of both the sympathetic and parasympathetic branches of the autonomic nervous system. This is followed by activation of glucagon secretion, which is inhibited by both muscarinic blockade by atropine and a-adrenergic receptor blockade by phentolamine.P' Also, chemical sympathectomy by 6-hydroxydopamine and adrenalectomy reduce the neuroglycopenia-induced glucagon secretion, which shows that this important counterregulation is mediated by both pancreatic nerves and the adrenals.l'" Hence, the autonomic nerves, together with the direct action of low glucose and the intraislet reduction of insulin, are of importance for a normal glucagon response to hypoglycemia, which is of major importance for avoiding hypoglycemic reactions during intense insulin treatment in diabetes. In fact, the risk for hypoglycemia is an important limiting factor for the treatment of many patients.l'"

Endocrine Pancreas and Stress Another important role of the endocrine pancreas is its involvement in the hyperglycemia that accompanies various kinds of stress. A few examples of stress are illustrated.

Physical Exercise During physical exercise, there is an increased hepatic glucose output, which underlies the hyperglycemia, as a result of increased activity in the sympathetic nerves and elevated arterial epinephrine levels.l'? Accompanying these changes is an inhibition of insulin secretion and a stimulation of glucagon secretion, which exaggerate the hepatic glucose output and also reduce the peripheral glucose uptake. This optimizes the availability of glucose to the central nervous system during stress. A system for studying the mechanisms of these influences was previously introduced in the swimming mouse model, in which standardized 2-minute swimming is

accompanied by a 50% inhibition of glucose-stimulated insulin secretion.l'" It was subsequently shown that both chemical sympathectomy and adrenalectomy prevented the impaired glucose-stimulated insulin secretion that occurred during swimming, 169 which shows that both the sympathetic nerves and the adrenals are of importance in this response. Thus, it might be assumed that stress stimulates the sympathetic nervous system, which inhibits insulin secretion through local release of norepinephrine as well as through arterially borne epinephrine. It has also been demonstrated that galanin immunoneutralization prevents the inhibition of glucose-stimulated insulin secretion that accompanies swimming.P" which indicates that the neuropeptide galanin, occurring in pancreatic adrenergic nerve terminals (see prior discussion), contributes, along with norepinephrine, to the islet response to swimming stress. In any case, the neural influences on islet function are of great importance for the glucose adaptation to the increased demand during exercise.

Hemorrhagic Stress An important factor for the restoration of blood volume during bleeding is an increase in the plasma glucose level, which induces osmotic absorption of fluid into the blood vessels. Elegant studies by Jarhult!" have shown that the increase in plasma glucose during bleeding is induced by increased hepatic glucose delivery caused by increased activity in the sympathoadrenal system. The mediating link seems to be alterations in islet function because bleeding is accompanied by impaired insulin secretion, resulting in unchanged or low plasma insulin levels in spite of hyperglycemia'?" together with increased glucagon secretion.!" Direct studies to examine the underlying mechanisms have shown that bleeding causes activation of the arterial baroreceptors in the carotid sinuses because of hypotension, which elicits activation of the sympathetic nerves causing inhibition of insulin secretion and stimulation of glucagon secretion through direct islet effects. The increased glucagon-insulin ratio, together with increased arterial concentrations of epinephrine resulting from the release of catecholamine from the adrenal medulla, stimulates glucose release from the liver, which increases plasma glucose levels and accentuates the gluco-osmotic force to restore the blood volume.

Sepsis In contrast to hemorrhagic stress, the metabolic stress in sepsis and bums is usually not accompanied by hyperglycemia. Instead, it is the overall glucose turnover that seems to be activated, with preservation of normoglycemia.l?" Only in advanced cases, and late during the course, hyperglycemia develops as a result of impaired peripheral glucose uptake.I" The endocrine pancreas seems to mediate the increased glucose turnover. For example, in a study of 18 septic patients, hyperinsulinemia evolved during the initial, normoglycemic phase, whereas inadequate insulin secretion was seen only in the late hyperglycemic phase.!" During late stages, cytokines, endotoxins, and other mediators impair both peripheral glucose uptake and insulin secretion, which cause hyperglycemia.'?' During the final stage, the

Pancreatic Endocrine Physiology - -

hepatic glucose delivery drops, leading to hypoglycemia. Hence, the endocrine pancreas ensures an optimal discharge of insulin until the septic insult becomes too strong. The mechanism of the hypersecretion of insulin during sepsis remains to be established. In one study, it was demonstrated that the glucose-induced insulin secretion from isolated islet cells was the same in septic rats as in control rats, indicating first, that islet cells derived from septic animals have a preserved insulin secretory capacity and second, that the hypersecretion observed in vivo is probably mediated by an indirect mechanism, hypothetically by neural influences or inflammatory mediators.!"

Endocrine Pancreas after Food Intake An important function of the endocrine pancreas is to deliver an optimal amount of insulin after a meal and to ensure optimal metabolism of the ingested nutrients to store the absorbed fuels as glycogen or fat or both. At least three different mechanisms account for this delivery of insulin. First, before the food is ingested or absorbed, insulin secretion is rapidly stimulated. This is evident from a study in the rat in which ingestion of glucose raised plasma insulin levels within 2 minutes, yet plasma glucose levels did not start to increase until 3 minutes. 176 Also, rats given meals without any digestible nutrients showed a clear-cut early insulin response. 177 Because this preabsorptive insulin secretion has been shown to be inhibited by atropine, it has been assumed that this early phase of food-stimulated insulin secretion is mediated by parasympathetic nerves.!" This has been confirmed in a study in humans, in whom autonomic blockade by trimetaphan has been shown to abolish the cephalic phase of insulin secretion.!" This phase has been suggested to be of great importance for the prevention of glucose intolerance after meal intake. Thus, inhibition of the cephalic phase of insulin secretion by trimetaphan was associated with defective glucose tolerance in humans.!" Similarly, a study has shown that sham-feeding improves glucose intolerance. 179 The second mechanism underlying food-stimulated insulin release is mediated by the incretins from the gastrointestinal tract, mainly GIP and GLP-I (see prior discussion). Finally, a third mechanism is the ingested nutrients, most notably glucose and amino acids, which by themselves stimulate insulin secretion. These different mechanisms ensure the optimal amount of insulin be delivered to the blood, optimizing carbohydrate metabolism.

Summary The endocrine pancreas is a well-organized and tightly controlled micro-organ producing a variety of biologic active peptides of particular importance for carbohydrate metabolism and the regulation of blood glucose levels. It integrates the signals generated by the autonomic nervous system and arterially borne hormones and nutrients to produce an optimal discharge of the various bioactive regulatory peptides. The micro-organ is of utmost importance for metabolic homeostasis after food intake, during starvation, and under

711

various conditions of stress. Furthermore, impairment of islet cell function results in severe metabolic consequences (e.g., impaired glucose tolerance and diabetes). An understanding of the physiologic and pathophysiologic processes in relation to glucose metabolism requires a detailed knowledge of the endocrine pancreas, its synthesis of the various regulatory peptides, and the regulation of peptide synthesis and secretion by hormones, nutrients, and neural influences. We are gaining a more detailed understanding of the mechanisms that regulate the synthesis and secretion of the islet cell hormones, and what is now evident is the critical importance of defective B cells for the development of type 2 diabetes. Future studies may more clearly define the involvement of the endocrine pancreas in various forms of stress and in the development of glucose intolerance and diabetes.

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Insulinomas Jeffrey D. Wayne, MD • Edwin L. Kaplan, MD

Insulinomas remain one of the most interesting endocrine tumors because of the diversity of symptoms associated with their hormonal secretion and because of the frequent inability of standard preoperative imaging studies to locate these small tumors. Advances in the diagnosis, localization, and surgical management of insulinomas are presented in this chapter. Specifically, the novel, minimally invasive techniques of endoscopic ultrasonography with fine-needle aspiration and laparoscopic pancreatectomy with splenic preservation are highlighted.

Historical Background Tumors of pancreatic islet cell origin were described by Nicholls I as early as 1902, well before the discovery of insulin by Banting and Best in 1922.2 It was known that some islet tumor extracts produced hypoglycemia when introduced into dogs; however, not until insulin was discovered was the significance of this observation appreciated. Harris' described the clinical pathophysiology of hyperinsulinemia in 1924 but did not associate the presentation of symptoms with islet cell adenomas of the pancreas. Shortly thereafter, Wilder and colleagues reported the first exploration for this tumor by William 1. Mayo in 1926.4 Unfortunately, the patient, a physician with an 18-month history of severe hypoglycemic attacks, was found to have a large, unresectable malignant insulinoma with hepatic metastases. The patient died within 1 month of surgery. An autopsy also revealed the presence of renal calculi, suggesting that this patient had multiple endocrine neoplasia type 1 (MEN 1). Roscoe Graham of Toronto reported the first successful resection of an insulin-secreting tumor." By enucleating a 2- to 3-cm malignant insulinoma, Dr. Graham was able to palliate his patient's hypoglycemic symptoms for a 14-month period. Evarts Graham was the first surgeon to espouse the concept of a blind subtotal pancreatectomy for cases of undetected insulinoma. Finally, in 1935, Whipple and Frantz described the classic clinical triad, now know as Whipple's triad, to help improve the diagnosis of this condition, after noting a 40% negative laparotomy rate for suspected insulinoma,"

Pathophysiology The pathophysiology of an insulinoma is based on excessive secretion of insulin, which results in the clinical presentation of hypoglycemia. During the 1960s, insulinomas and other endocrine tumors of the gastrointestinal tract were found to share common cytochemical characteristics as well as a common neuroectodermal origin. This diverse group of tumors was thus classified under the amine precursor uptake and decarboxylation (APUD) concept," Although the APUD concept is no longer accepted in its entirety, it played a very useful role at the time by allowing an explanation for the association of insulinomas with other neuroendocrine tumors under MEN 1. MEN 1 has now been definitively linked to a loss of heterozygosity on chromosome 11 (llq13).8 The gene for this disorder, called menin, has been described. In MEN 1, insulinomas are often associated with hormone-secreting tumors of the parathyroid, pituitary, adrenal cortex, and thyroid glands. In such patients, a variety of symptoms may be present, and diagnosis based on clinical findings alone is often difficult. Zeiger and Norton? reported the increased expression of messenger RNA encoding for the alpha subunit of the G, protein, seen in insulinomas but not normal endocrine tissues. G proteins, known to mediate hormonal transmembrane signaling, are thus thought to playa role in the unregulated secretion of insulin seen in these tumors. This seminal work has paved the way for further studies of the molecular basis of insulinoma and other endocrine neoplasms. To appreciate the modem tests used to diagnose an insulinoma requires an understanding of islet cell function. Insulin is released from the secretory granules within the cytoplasm of beta cells of the pancreatic islets (Fig. 79-1). Before exocytosis occurs, the inactive precursor, proinsulin, is proteolytically cleaved into insulin and a 31-amino acid connecting peptide called C peptide'? (Fig. 79-2). Some conversion of proinsulin to insulin may occur after it is secreted; however, the majority of the granule composition within the beta cells consists of equimolar amounts of C peptide and hormonally active insulin.

715

716 - - Endocrine Pancreas

FIGURE 79-1. Electron micrograph of the neurosecretory granules of a beta cell. Note the crystalline appearance as a result of the presence of insulin (arrows).

Clinical Aspects Signs and Symptoms The symptoms of an insulinoma are based on profound hypoglycemia with a lack of glycogen in the brain but also are due to the release of epinephrine secondary to a low serum glucose level. The signs and symptoms are best classified

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into neurologic, cardiovascular, and gastrointestinal manifestations'! (Table 79-1). Neurologic symptoms are most frequent and range from apathy, dizziness, clouded sensorium, and strange behavior to convulsions in very severe cases. In other instances, profound central nervous system depression occurs with coma and even death if left untreated. Cardiovascular signs and symptoms, such as palpitations, tachycardia, and chest pain, are less common and are primarily due to catecholamine release in response to low serum blood sugar levels. Gastrointestinal symptoms, such as hunger, nausea, and vomiting, may also occur in about 10% of patients, but by far the vast majority of symptoms are neurologic in nature. Many patients with insulinomas are obese because they find that they can prevent symptoms by eating more frequently. The diagnosis of insulinoma is often delayed and can take as long as several months to years, depending on the severity of symptoms and frequency of hypoglycemic attacks. Delays in diagnosis are due in part to the variability and severity of the clinical presentations but certainly depend on physician awareness as well. The attacks are usually associated with fasting; most commonly, they occur before breakfast and during the late afternoon. However, attacks of fasting hypoglycemia may occur during exercise as well. It must be understood that the severity of the clinical presentation predicts neither the size nor the malignant potential of the insulinoma.

Differential Diagnosis of Hypoglycemia FIGURE 79-2. Secretion of insulin from the pancreatic islet beta cells: Schema of rough endoplasmic reticulum (ER), where proinsulin is synthesized, and secretion granules, where proinsulin is cleaved into insulin and C peptide. (From Rubenstein AH, Kuzuya H, Horwitz DL. Clinical significance of circulating C-peptide in diabetes mellitus and hypoglycemia disorders. Arch Intern Med 1977;137:625. Used with permission. © 1977, American Medical Association. )

As shown in Table 79-2, there are many causes of hypoglycemia. Hypoglycemia may be due to inhibition of glucose production in the liver and stimulation of glucose utilization by adipose and muscle cells. Hypoglycemic attacks secondary to an insulinoma are predominantly due to an overuse of glucose by the cells in the body. These attacks are episodic because of the intermittent secretion of insulin, especially in

Insulinomas - - 717

to the overuse of glucose in the case of an insulinoma or to the underproduction of glucose. In many other instances, including alcoholism and hormone insufficiency syndromes, hypoglycemia can be due to antibodies that bind to insulin and release it inappropriately. This may be seen in multiple myeloma and systemic lupus erythematosus. A differentiation can often be made clinically by the amount of glucose that must be infused intravenously to prevent hypoglycemia and by testing for anti-insulin antibodies. Daily hepatic production of glucose ranges from 100 to 200 g. If more than 200 g of glucose is required to offset the hypoglycemia, the patient suffers from overuse of glucose, which would support the diagnosis of insulinoma.P

Diagnosis The limitations of a clinical diagnosis for insulinoma became apparent as early as 1935, when Whipple noted that 40% of explorations performed for insulinoma up to that time failed. Noting the numerous causes of hypoglycemia, Whipple set forth the strict diagnostic triad that bears his name: (1) the signs and symptoms of hypoglycemia occur during periods of fasting or exertion; (2) at the time of symptoms, blood sugar levels must be less than 45 mg/dL; and (3) symptoms are ameliorated by the administration of oral or intravenous glucose." Although these criteria still hold true, the diagnosis of insulinoma has been refined by our better understanding of the pathophysiology of normal and aberrant insulin secretion and our ability to measure circulating levels of insulin, C peptide, and proinsulin.

Glucose and Insulin Levels

early cases. It is not until advanced or metastatic disease is present that persistent hypoglycemia may ensue. This state of excessive glucose utilization should be differentiated from hypoglycemia that occurs after eating (see Table 79-2). Postprandial or reactive hypoglycemia is a much more common problem. It can occur in healthy individuals or in patients who have undergone previous gastric surgery. Patients after gastric resection, bypass, or drainage procedures often experience hypoglycemia as part of a "dumping" syndrome, which may also include diarrhea, and a host of other systemic symptoms secondary to catecholamine release. 12 In contradistinction, patients with insulinomas suffer hypoglycemiaafterfasting or exercise. Fasting hypoglycemia is due

Currently, the diagnosis of insulinoma is confirmed by demonstrating a circulating insulin level that is inappropriately high for the serum glucose level, measured at the time of hypoglycemia (Fig. 79-3). When a patient presents with symptoms of hypoglycemia (i.e.. coma, convulsions, or other neurologic symptoms), blood samples should be taken for the determination of both insulin and glucose levels. Samples should be drawn as early as possible to avoid complications of hypoglycemia and before treatment with glucose. Also, later, epinephrine secretion may cause mobilization of liver glycogen with a compensatory rise in serum glucose, possibly masking the hypoglycemia associated with an insulinoma. Although normal serum glucose levels are 60 to 95 mg/dL, symptoms of hypoglycemia usually do not occur until levels are less than 50 mg/dL. Normal serum insulin levels are typically below 30 ~U/mL.

Insulin-Glucose Ratio The insulin-glucose (I1G) ratio provides a relationship between these two values that aids in the determination of the presence of an insulinoma. In a normal individual, the ratio is always less 0.4, but in patients with an insulinoma the ratio approaches 1.0 and may in some cases exceed 1.0. The I1G ratio is important because as many as one third of patients with an insulinoma have insulin levels within normal limits when they have symptomatic hypoglycemia.

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FIGURE 79-3. Plasma insulin (in microunits per milliliter) and blood glucose (milligrams per deciliter). Relationships after overnight fasting in 33 normal persons and in 22 patients with solitary beta islet cell adenomas. Both plasma insulin and blood glucose show highly significant differences between the two groups. IRI = immunoreactive insulin. (From Harrison TS. Hyperinsulinism and its surgical management. In: Hardy JD red], Rhoads' Textbook of Surgery: Principles and Practice. Philadelphia, JB Lippincott, 1977.)

Fasting Test As most patients with an insulinoma have intermittent attacks, the physician is unlikely to see patients while they are acutely hypoglycemic. The most reliable method for documenting a hypoglycemic episode is the prolonged fasting test. This is the "gold standard" of testing. After baseline circulating insulin and glucose levels are obtained, the patient fasts for 72 hours or until hypoglycemic symptoms occur. Serum glucose levels are checked at regular intervals, usually every 1 to 2 hours and more frequently when the glucose level falls below 50 mg/dL. Simultaneous insulin levels are obtained with the onset of symptoms or if the glucose level falls below 50 mg/dL. Within 24 hours of fasting, 75% of patients with an insulinoma have glucose levels less than 38 mg/dL, and in 25% the glucose level is less than 30 mg/dL. In normal individuals, the serum glucose and insulin levels both fall; thus, the I/O ratio remains less than 0.4. In patients with an insulinoma, however, the serum insulin level remains elevated because of autonomous secretion of insulin by the tumor (Fig. 79-4) and the I/O ratio rises." The fasting test is diagnostic of insulinoma in 70% to 80% of patients at 24 hours, 90% to 95% of patients at 48 hours, and 98% of patients at 72 hours.

Measurement of Proinsulin and C Peptide Proinsulin is the precursor molecule for insulin and is found in the rough endoplasmic reticulum of the beta cells in the pancreatic islets. As shown in Figure 79-2, the proteolytic conversion of proinsulin results in the formation of equimolar amounts of insulin and its connecting peptide, C peptide. In the presence of an insulinoma, there is an elevation of both proinsulin and C peptide.P'" Furthermore, proinsulin levels, which are usually less than 20% of the total immunoreactive insulin in normal individuals, are elevated in the presence of an insulinoma. Levels higher than 50% are thought by some to be diagnostic of an islet cell carcinoma. Finally, should the diagnosis still be in doubt, measurement of circulating C peptide may be helpful. The normal C peptide level is less than 1.2 ng/dL. There are two specific instances in which measurement of C peptide levels has been particularly helpful. The first is in patients with insulin-dependent diabetes mellitus. Such patients may have circulating antibodies to insulin that interfere with the measurement of insulin in the blood. Elevated levels of C peptide help confirm the diagnosis of insulinoma in such patients. The second situation in which the C peptide level is most useful is in patients who are surreptitiously injecting insulin. Commercial insulin has no C peptide; thus, these patients have low levels of C peptide in the setting of a high insulin level and hypoglycemia.

Interpretation of the Fasting Test Plasma Insulin Concentrations. A plasma insulin concentration of 6 JlU/mL (36 pmol/L) by radioimmunoassay (or 3 JlU/mL by immunometric assay) when the plasma glucose concentration is below 45 mg/dL (2.5 mmol/L) indicates an excess of insulin and is consistent with insulinoma. Unfortunately, plasma glucose concentrations fall below 50 mg/dL (2.8 mmol/L) in some normal subjects and remain above 50 mg/dL in an occasional patient with an insulinorna."

Insulinomas - - 719

Plasma C Peptide Concentrations. It is essential to measure plasma C peptide at the end of the fast; measurement of plasma proinsulin can also be helpful. Measurements of plasma C peptide distinguish endogenous from exogenous hyperinsulinemia. In patients in whom plasma glucose concentrations fall below 45 mg/dL (2.5 mmollL), there is no overlap in the values in insulinoma patients and normal subjects at a plasma C peptide value of 0.2 nmollL. All insulinoma patients have higher values and all normal subjects who are hypoglycemic have lower values. For plasma proinsulin, the diagnostic criterion for insulinoma is 5 pmollL or greater. 16

Provocative Tests For patients in whom the diagnosis of insulinoma is suspected but other tests have been normal or equivocal, provocative tests may be used." A brief description of such tests follows.

Glucagon Test Glucagon stimulates the release of glucose from liver glycogen stores, thereby producing a rise in blood glucose levels. A baseline glucose level is obtained, and then 1 mg of glucagon is injected intramuscularly. Serum glucose levels are then obtained at 15 minutes, 30 minutes, and subsequent 30-minute intervals for 3 hours. Normally, there is a rapid rise in serum glucose levels during the first hour, with a return to fasting glucose levels by 3 hours. Reactive hypoglycemia does not occur. In the presence of an insulinoma, however, there is a greater than normal rise in the glucose levels, followed by severe hypoglycemia in the presence of elevated levels of insulin. This test is positive in 72% of patients with insulinomas.

Glucose Tolerance Test A glucose tolerance test may also indicate the presence of an insulinoma. Fifty grams of glucose in 100 mL of water is given orally and serum glucose levels are measured at 0, 30, 60, 90, 120, and 180 minutes. Normally, the peak glucose level is reached by 1 hour, and does not exceed 160 mg/dL. The normal serum fasting glucose level is regained at 2 hours. Patients harboring an insulinoma have an exaggerated hypoglycemic phase during which glucose levels may fall 20 mg/dL or more below fasting levels and remain depressed for several hours. Symptoms of hypoglycemia may be present. This test is noted to be positive in 60% of insulinoma patients.

Calcium Infusion Test Kaplan and colleagues demonstrated that infusion of calcium results in a rise of serum insulin, C peptide, and proinsulin levels in patients with an insulinoma'? (Fig. 79-5). In this study, calcium was infused at a concentration of 5 mglkg per hour, and hypoglycemia was noted to occur within 2 hours. In normal individuals, glucose and insulin levels remain normal in response to calcium infusion. More recently, this

FIGURE 79-5. Calcium infusion test. A patient with a welldifferentiated malignant insulinoma experienced hypoglycemic symptoms nearly 1112 hours after the start of the calcium infusion (*). Insulin levels increased maximally at 30 minutes, which was accompanied by a threefold increase in proinsulin (shaded bar). (From Kaplan EL, Rubenstein AH, Evans R, et a1. Calcium infusion: A new provocative test for insulinomas. Ann Surg 1979;190:501.)

test has been modified. A rapid intravenous calcium injection may be used preoperatively to confirm the diagnosis of insulinoma," or calcium may be infused intra-arterially as part of a localization study. This approach is described in greater detail subsequently.'? Calcium stimulation tests are used in infants with nesidioblastosis as well.

Pathology Insulinomas tend to be small lesions. A full 40% are 1 em or less in diameter at the time of operation, with 66% smaller than 1.5 em and 90% less than 2 em in maximal diameter." These lesions are distributed equally in the head, body, and tail of the pancreas. Ectopic tumors are rare (less than 1%), and when present they are found in close proximity to the pancreas. Malignant insulinomas are rare, accounting for 5% to 10% of cases. Malignancy is defined by evidence of local invasion into surrounding soft tissue or by the presence of distant (lymph node or liver) metastases. Multiple tumors are present in 8% to 17% of cases. When insulinomas are multiple, MEN 1 should be suspected (Fig. 79-6A). Approximately 10% of patients with hyperinsulinism have MEN 1.21 Hyperparathyroidism resulting from chief cell hyperplasia (Fig. 79-6B) and pituitary microadenomas resulting in hyperprolactinemia are the most common associated findings in this group of patients.

Preoperative Localization Studies Because of the small size, possible occurrence throughout the pancreas, and potential multiplicity of insulinomas, most

720 - - Endocrine Pancreas localize as few as 35% of insulinomas (range, 11% to 50%).23 The sensitivity can be increased by the use of bolus injections of intravenous contrast material coupled with 3- to 5-mm cuts through the pancreas. When such dynamic, triphasic CT scans are obtained, localization rates of 63% or higher have been reported.P CT scans also readily identify liver metastases should they be present.

Magnetic Resonance Imaging Magnetic resonance imaging (MRI) has localization rates comparable to those reported for triphasic CT scanning. Local expertise and availability thus often dictate which imaging modality is used. As an example, two small studies with 10 and 11 patients each revealed localization rates of 100% when gadolinium-enhanced and fat-suppressed MRI images were obtained.s'r"

Angiography

FIGURE 79-6. Pathologic specimen from a patient with multiple endocrine neoplasia I syndrome. This patient presented with hypoglycemia. Exploration of the pancreas revealed multiple benign insulinomas (as seen on cross sections, arrows) within the tail of the pancreas (A), necessitating a distal pancreatectomy. B, The patient later experienced hyperparathyroidism and was found to have parathyroid hyperplasia. A subtotal parathyroidectomy was performed.

experienced endocrine surgeons obtain one or more localization tests before embarking upon operative exploration.

Ultrasonography Transcutaneous ultrasonography has proved to be of limited efficacy in the evaluation of pancreatic insulinomas in many institutions"; however, some investigators remain enthusiastic about its efficacy as a first-line modality.F The reported sensitivity of preoperative ultrasonography is about 50% (range, 20% to 70%) and is dependent on the experience of the examiner. For tumors smaller than 1 em in diameter, the sensitivity is less than 40%. Furthermore, false-positive results may occur in up to 25% of cases." Advantages include the noninvasive nature of this examination and its relatively low cost.

Computed Tomography As with ultrasonography, the role of computed tomography (CT) scanning is limited in the localization of insulinomas as a result of the small size of the majority of the tumors (Fig. 79-7B). Routine preoperative CT scanning may

Most insulinomas are highly vascular tumors and produce a distinctive blush on angiography'? (see Fig. 79-7C). With the use of selective arterial injections, magnification views, and digital subtraction techniques, preoperative localization of these tumors can be obtained in 75% to 80% of cases, with a false-positive rate reported to be as low as 5%.23 As with other modalities, results are dependent on the size of the lesion, its location in the pancreas, and the experience of the radiologist.

Percutaneous Transhepatic Portal Venous Sampling Percutaneous transhepatic portal venous sampling (PTPVS) is one of the most sensitive methods for regionalizing an insulinoma to the head, body, or tail of the pancreas. In an interventional radiology suite, the portal venous system is reached through the liver parenchyma, and a catheter is passed through the portal vein into the splenic and superior mesenteric veins. Blood samples are then taken along these veins and at the entrances of the major pancreatic draining veins. Insulin, proinsulin, and C peptide levels can then be measured (see Fig. 79-7D). An insulin concentration that is 2 standard deviations higher than baseline in the portal vein indicates that the insulinoma lies in the area drained by that particular vein.23 This test can regionalize the tumor to an area of the pancreas (head and neck, body, or tail) but it does not identify a specific site. Usually, more than 15 samples must be taken at 2-cm intervals for the test to be considered valid. The average sensitivity of PTPVS is 82% (range, 70% to 95%) in the hands of experienced practitioners. Disadvantages of this technique include the occurrence of false-positive results and the morbidity associated with percutaneously cannulating the portal vein through the liver.

Arterial Stimulation and Venous Sampling Selective arterial injection of calcium as a means of regionalization of an insulinoma has also been reported and is one

Insulinomas - -

721

FIGURE 79-7. Preoperative localization studies for insulinomas. A, Percutaneous ultrasonography. Arrows delineate two hypoechoic regions within the pancreatic head. B, Computed tomography scan. Arrows depict insulinoma in the dorsum of the pancreas. C. Subtraction during the arterial phase of this celiac artery angiography clearly demonstrates the tumor (arrows) in the head of the pancreas. D, Percutaneous transhepatic portal venous sampling. Insulin radioimmunoassay demonstrates peak levels (227 and 329 flUlmL) in the area of the tail of the pancreas. (A, B. and D. From Bottger TC, Junginger T. Is preoperative radiographic localization of islet cell tumors in patients with insulinoma necessary? World J Surg 1993;17:427. C, From Kaplan EL, Lee C-H. Recent advances in the diagnosis and treatment of insulinomas. Surg Clin North Am 1979;59:119.)

of the best tests available.19 The test is a modification of the selective arterial secretin injection as developed by Imamura and Takahashi" for regionalization of gastrinomas and takes advantage of the fact that calcium is a potent stimulant of insulin release from insulinomas.F:" This technique requires the placement of arterial and venous catheters by femoral puncture. The venous catheters are maneuvered into the hepatic veins (Fig. 79-8A). Selective arteriography of the gastroduodenal, splenic, common hepatic, and superior mesenteric arteries is then performed. After this, calcium

gluconate is injected into each artery, and blood samples are taken from the hepatic veins at 0, 30, 60, and 120 seconds for measurement of insulin levels. A twofold elevation of insulin in the 30- or 60-second sample indicates a positive test result. A positive test after injection of the gastroduodenal or superior mesenteric artery, for example, indicates that the tumor lies in the head and neck region of the pancreas (Fig. 79-8B). Conversely, a positive insulin response to injection of the splenic artery with calcium indicates the presence of a tumor in the body and tail region. A positive

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FIGURE 79-8. A, Schema for selective arterial stimulation and venous sampling(ASVS). Standard pancreaticarteriography includes selective injections of contrast material into the gastroduodenal artery (Gastr.duod.a.), proximal splenic artery (Spl.a.), superior mesenteric artery (a.), and commonhepatic artery (Comm.hep.a.). After each selectivearteriogram, calcium gluconate (0.025 mEq Ca2+/kg) dilutedin saline to a 5-mL bolus is injected rapidly throughthe proximallypositioned catheter in each selectively catheterized artery. Five-milliliter samples of blood are obtainedfrom the right hepatic vein before calcium injection and at 30, 60 and 120 seconds after calcium injection. Each plasma sampleis frozenuntil assayed for insulin.A twofold rise in insulin levels after injectionof the gastroduodenal or superiormesenteric arteries localizes the tumor to the pancreatichead and uncinate process; a twofold rise after injection into the splenic artery localizesthe insulinoma to the body and tail. E, Results of selective intra-arterial calcium stimulationtest (ASVS) in a patient with an insulinoma of the pancreatic head. Note that when calcium was injected into the gastroduodenal artery (GDA), a rapid rise of circulating insulin occurred (within 30 seconds). No elevation in insulinvaluesfollowedinjectionsof calciuminto the superiormesentericartery (SMA), splenic artery, or hepatic artery. (A, Modified from Imamura M, Takahashi K, Adachi H, et al. Usefulness of selective arterial secretin injection test for localization of gastrinoma in the Zollinger-Ellison syndrome. Ann Surg 1987;205:230; technique modifiedfrom DoppmanJL et al.27 E, From DoppmanJL, MillerDL, Chang R, et al. Intraarterial calcium stimulation test for detectionof insulinomas. World J Surg 1993; 17:439.)

response to calcium infusion of the hepatic artery indicates radiographically occult hepatic metastases. Doppman and colleagues first described the technique of arterial stimulation and venous sampling (ASVS) in nine patients and reported a sensitivity of 66%.27 A subsequent report by Defreyne and associates also documented two patients in whom occult insulinomas were accurately localized by ASVS and confirmed by surgery." The advantages of ASVS over PTPVS are twofold: (1) there is decreased morbidity, because there is no need for hepatic puncture, and (2) the technique is far less time consuming, adding only a few minutes to standard selective arteriography. When invasive testing is required, ASVS has supplanted PTPVS for regionalization of insulinomas in most referral centers.P To illustrate the utility of ASVS, researchers at the National Institutes of Health analyzed 25 patients who were studied with multiple imaging modalities, including ASVS.30 They found correct localization in the pancreas in 94% of patients so studied. The sensitivity of other forms of imaging in the same patients was 13% for transabdominal ultrasonography, 24% for CT, 45% for MRI, and 43% for arteriography. This test and transgastric ultrasonography (discussed later) are the two most effective localization tests available.

Isotope-Labeled Somatostatin Analysis A great deal of interest has been generated by octreotide scintigraphy of endocrine tumors. Tumors that contain somatostatin receptors have been shown to bind isotopelabeled octreotide both in vivo and in vitro (Table 79-3). Effective scanning that enables localization of both primary and metastatic insulinomas has been achieved (Fig. 79-9). Krenning and coauthors summarized their work using indium-labeled octreotide on a variety of endocrine tumors (see Table 79-3). Most endocrine tumors of the pancreas demonstrate somatostatin receptors in vitro. They were able to visualize 14 of 23 insulinomas (61%) by octreoscan.v-P Other modifications of this technique that have been tried include use of a hand-held Geiger counter for intraoperative localization of small primary and occult metastatic foci'" and use of radiolabeled vasoactive intestinal peptide as the localizing agent. Using this method, Virgolini and coworkers were able to visualize the primary tumor correctly in four of four patients with insulinomas.l"

Endoscopic Ultrasonography Endoscopic transgastric ultrasonography (with radial scanning of 360 degrees and an ultrasonographic frequency of

InsuIinomas - - 723

the pancreatic duct can also be seen in most cases. Fineneedle aspiration may be added to the procedure when diagnosis is required (see "Laparoscopic Resection'Y" Finally, this method of localization was shown to be cost-effective in a case-control study of 36 patients who underwent EUS versus 36 retrospective control patients who underwent localization in the pre-EUS era." EUS was able to reduce localization charges significantly, largely through a reduction in diagnostic angiography and venous sampling procedures. As with any ultrasonographic test, however, results are operator dependent.

Intraoperative Ultrasonography The first report of intraoperative imaging of an insulinoma by ultrasonography was by Lane and Coupland in 1982.38 In 1985, Norton and colleagues reported the first intraoperative localization by ultrasonography of an insulinoma that had eluded preoperative identification." In the last 20 years, numerous studies have documented that intraoperative ultrasonography (IOUS) is a very sensitive method for the localization of pancreatic insulinomas (Fig. 79-llA). The reported sensitivity of IOUS is 75% to 91%, and it improves with experience.f-" In addition, IOUS can provide valuable information about the relationship of the tumor to critical structures such as the pancreatic duct, portal vein, common bile duct, and superior mesenteric vessels. This technique is shown in Figure 79-l2A. Note that full mobilization of the pancreas is required to perform the procedure properly.

Intraoperative Palpation

7.5 MHz) has shown widespread efficacy in the diagnosis of benign and malignant pancreatic disease (Fig. 79-10). In expert hands, endoscopic ultrasonography (EUS) has been shown to have a sensitivity of greater than 80% for the diagnosis of insulinomas, especially when located in the pancreatic body and head." The relationship of the tumor to

FIGURE 79-9. Isotope-labeled somatostatin scanning. Indium l l I-diethylenetriamine pentaacetic acid (DTPA)-octreotide scan of a patient with an insulinoma within the head of the pancreas at 24 hours (A) and 48 hours (B). The tumor is represented by a hot spot just medial to the right kidney (arrow). (From van Eyck CHJ, Bruining HA, Reubi J-C, et al. Use of isotope-labeled somatostatin analogs for visualization of islet cell tumors. World J Surg 1993; 17:444.)

Most insulinomas of the pancreas can be palpated by carefully exploring the pancreas at the time of surgery. The sensitivity of palpation is 75% to 95% in different studies and depends on the experience of the surgeon." Small tumors and those located in the pancreatic head and uncinate process are generally more difficult to palpate. The combination of IOUS and palpation has been reported to increase the sensitivity to 100%.42 Like mus, proper intraoperative palpation requires full mobilization of the pancreas.

724 - - Endocrine Pancreas

FIGURE 79-10. Endoscopic ultrasonography of the pancreas.

A, Preoperative localization of a suspected insulinoma of the pancreatic neck. B, Transgastric fine-needle aspiration confirmed

the presence of an insulinoma, which was later resected by enucleation. (Courtesy of RameezAlasadi, MD.)

Are Preoperative Localization Tests Beneficial? There is no question that preoperative localization tests are essential for all reoperative cases of insulinoma. However, for the initial operation of an insulinoma, some differences of opinion exist. Some investigators shun most preoperative testing and rely almost exclusively on IOUS with careful palpation. 40 ,43 Others, however, favor administering a battery of preoperative localization tests before the initial operation. In a national study of German institutions, it was shown that when no invasive preoperative localization studies were used, 7.4% of all insulinomas were undetected at operation. However, when invasive testing was employed, the negative laparotomy rate dropped to 3.7%.23 It should be remembered that there is a learning curve associated with the use of IOUS, and thus in many centers the use of currently available localization studies does aid in curative surgery for small, occult insulinomas. In general, we start with transgastric ultrasonography and proceed to calcium-stimulated arteriography if the former study is negative.

FIGURE 79-11. Intraoperative sonogram. A, Insulinoma of the

tail of the pancreas.The arrowsdesignate the insulinoma, which is hypoechogenic compared with the surrounding pancreas. B, A hypoechoic tumor (T) of the pancreas is visualized by intraoperative ultrasonography. Note that the pancreatic duct (arrow) and its proximity to the tumor are clearly shown. (A, From Kaplan EL, Arganini M, Kang S-l. Diagnosis and treatment of hypoglycemic disorders. Surg Clin North Am 1987;67:395-410. B, From Zeiger MA, ShawkerTH, Norton lA. Use of intraoperative ultrasonography to localize islet tumors. World J Surg 1993;17:448.)

Perioperative Management of Serum Glucose Preoperative Management Until the tumor is removed, the mainstay of therapy is the prevention of hypoglycemia. This may entail frequent meals and minimizing prolonged exercise. Intravenous glucose

Insulinomas - - 725

79-12. Intraoperative ultrasonography (lDUS). A. IOUS of the head of the pancreas using a lO-MHz probe after extensive kocherization of the duodenum. B. IOUSof the bodyand tail of the pancreas after extensive mobilization along its inferiorand superior borders. C. IOUS of the body and tail of the pancreas posteriorly after medial reflection of the spleen and tail of the pancreas. D. IOUS of the liver depicting a right hepatic lobe tumor surrounded by major hepatic vessels. (From Zeiger MA, Shawker TH, Norton JA. Use of intraoperative ultrasonography to localize islet cell tumors. World J Surg 1993; FIGURE

17:448.)

should be given the night before surgery, especially after the patient ceases oral intake. Administration of diazoxide or the somatostatin analog octreotide is employed preoperatively in some centers, not only to control hypoglycemic attacks but also to determine the patient's response and tolerance to such therapy should surgical exploration be unsuccessful. We rarely use diazoxide preoperatively because it interferes with the intraoperative glucose monitoring.

requires insulin therapy unless the patient was diabetic preoperatively. This rebound hyperglycemia usually resolves spontaneously within 1 week, although it may last longer. Diabetes mellitus may occur in the minority of patients who require a significant pancreatic resection.

Intraoperative Management

Operative exposure may be achieved through a bilateral subcostal or long midline incision. Upon entering the peritoneal cavity, a thorough exploration is performed to exclude metastatic disease. Tru-Cut needle or wedge biopsy of any suspicious liver lesions is performed and suspicious lymph nodes are sent to the pathologist for frozen section analysis. A generous Kocher maneuver is then performed from the level of the right gonadal vein to the aorta medially. At this time, the head and neck of the pancreas may be carefully palpated (Fig. 79-13A). The omental bursa is then divided to the left of the midline, allowing access to the lesser sac. Mobilization of the body and tail of the pancreas is then begun in the usual fashion, by dividing the peritoneum along the inferior aspect of the gland. The inferior mesenteric vein may be divided at this point if necessary. Careful visual inspection and manual palpation of the body and tail of the pancreas are then undertaken (Fig. 79-13B). To examine the posterior aspect of the gland, the spleen must be mobilized by incising its attachments to the diaphragm, kidney, and colon. IOUS may now be performed.

Frequent blood sugar determinations are necessary to prevent hypoglycemia during the operation. Our current protocol is to monitor blood sugar levels at 15- to 3D-minute intervals both during the procedure and for several hours thereafter. A rise in serum glucose suggests that a curative operation has been performed. However, this is not always the case, especially when multiple tumors are present, such as in MEN 1. Thus, several groups have investigated the technique of intraoperative insulin measurement." Using a rapid radioimmunologic assay, Proye and colleagues described a sensitivity of 84% with specificity and positive predictive values of 100% for this new technique. Clearly, this technique warrants further study.

Postoperative Management After the successful removal of an insulinoma, a short period of hyperglycemia usually occurs. Hyperglycemia rarely

Operative Approach

726 - - Endocrine Pancreas

A

FIGURE 79-14. An insulinoma of the inferior surface of the body of the pancreas is demonstrated. This was easily enucleated.

IODS is invaluable when performing enucleation of lesions in the head of the pancreas. Care must be taken to avoid injury to the main pancreatic and common bile ducts. Cannulating the common bile duct through the cystic duct and inflating the balloon at the ampulla of Vater may also be employed. However, the main factor in preventing a fistula is to stay immediately on the capsule of the tumor and to use gentle, blunt dissection. FIGURE 79-13. A, After a generous Kocher maneuver of the duodenum, the pancreatic head should be palpated between the thumb and fingers. B, The gastrocolic omentum is divided and the stomach is elevated. The body and tail of the pancreas are gently mobilized. The areas can now be visualized and palpated carefully. (From Findley A, Arenas RB, Kaplan EL. Insulinoma. In: Percopo V, Kaplan EL [eds], GEP and Multiple Endocrine Tumors. Padova, Italy, Piccin Nuova Libreria SpA, 1996, P 314.)

When an insulinoma has been located, an attempt to enucleate it should be made, regardless of its location within the gland (Fig. 79-14). Distal pancreatectomy is performed in the setting of multiple lesions within the body and tail (see Fig. 79-6) if the lesion is large and malignancy cannot be excluded (Fig. 79-15) or if the lesion abuts the pancreatic duct. Enucleation of lesions intimately associated with the pancreatic duct predictably leads to fistula formation. Most lesions of the head of the pancreas are enucleated (Fig. 79-16). Only rarely should a pancreaticoduodenectomy be performed for a benign lesion. Occasionally, the Whipple procedure may be indicated for a malignant lesion of the head or uncinate process with regional nodal involvement.

FIGURE 79-15. A distal resection was performed for this large lesion of the tail of the pancreas. A lymph node metastasis was present; thus, this was a malignant insulinoma.

Insulinomas - - 727 benign tumot/" Preoperative testing, usually by EUS with fine-needle aspiration, is required to ensure correct localization and to exclude malignancy. IOUS is frequently employed. One of the largest series to date reported an average hospital stay of only 5 days after such an approach was used for 10 endocrine tumors of the pancreas, 7 of which were insulinomas, either sporadic or multiple." Both enucleation and distal resections of the pancreas can be performed by this technique. Although these initial results are encouraging in this highly selected group of patients, conversion to an open procedure was required in 2 patients and postoperative fistulas were noted in 5 of 18 (28%) total patients in the series.

Complications As discussed earlier, transient elevations in serum glucose may be observed postoperatively but are rare beyond several weeks when tumors are enucleated. Diabetes increases with the extent of the pancreatic resection. Persistent hypoglycemia is currently less than 5% in cases of benign insulinoma." Hypoglycemia is common, however, in cases of malignant insulinoma when not all tumor can be resected. Other postoperative complications include hemorrhage, abscess, pancreatitis, and pancreatic duct or biliary fistulas."

Long- Term Therapy for Hypoglycemia

FIGURE 79-16. A, Insulinoma of the head of the pancreas (arrow). These lesions can almost always be enucleated. During enucleation, careful blunt dissection should be used immediately on the capsule of the insulinoma to prevent damage to the common bile or pancreatic duct, which could result in a fistula. B, This lesion was carefully enucleated and proved to be benign.

If MEN 1 is suspected, a thorough exploration of the pancreas is mandatory to exclude multiple lesions. Additional lesions may then be enucleated. However, in most instances of MEN 1, a distal pancreatectomy with enucleation of any remaining lesions of the head of the pancreas is preferable. Finally, if all efforts at exploration fail to identify the primary lesion, the operation should be terminated and the patient referred to a center of excellence. Although blind distal resection of the pancreas was advocated in the past, the development of modem localization studies such as EUS and ASVS allows the eventual detection of almost all insulinomas."

Laparoscopic Resection Originally described in 1996, laparoscopic distal pancreatectomy for the removal of an insulinoma is an approach that appeals to many who view a laparotomy with extensive retroperitoneal dissection as excessive to treat what is a usually

As noted previously, the first appropriate therapy for a failed operation is a referral to a high-volume center where localization studies will be performed and a surgical cure should be obtained in the majority of patients at reoperation. Several drug regimens have been employed in patients with unresectable disease.

Diazoxide Diazoxide is a nondiuretic benzothiadiazine. Both in vitro and in vivo studies have shown that diazoxide reduces insulin secretion and raises circulating glucose levels by acting directly on the beta cells as well as by other extrapancreatic mechanisms.t" Side effects include hypotension, peripheral edema, hirsutism, nausea, and vomiting. Studies have shown that its efficacy in controlling hypoglycemia is approximately 60% in patients with insulinomas."

Somatostatin Analogs Somatostatin analogs have been used for treatment of different types of endocrine tumors with considerable success.P Octreotide acetate is an analog that has retained the active region of somatostatin but with certain modifications that make the derivative more resistant to peptidase degradation while increasing its biologic availability. Octreotide has been used to reduce hypoglycemic attacks in patients with unresectable insulinomas. A typical starting dose is 100 ug, given intravenously or subcutaneously every 8 hours. Doses may be increased to as high as 600 to 1500 ug per day.52 Long-acting somatostatin preparations, which may be administered on a monthly basis, are now also available.

728 - - Endocrine Pancreas

Other Therapeutic Approaches The effectiveness of chemotherapy against malignant insulinomas is limited at best. Regimens including streptozocin in combination with 5-fluorouracil and doxorubicin are usually employed." Hepatic artery chemoembolization has been tried with some success, as has operative debulking. Given the considerable morbidity of a hepatic resection in the setting of unresectable disease, radiofrequency ablation of hepatic metastases from a pancreatic insulinoma has been reported. 54 This is a procedure that may be performed percutaneously in the outpatient setting in highly selected patients with limited hepatic metastases.

Summary Insulinomas are usually small, solitary tumors except in patients with MEN I, in whom multiple tumors are the rule. Ninety percent of insulinomas are benign. Patients with insulinomas may experience neurologic, cardiovascular, and gastrointestinal symptoms. In most patients, the diagnosis can be made by documenting inappropriately high circulating insulin and C peptide levels at the time of profound hypoglycemia, along with the absence of sulfonylureas in the urine. Provocative tests are sometimes necessary to confirm the diagnosis. Preoperative localization studies, especially transgastric ultrasonography and highly selective, calcium-stimulated arteriography with insulin measurement (ASVS), appear to decrease failure rate and are used frequently by many surgeons, although they are essential only in the reoperative setting. In experienced hands, surgical cure may be obtained in more than 95% of cases.

REFERENCES 1. Nichols AG. Simple adenoma of the pancreas arising from an island of Langerhans. J Med Res 1902;8:385. 2. Banting FG, Best CH. Internal secretion of the pancreas. J Lab Med 1922;7:251. 3. Harris S. Hyperinsulinism and dysinsulinism. JAMA 1924;83:729. 4. Wilder RM, Allan FN, Power MH, et al. Carcinoma of the islets of the pancreas: Hyperinsulinism and hypoglycemia. JAMA 1927;89:348. 5. Howland G, Campbell WR, Maltby EJ, et al. Dysinsulinism: Convulsions and coma due to islet cell tumor of the pancreas with operation and cure. JAMA 1929;93:674. 6. Whipple AO, Frantz VK. Adenomas of the islet cells with hyperinsulinism: A review. Ann Surg 1935;101:1299. 7. Pearse AGE. Common cytochemical and ultrastructural characteristics of cells producing polypeptide hormones (the APUD series) and their relevance to ultimobranchial C cells and calcitonin. Proc R Soc Lond B Bioi Sci 1968;170:71. 8. Marx S, Spiegel AM, Skarulis MC, et al. Multiple endocrine neoplasia type 1: Clinical and genetic topics. Ann Intern Med 1998;129:484. 9. Zeiger MA, Norton JA. Gs alpha-Identification of a gene highly expressed in insulinoma and other endocrine tumors. Surgery 1993;114:458. 10. Rubenstein AH, Kuzuya H, Horowitz DL. Clinical significance of circulating C-peptide in diabetes mellitus and hypoglycemia disorders. Arch Intern Med 1977;137(5):625. 11. Stefanini P, Carboni M, Petrassi N. Surgical treatment of and prognosis of insulinoma. Clin GastroenteroI1974;3:697. 12. Boden G. Insulinoma and glucagonoma. Semin Oncol 1987;14:253. 13. Jaspan JB, Polonsky KS, Foster DW, et al. Clinical features and diagnosis of islet-cell tumors. In: Moosa AR (ed), Tumors of the Pancreas. Baltimore, Williams & Wilkins, 1980, p 469.

14. Merimee TJ, Tyson, JE. Hypoglycemia in man: Pathological and physiologic variants. Diabetes 1977;26:161. 15. Gutman RA, Lazarus NR, Penhos JC, et al. Circulating proinsulin-like material in patients with functioning insulinomas. N Engl J Med 1971;284:1003. 16. Service, FJ, Natt N. The prolonged fast. J Clin Endocrinol Metab 2000;85:3973. 17. Kaplan EL, Rubenstein AH, Evans R, et al. Calcium infusion: A new provocative test for insulinomas. Ann Surg 1979;190:501. 18. Brunt LM, Veldhius JD, Dilley WG, et al. Stimulation of insulin secretion by a rapid intravenous calcium infusion in patients with B-cell neoplasms of the pancreas. J Clin Endocrinol Metab 1986;62:210. 19. Doppman JL, Chang R, Fraker DL, et al. Localization of insulinomas to regions of the pancreas by intra-arterial stimulation with calcium. Ann Intern Med 1995;123:269. 20. Kaplan EL. Insulinoma-Surgical and diagnostic approach. In: van Heerden JA (ed), Common Problems in Endocrine Surgery. Chicago, Year Book Medical, 1988, p 272. 21. Sheppard BC, Norton JA, Doppman JL, et al. Management of islet cell tumors in patients with multiple endocrine neoplasia: A prospective study. Surgery 1989;106:1108. 22. Doherty GM, Doppman JL, Shawker TH, et al. Results of a prospective strategy to diagnose, localize and resect insulinoma, Surgery 1991;110:989. 23. Bottger TC, Junginger T. Is preoperative radiographic localization of islet cell tumors in patients with insulinoma necessary? World J Surg 1993;17:427. 24. Semelka RC, Cumming MJ, Shoenut JP, et al. Islet cell tumors: Comparison of dynamic contrast-enhanced CT and MR imaging with dynamic gadolinium enhancement and fat suppression. Radiology 1993;186:799. 25. Pavone P, Mitchell DG, Leonetti F, et al. Pancreatic beta cell tumors: MRI. J Comput Assist Tomogr 1993;17:403. 26. Imamura M, Takahashi K. Use of selective arterial secretin injection test to guide surgery in patients with Zollinger-Ellison syndrome. World J Surg 1993;17:433. 27. Doppman JL, Miller DL, Chang R, et al. Intraarterial calcium stimulation test for detection of insulinomas. World J Surg 1993;17:439. 28. Defreyne L, Moser C, Scheidt T, et al. Intraarterial calcium provocation for the preoperative diagnosis of the location of an occult insulinoma. Dtsch Med Wochenschr 1992; 117: 1829. 29. Lo CY, Chan FL, Tam SC, et al. Value of intraarterial calcium stimulated venous sampling for regionalization of pancreatic insulinomas. Surgery 2000;128:903. 30. Brown CK, Bartlett DL, Doppman JL, et al. Intraarterial calcium stimulation and intraoperative ultrasonography in the localization and resection of insulinomas. Surgery 1997;122:1193. 31. Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with [lllIn-DPTA-D-Phel]- and [l 23I-Tyr3]-octreotide: The Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993;20:716. 32. Van Eyck CHJ, Bruining HA, Reubi J-C, et al. Use of isotope-labeled somatostatin analogs for visualization of islet cell tumors. World J Surg 1993;17:444. 33. Rosiere A, Ernst YJ, Roelants V, et al. Intraoperative gamma probe detection of insulinoma in an elderly patient with pancreatic cystic lesions. Clin Endocrinol (Oxf) 2002;57:547. 34. Virgolini I, Raderer M, Kurtaran A, et al. Vasoactive intestinal peptidereceptor imaging for the localization and detection of intestinal adenocarcinomas and endocrine tumors. N Engl J Med 1994; 331:1116. 35. Ardengh JC, Rosenbaum P, Ganc AJ, et al. Role of EUS in the preoperative localization of insulinomas compared with spiral CT. Gastrointest Endosc 2000;51 :552. 36. Kirkeby H, Vilmann P, Burcharth F. Insulinoma diagnosed by endoscopic ultrasonography-guided biopsy. J Laparoendosc Adv Surg Tech 1999;9:295. 37. Bansal R, Tierney W, Carpenter S. Cost effectiveness of EUS for preoperative localization of pancreatic tumors. Gastrointest Endosc 1999;49:19. 38. Lane RJ, Coupland GAE. Operative ultrasonic features of insulinomas. AmJ Surg 1982;144:585. 39. Norton JA, Sigel B, Baker AR, et al. Localization of an occult insulinoma by intraoperative ultrasonography. Surgery 1985;97:381.

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40. Boukhman MP, Karam JM, Shaver J, et al. Localization of insulinomas. Arch Surg 1999;134:818. 41. Zeiger MA, Shawker TH, Norton JA. Use of intraoperative ultrasonography to localize islet cell tumors. World J Surg 1993;17:448. 42. Norton JA. Intraoperative methods to stage and localize pancreatic and duodenal tumors. Ann OncoI1999;IO(SuppI4):182. 43. Grant CS, van Heerden J, Charboneau JW, et al. Insulinoma-The value of intraoperative ultrasonography. Arch Surg 1988;123:843. 44. Proye C, Pattou F, Camaille B, et al. Intraoperative insulin management during surgical management of insulinomas. World J Surg 1998;22:1218. 45. Hirshberg B, Libutti SK, Alexander HR, et al. Blind distal pancreatectomy for occult insulinoma, an inadvisable procedure. J Am Coli Surg 2002;194:761. 46. Sussman LA, Christie R, Whittle DE. Laparoscopic excision of distal pancreas including insulinoma. Aust NZ J Surg 1996;66:414. 47. Fernandez-Cruz L, Saenz A, Astudillo E, et al. Outcome of laparoscopic pancreatic surgery: Endocrine and nonendocrine tumors. World J Surg 2002;26:1057.

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48. Edis AJ, McIllrath DC, van Heerdan JA, et al. Insulinoma: Current diagnosis and surgical management. Curr Probl Surg 1976;13:1. 49. Rothmund M, Angelini L, Brunt LM, et al. Surgery of benign insulinoma: An international review. World J Surg 1990;14:393. 50. Goode PN, Famdon JR, Anderson J. Diazoxide in the management of patients with insulinoma. World J Surg 1986;10:586. 51. Gill GV, Rauf 0, MacFarlane IA. Diaxoxide treatment for insulinoma: A national UK survey. Postgrad Med J 1997;73:640. 52. Maton PN. Use of octreotide acetate for the control of symptoms in patients with islet cell tumors. World J Surg 1993;17:504. 53. Modlin 1M, Lewis JJ, Ahlman H, et al. Management of unresectable malignant endocrine tumors of the pancreas. Surg Gynecol Obstet 1993;176:507. 54. Scott A, Hinwood D, Donnelly R. Radio-frequency ablation for symptom control in a patient with metastatic pancreatic insulinoma. Clin Endocrinol (Oxf) 2002;56:557.

Localization of Endocrine Pancreatic Tumors Volker Fendrich, MD • Matthias Rothmund, MD

The functioning endocrine tumors of the pancreas most often encountered are insulinomas and gastrinomas. Both tumors cause spectacular clinical syndromes, hyperinsulinism and the Zollinger-Ellison syndrome (ZES), respectively. The tumors are often difficult to localize because they are almost always smaller than 2 em in diameter. Duodenal gastrinomas are usually even smaller than 1 ern. This is not the case for the rarer functioning endocrine pancreatic tumors such as glucagonomas, vasoactive intestinal polypeptide tumors, somatostatinomas, and the nonfunctioning tumors, which are usually large and easy to localize by standard localization techniques such as abdominal ultrasonography (US), computed tomography (CT), or magnetic resonance imaging (MRI). Therefore, this chapter focuses mainly on the localization of insulinomas and gastrinomas and includes only briefly the nonfunctioning tumors; the rarer tumors mentioned previously were excluded. Because the approach to localize insulinomas and gastrinomas differs in patients with the multiple endocrine neoplasia type 1 (MEN 1) syndrome compared with sporadic tumors, localization in MEN 1 is discussed separately. However, localization techniques should not be used to make the diagnosis of hyperinsulinism or ZES. They should be used only after the diagnosis is made on the basis of the patient's history as well as clinical and laboratory data.

Insulinomas Ninety percent of insulinomas are benign and are smaller than 2 em in diameter. Ninety-nine percent are located in the pancreas. A variety of preoperative imaging modalities for the detection of insulinomas are currently available, such as US, CT, MRI, somatostatin receptor scintigraphy (SRS), and various invasive methods, including endosonography (ES), selective angiography (SA), selective portal venous

730

sampling (PVS), and selective hepatic venous sampling after arterial stimulation (modified Imamura procedure). But those procedures often fail to detect the tumor. On the other hand, there is agreement that skilled surgeons who are experienced in careful and meticulous exploration of the pancreas as well as in the use of intraoperative US (IOUS) can achieve much better results than any of the preoperative methods mentioned, including a combination of most. 1,2 Endosonography (ES) is the most sensitive preoperative procedure. It was introduced in the 1980s and provides direct visualization of the pancreas and is able to detect tumors down to 0.3 to 0.5 em in diameter (Fig. 80-1). An early study by Rosch and colleagues in 19923 identified endocrine tumors by ES in the head of the pancreas in 95% of their patients and in the body and tail in 78% and 60%, respectively (Table 80-1). One year later, Palazzo and coworkers" underlined its accuracy for localizing small endocrine pancreatic tumors. Thirteen insulinomas less than 15 mm in diameter were imaged by ES, US, and CT. Accuracy for these procedures was 79%, 7%, and 14%, respectively. Since then, we and other have confirmed the results of this method, which is superior to CT, US, MR!, SA, and SRS,5-6 despite the fact that the sensitivity decreases the more left sided the insulinomas are situated. Richards and associates found 83% sensitivity ofES for pancreatic head insulinomas versus 37% for distal pancreatic insulinomas." On the basis of these results, ES is the method of choice if one wants to use preoperative imaging. It is mandatory before reoperation or if laparoscopic resection is planned. CT scanning is probably still the most widely used noninvasive technique for initial localization of insulinomas. It has shown varying results in several extensive studies, with a sensitivity of only 25% to 70%. The most important reason for this is that the sensitivity of CT to localize tumors accurately is dependent on the size and location of the neoplasm. 1,6,9-18 Perhaps new techniques such as multislice

Localization of Endocrine Pancreatic Tumors - -

731

FIGURE 80-1. Preoperative endosonography shows a typical 22-mm hypoechoic insulinoma (arrows) in the head of the pancreas. D I and D2 = tumor margins.

FIGURE 80-2. Transverse preoperative ultrasonography (5-MHz linear-array transducer) shows typical hypoechoic insulinoma (15 mm) (TV) within the echogenic parenchyma of the pancreatic head (P), AO = aorta; VC = vena cava; WS = spine.

spiral CT, which is capable of investigating the whole gland in thin sections in 10 to 15 seconds, could improve these numbers (see Table 80-1). Preoperative US offers a less expensive alternative but is extremely operator dependent. In addition, the sensitivity of US ranges from 0% to 62% and does not exceed that of CT (Fig. 80-2; see Table 80-1).1,6,9-14,16-18 In MRI technique, the improved technology in software, gadolinium-gated studies, magnetic echo delays, and the introduction of oral contrast agents have led to better results in detecting insulinomas. 17,19,20 Today, Tl-weighted fatsuppressed images are acquired in arterial phase, portal phase, and equilibrium phase following the administration of intravenous gadolinium.'? However, on the basis of published studies, the sensitivity of MRI is usually 15% to 50% (see Table 80_1).6,9,11,17

In the 1970s, SA was considered a useful localization procedure for detecting insulinomas. Because islet cell tumors are well vascularized, they can be detected by the hypervascular blush if the catheter is placed in the appropriate artery. Different series have shown sensitivity between 35% and 91% (see Table 80-1). However, more recently a decrease in its use has been noted because the excellent sensitivity just mentioned could not be reproduced by many authors. SA also usually identified the larger tumors, which would be relatively easy for experienced surgeons to find at

exploration.w"

Using selective PVS, insulin levels in blood samples obtained from specific sites along the splenic, mesenteric, pancreaticoduodenal, and portal veins are measured. This procedure requires transhepatic catheterization of these veins. It is maximally invasive and can be associated with

732 - - Endocrine Pancreas

serious complications. Significantly increased hormone concentrations from one area compared with others are considered a positive study result. Although PVS could reach sensitivity rates of 80% to 100%6,9.11-15,21 (see Table 80-1), the procedure does not really localize but only helps to regionalize the tumor to the part of the pancreas drained by a particular vein. 22 SRS was believed to be a promising method after the initial data were published. Large numbers of somatostatin receptors (SS-Rs) are found on most endocrine pancreatic tumors. At least five different human SS-R subtypes have been cloned. Octreotide binds with high affinity to SS-R subtype 2 (sst2) and sst5. 23 The efficacy of SRS using this agent in 350 patients with proven endocrine tumors was evaluated in a European multicenter trial.24 The highest success rates were observed with glucagonomas (100%), vasoactive intestinal polypeptide-secreting tumors (88%), gastrinomas (73%), and nonfunctioning islet cell tumors (82%). Insulinomas were detected in only 46% to 63% of cases due to the low incidence of sst2 on insulinoma cells. Therefore, the method is already losing favor (see Table 80-1). In this context, a modification of the Imamura method is also worth mentioning. In this procedure, known as arterial stimulation and venous sampling, calcium gluconate is injected into various gastroduodenal and splenic arteries. After the injection, blood is obtained for insulin assay from the hepatic veins. 25 Doppmann and others demonstrated high (88% to 100%) sensitivity rates 25-27 of this method, which is less painful, is less difficult for the interventional radiologist to perform, and is associated with fewer complications than transhepatic catheterization of the pancreatic veins. Daggett and colleagues 1 were the first to show that intraoperative exploration of the pancreas might be the best method to localize insulinomas. In their survey, 29 patients underwent laparotomy for suspected insulinoma. The tumors were correctly localized before operation in 13% by CT, in 18% by US, in 25% by selective PVS, and in 50% by SA. On the other hand, the tumors were detected and resected in 27 of these 29 patients at surgical exploration of the pancreas, Since then, many studies 2,lO,13,14,17,18,21 confirmed these results, and our survey" of 40 patients with insulinoma has shown that the tumor was correctly localized before operation in 65% by ES, 37% by SA, 33% by CT and US, 15% by MRI, and 0% by SRS. On the other hand, all tumors were identified and resected using IOUS and meticulous palpation of the pancreas after extensive mobilization of the gland.

to determine the relation of the tumor to the pancreatic duct. This should be performed by an experienced surgeon who is familiar with IOUS or asks an ultrasonographer to participate, If one desires a preoperative method besides US or CT, ES is the procedure of choice, but it can be omitted according to our experience. For patients requiring reoperation or for patients in whom laparoscopic resection is planned, ES is recommended as the second procedure after US or CT. When no lesion is identified and one can rely on the biochemical tests for diagnosis, laparotomy should follow.

Gastrinomas Eighty percent to 90% of all gastrinomas are located in the so-called gastrinoma triangle, which includes the duodenum, the pancreatic head, and the hepatoduodenal ligament." In contrast to previous reports, which stated that 80% of all gastrinomas are localized in the pancreas and only 20% in the duodenum, Sugg and colleagues-? showed that 70% to 80% of gastrinomas are found in the duodenal wall. The size of gastrinomas varies with the site of the tumors; pancreatic gastrinomas are often larger than I em, whereas gastrinomas of the duodenum are usually smaller than 1 em." Therefore, it is nearly impossible to identify duodenal gastrinomas by preoperative imaging procedures.P In 1999, Norton and colleagues" presented their results of surgical resection in more than 150 patients with ZES. In patients with sporadic ZES gastrinomas were detected by US in 24% (Fig. 80-3), by CT in 39% (Fig, 80-4), by MRI in 46%, and by SA in 48%. In approximately one third of patients with sporadic gastrinomas, the results of conventional imaging studies were negative, Different studies on patients with ZES confirmed these results. 3,4,19,29,32 As mentioned previously, ES is able to detect even small tumors in the pancreas. After first reports.v' many studies confirmed these results; for example, Zimmer and colleagues found pancreatic gastrinomas by ES in 79%.33 Anderson and coworkers' were able to localize all 36 pancreatic gastrinomas investigated by ES, whereas SA detected only 44% of the lesions.

Recommendation We recommend US or CT scan as the only preoperative test before primary operations, not to find the tumor but to exclude metastases of possibly malignant insulinomas, which are usually found in the liver. The patients should then undergo laparotomy that includes meticulous surgical exploration, including an extended Kocher maneuver to be able to palpate the head of the pancreas and mobilization of the body and tail from the retroperitoneum (including the spleen if necessary) to examine the distal pancreas carefully and completely. IOUS should then be used to confirm the presence of tumor or to find nonpalpable lesions and also

FIGURE 80-3. Transverse preoperative ultrasonography (5-MHz linear-array transducer) shows typical hypoechoic gastrinoma (20 mm) (TV) within the echogenic parenchyma of the pancreatic head (PA). CO = confluence.

Localization of Endocrine Pancreatic Tumors - -

FIGURE S0-4. Enhanced computed tomographic scan demonstrates a 16-mm enhancing gastrinoma in the pancreatic head.

The European multicenter trial to evaluate the efficacy of SRS showed positive results for pancreatic gastrinomas in 73%.24 In a prospective study comparing the sensitivity of SRS with that of CT, MR!, US, and SA in detection of primary and metastatic pancreatic gastrinomas, SRS altered clinical management in 47% of instances and had superior sensitivity and specificity." Cadiot and coauthors" compared the results of SRS with those of conventional imaging techniques, including ES, and with surgical findings in 21 consecutive patients with ZES. SRS added information to other imaging results and improved the preoperative detection of extrapancreatic gastrinomas. By combining SRS with ES, they were able to detect 90% of the tumors. Our experiences with SRS do not show any advantage when compared with the localization methods mentioned previously.F The gastrinomas that were visualized were either larger than 1 em in diameter or had widespread metastases (Fig. 80-5). Invasive localization methods, such as PVS and the selective intra-arterial injection of secretin combined with venous sampling (Imamura technique), show comparatively high sensitivity of 77% and 100%, respectively;

FIGURE S0-5. Somatostatin receptor scintigraphy shows two circular enhancements that represent two retroperitoneal tumors (arrow). The primary tumor, a gastrinoma, couldnot be identified.

733

however, they allow only regionalization and not exact localization of the tumors 29,31,36,37.38 (Table 80-2). Again it seems that the best method for localization is surgical exploration and IOUS (Fig. 80-6). The sensitivities of palpation and IOUS are 91% and 95%,39 respectively. We recommend a surgical approach similar to that used for patients with insulinomas, including preoperative US or CT scan to rule out large tumors with liver metastases and then IOUS. A study from the National Institutes of Health tested four different intraoperative procedures." All 31 duodenal tumors were detected after longitudinal incision of the second part of the duodenum and separate palpation of the posterior and anterior walls. The second best result was achieved by intraoperative endoscopy and transillumination of the duodenal wall (64%). Standard palpation and IOUS, on the other hand, detected only 61% and 26% of gastrinomas, respectively. Norton and colleagues underlined the importance of duodenotomy (DUODX) in patients with ZES.4o They performed DUODX in 79 patients and did not perform DUODX in 64 patients. Gastrinoma was found in 98% with DUODX compared with 76% with no DUODX. They could show that the use of routine DUODX increases the short-term and long-term cure rate.

Recommendation On the basis of these studies and our own experience, we recommend using either US or CT and SRS before primary operations, mainly for staging of the disease. This should be followed by exploratory laparotomy including DUODX and complete mobilization of the pancreas followed by IOUS. For reoperative cases ES and the Imamura technique should be used to localize or regionalize solitary or multiple tumors.

Multiple Endocrine Neoplasia Type 1 Nearly all patients with MEN 1 develop islet cell tumors of the pancreas, mostly gastrinomas (70%) or insulinomas (30%). Other endocrine pancreatic tumors such as glucagonomas and nonfunctioning tumors are rare. The endocrine pancreatic tumors in patients with MEN 1 are always multiple, small, and distributed throughout the entire organ. Gastrinomas are often found when they have already attained an advanced stage with metastases to regional lymph nodes and rarely the liver. In MEN 1 insulinomas, about 90% of patients have multiple tumors. Most often, only the large insulin-secreting tumors are localized by CT, US, and angiography, whereas small tumors remain undetectable. Spiral CT with contrast enhancement, MRI at high resolution, and positron emission tomography have all been used to identify MEN 1 endocrine pancreatic tumors, but they have generally been unable to reveal the small lesions." These methods, especially CT, can be used selectively, with longer intervals for screening. They can also be used to determine the anatomy and to exclude liver metastases and other extrapancreatic tumor burden. As mentioned previously, SRS had superior sensitivity and specificity in detection of pancreatic endocrine tumors compared with conventional

734 - - Endocrine Pancreas

imaging methods." Although even SRS fails to identify tumors smaller than I em in diameter, it may verify the endocrine nature of a tumor and may visualize metastatic spread within the abdomen, especially the presence of extraabdominal metastases, so we recommend the use of SRS in patients with MEN I preoperatively and with longer intervals for screening. ES has proved particularly sensitive for detection of tumors in the pancreatic head and body. ES had a sensitivity of 70% to 90% and has been convincingly shown to reveal lesions as small as 5 mm in diameter, and it now appears to be the outstanding method for screening of MEN I patients (Fig. 80_7).33,42,43 On the other hand, because ES has poor results in detecting tumors in the duodenal wall.v' an adequate surgical exploration of the pancreas, including the duodenum if ZES is present, seems to be superior to preoperative imaging procedures, especially if combined with IOUS and DUODX. 31

The intra-arterial stimulation test (Imamura test) using pentagastrin or calcium to stimulate gastrin and insulin secretion, respectively, is very accurate for regionalization of hormone excess with both gastrinomas and insulinomas, but it has not been routinely applied in many series.37 .44 In patients with ZES, one study using PVS showed a sensitivity of only 50%.36 In a survey by Sheppard and colleagues," eight of nine patients with MEN I had an identifiable hormone gradient on PVS. On the other hand, none of the patients was cured of ZES despite the fact that islet cell tumors were removed from the region of the gastrin gradient in five of six patients. The authors concluded that PVS is not successful in selecting patients for curative surgery. With respect to PVS, the interpretation of regionalization findings is fairly difficult because of multiple occurrences of insulinomas. Thus, this technique provides little information to improve surgical results. O'Riordain and associates'?

FIGURE S0-7. Preoperative endosonography shows one of multiple FIGURE SO-6. Longitudinal intraoperative ultrasonography (7.5-MHz linear-array transducer) of the pancreatic head demonstrates an 8-mm hypoechoic gastrinoma (arrow). This gastrinoma was not identified by any preoperative imaging procedure.

nonfunctioning endocrine pancreatic tumors in a 20-year-old patient with multiple endocrine neoplasia type 1. It demonstrates a 15-mm typical hypoechoic tumor (arrowheads) in the tail of the pancreas. D I and D2 =tumor margins; V lienalis =splenic vein; cauda pancr =pancreatic tail; largearrow, pancreatic duct; small arrows, splenic artery.

Localization of EndocrinePancreaticTumors - - 735 confirmed this observation and showed in 18 patients that small tumors could not be localized, although preoperative imaging studies including intraoperative palpation and IOUS were used. In this study, 17 of 18 patients were cured after a 75% to 85% subtotal distal pancreatectomy, including enucleation of tumors from the head of the pancreas. Similar findings had previously been reported by Demeure and coworkers."

Recommendation Surgery is the treatment of choice in MEN 1 pancreatic tumors if no extensive extrapancreatic (hepatic) spread is present. Because for both MEN 1 gastrinomas and MEN 1 insulinomas the procedures are standardized, localization is of limited importance. In MEN 1 gastrinomas, the procedure of choice is probably distal pancreatectomy, exploration of the duodenum after DUODX, enucleation of tumors of the pancreatic head, and regional lymph node dissection (according to Thompson and colleaguesj.t" We and other authors recommend'? a pylorus-preserving pancreaticoduodenectomy because most MEN 1 gastrinomas are situated in the head of the gland (gastrinoma triangle) and duodenal gastrinomas almost always recur after local excision. Therefore, localization of tumors within the pancreas is of little value. This is more so in MEN 1 insulinomas, for which distal pancreatectomy and enucleation of tumors from the head of the gland can be called a standard procedure. Therefore, localization procedures make sense only to show tumors in the head. On the basis of the studies mentioned previously, we recommend using preoperative US or CT and SRS to localize large tumors and to show liver metastases and other extrapancreatic metastatic spread; we also recommend ES preoperatively to localize tumors outside the pancreatic region resected. In patients with recurrent or persistent disease, other localization techniques such as the Imamura procedure are useful.

Nonfunctioning Tumors Islet cell tumors are called "silent" or "nonfunctioning" if they are not associated with a specific clinical syndrome, such as ZES. Either these tumors do not secrete enough hormones to produce a clinical syndrome or the secreted hormone does not cause specific symptoms (e.g., pancreatic polypeptide-secreting tumor). Preoperatively, US and CT scanning are the procedures of choice and are usually effective because these tumors are relatively large, usually more than 5 em in diameter." Also, SRS can be performed to differentiate endocrine from non endocrine pancreatic tumors. We recommend that all patients with nonfunctioning tumors undergo CT or US to localize the tumor and to exclude diffuse metastases.

Summary Preoperative US or CT scanning is helpful in patients with endocrine pancreatic tumors to show large primaries and

metastases if malignancy is present. No other procedures are necessary and indicated for patients who have not had previous operations. ES can be used preoperatively in gastrinomas or insulinomas if a laparoscopic approach is planned. At laparotomy, IOUS is useful for patients with gastrinoma and insulinoma. Because about 70% of gastrinomas are located in the duodenum, a DUODX is necessary to identify these often small tumors. For patients with persistent or recurrent gastrinoma or insulinoma, a similar approach is used, including ES and the Imamura procedure. The results of localization procedures in patients with MEN 1 gastrinomas or insulinomas have been frustrating because these patients usually have multiple small tumors throughout the gland. On the other hand, both tumor syndromes are treated by standardized resections, leading to limited value of these techniques.

Acknowledgment We thank Prof. Kann, Department of Internal Medicine and Endocrinology, for giving us the endosonography figures.

REFERENCES I. Daggett PR, Kurtz AB, Morris DV, et al. Is preoperative localisation necessary? Lancet 1981;318:483. 2. Van Heerden JA, Grant CS, Czako PF, et al. Occult functioning insulinomas: Which localizing studies are indicated? Surgery 1992;112:1010. 3. Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med 1992;326: 1721. 4. Palazzo L, Roseau G, Chaussade S, et al. Pancreatic endocrine tumors: Contribution of ultrasound endoscopy in the diagnosis of localization. Ann Coo 1993:47:419. 5. Anderson MA, Carpenter S, Thompson NW, et al. Endoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas. Am J Gastroenterol 2000; 95:2271. 6. Fendrich V, Langer P, Bartsch DK, et al. Diagnosis and therapy in 40 patients with insulinoma. Dtsch Med Wochenschr 2004; 129:941. 7. Kann P, Bittinger F, Engelbach M, et aI. Endosonography of insulinsecreting and clinically non-functioning neuroendocrine tumors of the pancreas: Criteria for benignancy and malignancy. Eur J Med Res 2001;6:385. 8. Richards ML, Gauger PG, Thompson NW, et al. Pitfalls in the surgical treatment of insulinoma. Surgery 2002;132: 1040. 9. Vinik AI, Delbridge L, Mottari R, et al. Transhepatic portal vein catheterization for localization of insulinomas: A ten-year experience. Surgery 1991;109:1. 10. Galiber AK, Reading CC, Charboneau JW, et al. Localization of pancreatic insulinoma: Comparison of pre- and intraoperative US with CT and angiography. Radiology 1988;166:405. 11. Doherty GM, Doppman JL, Shawker TH, et al. Results of a prospective strategy to diagnose, localize and resect insulinomas. Surgery 1991;110:989. 12. Fraker DL, Norton JA. Localization and resection of islet cell tumors of the pancreas. JAMA 1988;259:3601. 13. Rothmund M, Angelini L, Brunt M, et al. Surgery for benign insulinoma: An international review. World J Surg 1990;14:393. 14. Bottger TC, Weber W, Beyer J, Junginger T. Value of tumor localization in patients with insulinomas. World J Surg 1990;14:107. 15. Pasieka JL, McLeod MK, Thompson NW, Burney RE. Surgical approach to insulinomas: Assessing the need for preoperative localization. Arch Surg 1992;127:442. 16. Kuzin NM, Egorov AV, Kondrashin SA, et al. Preoperative and intraoperative topographic diagnosis of insulinomas. World J Surg 1998;22:593. 17. Boukhrnan MP, Karam JM, Shaver J, et al. Localization of insulinomas. Arch Surg 1999;134:818.

736 - - Endocrine Pancreas 18. Hashimoto LA, Walsh RM. Preoperative localization of insulinomas is not necessary. Am Coli Surg 1999;189:368. 19. Kalra MK, Maher MM, Mueller PR, Saini S. State-of-the-art imaging of pancreatic neoplasms. Br J RadioI2003;76:857. 20. Owen NJ, Sohaib SAA, Peppercorn PD, et al. MRl of pancreatic neuroendocrine tumours. Br J RadioI2001;74:968. 21. Hiramoto JS, Feldstein VA, LaBerge JM, Norton JA. Intraoperative ultrasound and preoperative localization detects all occult insulinomas. Arch Surg 2001;136:1020. 22. Rothmund M. Localization of endocrine pancreatic tumours. Br J Surg 1994;81:164. 23. Siooter GD, Mearadji A, Breeman WAP, et al, Somatostatin receptor imaging, therapy and new strategies in patients with neuroendocrine tumors. Br J Surg 2001;88:31. 24. Krenning EP, Kwekkeboom OJ, Pauwels EK, et al. Somatostatin receptor scintigraphy. In: Nuclear Medicine Annual. New York, Raven Press, 1995, p l. 25. Doppmann JL, Miller DL, Chang R, et al. Insulinomas: Localization with selective intraarterial injection of calcium. Radiology 1991;178:237. 26. Doppmann JL, Chang R, Fraker DL, et al. Localization of insulinomas to regions of the pancreas by intra-arterial stimulation with calcium. Ann Intern Med 1995;123:269. 27. Aoki T, Sakon M, Ohzato H, et al. Evaluation of preoperative and intraoperative arterial stimulation and venous sampling for diagnosis and surgical resection of insulinoma. Surgery 1999; 126:968. 28. Stabile BE, Morrow DJ, Passaro E. The gastrinoma triangle: Operative implications. Am J Surg 1987;209:550. 29. Sugg SL, Norton JA, Fraker DL, et al. A prospective study of intraoperative methods to find and resect duodenal gastrinomas. Ann Surg 1993;218:138. 30. Zogakis TG, Gibril F, Libutti SK, et al. Management and outcome of patients with sporadic gastrinoma arising in the duodenum. Ann Surg 2003;238:42. 31. Norton JA, Fraker DL, Alexander HR, et al. Surgery to cure the Zollinger-Ellison syndrome. N Engl J Med 1999;341:635. 32. Kisker 0, Bastian D, Bartsch D, et al. Localization, malignant potential and surgical management of gastrinomas. World J Surg 1998; 22:651. 33. Zimmer T, Scheriibl H, Faiss S, et al. Endoscopic ultrasonography of neuroendocrine tumors. Digestion 2000;62(Suppll):45. 34. Gibril F, Reynolds JC, Doppmann JL, et al. Somatostatin receptor scintigraphy: Its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas. A prospective study. Ann Intern Med 1996;125:26. 35. Cadiot G, Lebtahi R, Sarda L, et al. Preoperative detection of duodenal gastrinomas and peripancreatic lymph nodes by somatostatin receptor

36. 37.

38. 39. 40.

41. 42. 43. 44. 45. 46. 47. 48. 49. 50.

scintigraphy. Groupe D'etude Du syndrome de Zollinger-Ellison. Gastroenterology 1996; 111:845. Vinik AL, Moattari AR, Cho K, Thompson N. Transhepatic portal vein catheterization for localization of sporadic and MEN gastrinomas: A ten-year experience. Surgery 1990;107:246. Imamura M, Takahashi K, Adachi H, et al. Usefulness of selective arterial secretin injection test for localization of gastrinoma in the Zollinger-Ellison syndrome. Ann Surg 1976;205:230. Imamura M, Takahashi K, Isobe Y, et al. Curative resection of multiple gastrinomas aided by selective arterial secretin injection test and intraoperative secretin test. Ann Surg 1989;210:710. Norton JA, Cromack DT, Shawker TH, et al. Intraoperative ultrasonographic localization of islet cell tumors. Ann Surg 1988;207: 160. Norton JA, Alexander HR, Fraker DL, et al. Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases, or survival in patients with Zollinger-Ellison syndrome? Ann Surg 2004;239:617. Skogseid B, Grama D, Rastad J. Operative tumour yield obviates preoperative pancreatic localization in multiple endocrine neoplasia type 1. J Intern Med 1996;238:281. Thompson NW, Czako PF, Fritts LL, et al. Role of endoscopic ultrasonography in the localization of insulinomas and gastrinomas. Surgery 1994;116:1131. Proye C, Malvaux P, Pattou F, et al. Noninvasive imaging of insulinomas and gastrinomas with endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery 1998;124:1134. Kato M, Imamura M, Hosotani R, et al. Curative resection of microgastrinomas based on the intraoperative secretin test. World J Surg 2000;24: 1425. Sheppard BC, Norton JA, Doppmann JL, et al. Management of islet cell tumors in patients with multiple endocrine neoplasia: A prospective study. Surgery 1989;106:1108. O'Riordain DS, O'Brien T, van Heerden JA, et al. Surgical management of insulinoma associated with multiple endocrine neoplasia type 1.World J Surg 1994;18:488. Demeure MJ, Klonoff DC, Karam JH, et al. Insulinomas associated with multiple endocrine neoplasia type I: The need for a different surgical approach. Surgery 1991;110:998. Thompson NW, Bondeson AG, Bondeson L, et al. The surgical treatment of gastrinoma in MEN I syndrome patients. Surgery 1989; 106:1081. Bartsch DK, Langer P, Wild A, et al. Pancreaticoduodenal endocrine tumors in multiple endocrine neoplasia type I: Surgery or surveillance? Surgery 2000;128:958. Bartsch DK, Schilling T, Ramaswamy A, et al. Management of nonfunctioning islet cell carcinomas. World J Surg 2000;24:1418.

Pancreatic Surgery for Endocrine Tumors Norman W. Thompson, MD

A variety of surgical procedures are useful in the treatment of endocrine tumors of the pancreas. The selection of a specific surgical technique or procedure in the management of an endocrine tumor of the pancreas depends on a number of important factors that must be considered in each case: the functionalnature of the tumor,its benignity or malignancy, and whether it is a component of multiple endocrine neoplasia (MEN) type 1 or is sporadic in its occurrence. Furthermore, when a tumor is malignant, one must determine whether it invades essential contiguous structures such as the superior mesenteric vessels or whether metastases are present but are limited to lymph nodes. Usually hepatic metastasis implies incurability, although a solitary liver metastasis from an islet cell tumor should be treated aggressively, provided that the primary tumor can be completely removed. For the purposes of this discussion, endocrine tumors are classified into those that are sporadic and those that are associated with MEN 1. They are then further subdivided into those that are functional and those with no apparent hormonal activity.

Sporadic Endocrine Pancreatic Tumors The most common functional endocrine tumor of the pancreas is the insulinoma; unlike other tumors in this category it is usually benign (90%).1,2 As a result, most can be treated by enucleation when located in the head or uncinate process.' In our experience in managing more than 75 insulinomas during the past 25 years, only two insulinomas arising in the head required a pancreatoduodenectomy for excision. One was because of malignant local infiltration and the other was a small benign tumor that was neither palpable nor detectable with intraoperative ultrasound because it was isoechoic. It had been localized to the pancreatic head with selective arterial stimulation using calcium and hepatic

venous insulin assays. In all other patients with benign insulinomas arising in the head or uncinate, enucleation could be accomplished after adequate mobilization. To accomplish this, an extended Kocher maneuver of the duodenum to the level of the superior mesenteric vein is often necessary. After this extended mobilization has been performed, frequently several small branches of the superior mesenteric vein from the uncinate process must be divided between ligatures so that the entire uncinate can be palpated and exposed when the superior mesenteric vein is retracted medially (Fig. 81-1). Fine metal clips are used to secure small pancreatic vessels because a plane is developed between the tumor capsule and the surrounding parenchyma using a fine-tip mosquito hemostat. The approach to the insulinoma may be either anterior or posterior depending on an evaluation after bimanual palpation or ultrasonography to determine which surface the intraparenchymal tumor most closely approximates. Many insulinomas are partially visible on one surface or another, making that decision obvious in those cases. With careful technique, even tumors that are very close to either the common bile duct or major pancreatic duct can be enucleated without jeopardizing these structures. After enucleating a tumor in approximation to the major pancreatic duct, it is prudent to inject secretin intravenously and carefully evaluate for any exocrine secretion leak. We make no attempt to oversew the enucleation site but do place a Jackson-Pratt drain in its location. For insulinomas involving the neck, body, or tail, the decision to enucleate or resect is based on the size of the tumor and its specific location with respect to the pancreatic duct. Most insulinomas along either edge of the body or tail and those apparent on either the anterior or the posterior surface of the neck, body, or tail can be enucleated safely without resection. However, if a plane between the tumor capsule and the pancreatic parenchyma cannot be easily established, resection is indicated.'

737

738 - - Endocrine Pancreas

FIGURE 81-1. Illustration of an insulinoma in the uncinate process exposed in full after mobilization and retraction of the superior mesenteric vein. The enucleation site is left open.

In approximately 5% of insulinomas, the only manifestation of malignancy is local infiltration. These tumors are usually curable by resection if no hepatic metastases are present. When resection is indicated on the basis of location or size, we attempt splenic preservation whenever possible. This is usually feasible unless the splenic vein is within the posterior pancreatic parenchyma. If malignancy is suspected, a distal resection in continuity with the spleen and peripancreatic lymph nodes is performed. For patients with hypoglycemia caused by islet cell hyperplasia or nesidioblastosis rather than a tumor, a distal pancreatectomy to the level of the superior mesenteric vein is performed in those whose hypoglycemia is responsive to a trial of preoperative diazoxide testing. A more extensive (85%) resection is done in those patients who are refractory to this drug in preoperative testing.' We currently use only endoscopic ultrasonography (EUS) for preoperative localization when positive." If an insulinoma is not identified, we use a selective calcium arterial stimulation test with insulin samples from the right hepatic vein.? This technique regionalizes the tumor or identifies those with multiple sites of insulin hypersecretion and is equally sensitive as selective venous sampling, which we formerly used.' This is done in preference to relying solely on intraoperative ultrasonography for localization in the infrequent patient in whom an insulinoma cannot be palpated after a complete exploration.s? Blind distal pancreatectomy is avoided when a tumor is not found and is, in our opinion, never indicated in a patient who has not had localization preoperatively or who has a negative intraoperative ultrasonographic examination. When there is evidence that the disease is multifocal (hyperplasia or nesidioblastosis), a distal pancreatectomy is performed, and its extent is based on preoperative diazoxide testing.

Sporadic Gastrinomas Unlike insulinomas, most gastrinomas are malignant. However, unless detected at a stage in which hepatic metastases are

already present, most patients are candidates for a curative procedure. The surgical treatment of gastrinoma is dependent on its location, whether within the pancreatic parenchyma or arising within the duodenal wall. Our experience is similar to that of others who have noted that sporadic gastrinomas are always solitary tumors; those within the pancreas causing Zollinger-Ellison syndrome (ZES) are invariably larger than I em in diameter and can be readily identified at exploration. to Although most gastrinomas are within the gastrinoma triangle, a pancreatic gastrinoma can arise from the neck or body of the pancreas as well. For these unusual patients, a distal pancreatectomy is preferable to enucleation because of the greater likelihood that the neoplasm is malignant. When the gastrinoma is within the pancreatic head or uncinate, we attempt enucleation and reserve resection (pancreatoduodenectomy) for when there is local infiltration and absence of hepatic metastases.v!' Surprisingly, in nearly all gastrinomas of the head without liver metastases, it has been possible to enucleate the tumor. When no neoplasm is found within the pancreas after its complete mobilization and exploration, it should be assumed that the tumor is within the duodenum.P A duodenotomy should be performed routinely in sporadic patients with ZES when the pancreatic exploration is negative.'>" Before this is performed, the duodenum should be carefully palpated from the pylorus to the level of the superior mesenteric vein. However, fewer than half of sporadic duodenal gastrinomas are palpable. Because a sporadic gastrinoma is singular, the duodenectomy can be placed for its excision when it is palpable. In these cases, the neoplasm is usually 0.5 em or larger and may locally infiltrate the submucosa. As a result, its excision with a full-thickness margin of duodenal wall is required. 12,14When no tumor is palpable, we make a 6- to 8-cm vertical duodenotomy centered in the second portion of the duodenum. After inspection and gentle finger palpation circumferentially, a small submucosal lesion can usually be identified in the first, second, or proximal third portion of the duodenum. When no tumor is initially palpable, the duodenal wall, both proximally and distally, is everted into the duodenotomy for further inspection and palpation. Tumors as small as 1.5 mm can be detected by these maneuvers. 12 Once identified, we place a stay stitch on either side of the tumor, make an elliptical incision through the mucosa around the tumor, and enucleate the tumor from the underlying submucosa. If this cannot be easily accomplished, a full-thickness excision of the duodenal wall around the tumor is performed. It has been our experience that nearly all gastrinomas that are 0.5 em or smaller can be enucleated. When a full-thickness excision has been performed, unless it is at the edge of the duodenotomy, two separate closures are required. We prefer a two-layer closure with a running full-thickness absorbable stitch followed by an interrupted Lembert silk closure. Our duodenotomies are closed vertically rather than in a transverse direction. Regardless of a duodenal tumor's size, a regional lymph node dissection is indicated. Gastrinomas as small as I mm may be associated with one or more metastatic nodes. We excise any visible nodes on both surfaces of the pancreatic head and those along the common bile duct and along the common hepatic artery to the level of the celiac axis.

Pancreatic Surgeryfor Endocrine Tumors - - 739 When any of them are positive for metastatic disease, we excise all of the lymph nodes in the porta hepatis as well. A complete exploration of the pancreas and duodenum is currently rarely negative. Although for a decade we routinely used percutaneous transhepatic selective venous sampling in localizing gastrinomas, we currently rely on EUS after screening for hepatic metastases with a computed tomographic (CT) scan.6,17,18 We also routinely obtain an octreotide scan, primarily to identify any liver metastases or otherwise occult distant metastases. Most gastrinomas 2 cm or larger (either primary or metastatic) have sufficient somatostatin receptors to be detectable with an octreotide scan. Most primary duodenal gastrinomas are too small to be identified by octreotide scans or any other localization techniques, although their larger metastatic lymph nodes may be detectable. During the past 15 years, more than 70% of sporadic gastrinomas, in our experience have been duodenal in origin with about 60% having associated metastatic lymph nodes in the periduodenal or pancreatic region. Only one of these patients had a liver metastasis «10%). During this time, we recognized that tumors arising in the third or fourth portions of the duodenum may also metastasize to lymph nodes along the superior mesenteric vein and in the base of the mesentery. These nodes are also now routinely resected for primary tumors in these locations. Because of the likelihood of recurrence in patients with malignant metastatic gastrinoma and the possible future need for long acting somatostatin therapy, we routinely perform a cholecystectomy as well. If EUS is negative for a pancreatic tumor, it may be assumed that a duodenal primary is present. Nevertheless, it is reassuring to confirm regionalization with a selective arterial secretin stimulation test,19,20 In such cases, the liver not only is palpated but also is examined by ultrasonography for a rare primary hepatic gastrinoma. The distal duodenum and proximal jejunum should also be evaluated as well as the ovaries in a female patient.Although some have recommended a blind Whipple procedure after a negative exploration in a patient with proven localized gastrin hypersecretion in the region of the head or duodenum, we do not favor that approach. However, the possibility of re-exploration after 1 or 2 years should always be considered after a complete re-evaluation in the patient with rising gastrin levels.

Other Sporadic Islet Cell Tumors Most other functional islet cell tumors such as glucagonomas, vasoactive intestinal polypeptide tumors (VIPomas), and somatostatinomas are too large at diagnosis to be amenable to enucleation and require resection when feasible. 21-23 More than half of these tumors are malignant with either local invasion or hepatic metastases at the time of diagnosis. Whenever feasible, debulking of tumors is desirable short of Whipple's procedure even when hepatic metastases are present. When local invasion of the superior mesenteric vein is the only apparent factor preventing complete tumor resection, the proximal portion of the vein and portal vein, if uninvolved, can be mobilized and clamped and either an autologous jugular vein or a ribbed Gore-Tex graft used for

replacement after the tumor has been resected. Another option is the use of the distal right renal vein as a graft for the resected superior mesenteric vein. Although we would not usually perform superior mesenteric vein resection for an adenocarcinoma of the pancreas, local venous involvement by an islet cell tumor may lead to portal hypertension and mesenteric thrombosis in the absence of disseminated disease. Every effort should be made to free the mesenteric vessels of malignancy in patients without liver metastases. When the superior mesenteric vein is locally invaded proximal to the confluence with the splenic vein, it may be possible to use the splenic vein as graft, swinging it down to the proximal transected superior mesenteric vein and anastomosing it end to end (Fig. 81-2). We have used this simple bypass on three occasions with success. One lesson learned when there is complete occlusion of the vein is that the superior mesenteric vein should be shunted or bypassed to the portal vein with an elongated graft over and around the tumor before resecting the pancreas. Incisions into the pancreas filled with venous collaterals in these cases can result in massive blood loss unless decompressed by shunting. An elongated graft can be clamped, divided, and shortened to an appropriate length and anastomosed after the tumor has been excised. We have not been as aggressive in resecting an involved superior mesenteric artery, but we currently have several patients without liver metastases in whom resection and bypassing the artery are being considered because of the development of visceral angina. In both cases, the only residual islet cell tumor is in the superior mesenteric artery after an 85% resection of the pancreas. In neither case was the aorta invaded, although the superior mesenteric artery was encased within 1 ern of its origin. When functional islet cell tumors are associated with liver metastases, we resect those that can be readily excised and use radiofrequency ablation for those still remaining. The occasional patient with a single large liver metastasis, usually involving the right lobe, however, is a candidate for a liver lobectomy. The effectiveness of somatostatin analogs in the treatment of both metastatic glucagonoma and VIPoma has lessened the need for more radical excisions of metastatic deposits in the liver.24,25 Somatostatin analogs may cause tumor regression in some VIPoma cases and can control the secretion of VIP in nearly all cases. In patients with progressive enlargement of liver metastases in both liver lobes, we recommend hepatic arterial embolizations in two stages, which may prove effective for 6 months to 1 year or even longer. Because a somatostatin analog (octreotide) is used eventually in the treatment of most incurable islet cell tumors, cholecystectomy should always be considered in the patient found to have liver metastases at exploration. Long-term use of octreotide has been associated with a high incidence of cholelithiasis and cholecystitis in those patients with retained gallbladders.

Nonfunctional Sporadic Islet Cell Tumors The general principles applied to the surgical treatment of nonfunctional islet cell tumors are essentially the same as those identified for the treatment of tumors associated with clinical syndromes. Most nonfunctional tumors are diagnosed after

740 - - Endocrine Pancreas

A

FIGURE 81-2. A, Neuroendocrine tumor of head, neck, or uncinate region encasing or invading the superior mesenteric vein proximal to the confluence of the splenic and portal veins. B, Distal splenic vein mobilized and clamped in preparation for transposition as graft involvement. C, Proximal superior mesenteric vein transection is oversewn, and splenic vein is transposed and anastomosed end to end with proximal superior mesenteric vein. A 95% pancreatectomy is performed. (A to C, From Thompson NW, Eckhauser F. Malignant islet cell tumors of the pancreas. World J Surg 1984;8:946.)

B

c

Pancreatic Surgery for Endocrine Tumors - -

they have attained a size large enough to cause local symptoms. 21-23,26 These include jaundice, pancreatitis, steatorrhea, gastrointestinal bleeding, duodenal obstruction, abdominal pain, and palpable abdominal mass. Most are malignant, as manifest by local invasion, liver metastases, or lymph node involvement. Nevertheless, even some of the largest tumors are resectable for cure, and most can be resected with expectation of palliation for extended periods. Many of the nonfunctional tumors arise in the pancreatic head, and a Whipple procedure is frequently feasible. This operation should not be withheld because of local lymph node metastases. An octreotide scan should be done preoperatively in all patients with suspected nonfunctional islet cell tumors to confirm the diagnosis (when positive), for staging, and to determine whether octreotide may be useful as adjunctive therapy.

MEN 1 The most common functional islet cell tumor in MEN 1 patients is the gastrinoma. 22,27-34 MEN 1 patients account for approximately 30% of all patients with the ZES, and, even without a family history or other symptoms, all "sporadic" ZES patients should be evaluated for the possibility of MEN 1 and at least a serum calcium and prolactin level obtained. The surgical treatment of ZES in the MEN 1 patient has remained controversial because of a previously high failure rate in curing the disease. 28-31,35-39 Furthermore, with the use of omeprazole, symptoms can be controlled or completely alleviated in most patients. As a result, an operation designed to excise the primary tumor has been deferred in many centers until a pancreatic tumor has been imaged by CT or other study.31.34 There are a number of obvious drawbacks to such an approach. The first is that it ignores the potential malignancy of neuroendocrine tumors that arise in the pancreas and the duodenum. It eliminates the possibility of cure and concedes that the patient will require drug therapy for life. It also potentially subjects these patients to the development of enterochromaffin-like neuroendocrine tumors in the body of the stomach." It appears that MEN 1 patients, in contrast with those with sporadic gastrinoma, are genetically susceptible to the development of such tumors, and this possibility may be enhanced by the long-term use of omeprazole in the presence of high levels of serum gastrin. A policy of delay until a tumor is imaged is based on the presumption that MEN 1 patients have such diffuse functional islet cell disease that eugastrinemia cannot be achieved without a total pancreatectomy. The evidence against this concept is that immunohistochemical staining of the MEN 1 pancreas in patients with ZES shows that the diffuse islet cell dysplasia commonly found is not the source of gastrin hypersecretion." Discrete tumors secrete gastrin, and most of these are in the pancreatic head and the duodenum. Furthermore, during the last decade, it has been shown that duodenal tumors are present in most MEN 1 patients and that most of these are associated with lymph node but not liver metastases. IO,29,30.37.38,42-45 Complete excision of all involved foci of disease can result in eugastrinemia in most patients. 14,29.44

741

Our policy during the past 20 years has been to attempt to cure all MEN 1 patients with ZES who do not have liver metastases at presentation. The multifaceted approach we currently use has evolved during this time and is based on our previous experience and knowledge gained during this time. Although liver metastases are currently infrequent (< 10%) in MEN 1 ZES patients at the time of diagnosis, a CT or magnetic resonance and an octreotide scan is performed to exclude their presence with reasonable certainty. These studies may also demonstrate one or more pancreatic neuroendocrine neoplasms, although it is considered insensitive in detecting small tumors. The only other localization study that we now consider useful is EUS, with attention directed primarily to the head and uncinate process." EUS may detect tumors as small as 0.5 em within the pancreatic parenchyma that might not be detected intraoperatively by palpation. During the past 10 years in which this procedure has been routinely performed, duodenal tumors have also been detected, in some cases during the preliminary endoscopic visualization of the duodenum/' However, the detection of small submucosal gastrinomas is the exception rather than the rule, and a negative duodenal evaluation in no way rules out the presence of such tumors.f Our operative procedure is done through an upper abdominal transverse incision midway between the umbilicus and the xiphoid process. After an initial careful bimanual exploration and ultrasonography of the liver for possible occult metastases, the duodenum and pancreas are widely mobilized by extending the Kocher maneuver to the superior mesenteric vein. Small venous branches on the lateral side of the superior mesenteric vein entering the uncinate process are divided between clips so that the entire uncinate may be freed sufficiently that it can be bimanually palpated. Any palpable nodules or those identified on EUS are exposed after incising the pancreatic capsule and spreading the parenchymal tissue with a fine-tip mosquito hemostat until the capsule of the tumor has been identified. Any detectable neoplasms in the head or uncinate are enucleated. When this has been completed, the greater omentum is reflected from the transverse colon by incising and reflecting its fusion fascia, which allows entrance into the lesser omental space. The splenic flexure is mobilized caudally away from the inferior splenic pole. The retroperitoneum, from the superior mesenteric vein to the spleen, is then incised sharply just below the inferior border of the pancreas. The entire distal pancreas is then mobilized by blunt dissection. When feasible, the small pancreatic branches from the splenic vessels are isolated, clipped, and divided, freeing both the splenic artery and vein from the body and tail to preserve the spleen. In most patients, one or more neuroendocrine tumors is readily identified in either the body or tail (Fig. 81-3). In these cases, we include any lymphatics along the splenic vessels and those around the celiac axis as well. The pancreas is mobilized so that the neck can be transected just to the right of the superior mesenteric vein. The neck is then oversewn with mattress sutures after separately ligating the pancreatic duct. We prefer this technique to the use of either a stapler or cross-clamping of the neck because there is no crushed edge of tissue and the pancreatic duct can be seen and securely ligated.

742 - - Endocrine Pancreas

FIGURE 81-3. Multiple endocrine neoplasia type I pancreas with islet cell tumors. Multiple neuroendocrine neoplasms are common.

After the pancreatic portions of the operation have been completed, the duodenum is carefully palpated from the pylorus to the superior mesenteric vein. A longitudinal duodenotomy centered in the second portion of the duodenum allows excision of any palpable tumors in the anterior and medial aspects of the duodenum. However, in many cases, no tumors are palpable until the duodenotomy allows direct exposure of the mucosal surface. Both proximal and distal areas of the duodenum must be everted into the incision and the mucosa palpated circumferentially to rule out neuroendocrine tumors as small as 1 mm in diameter. Tumors that are 0.5 em or smaller can usually be enucleated from the submucosa after an elliptical mucosal incision around the tumor. Most larger tumors should be excised with a margin of fullthickness duodenal wall. One or more small excision sites will require separate closure unless the tumor is close to the original duodenotomy. Most MEN 1 patients with ZES have one or more tumors in the first three parts of the duodenum. One of our patients who had a previous Billroth II procedure was found to have 29 separate tumors in the remaining stump and second part of the duodenum proximal to the ampulla of Vater. After local excision of the tumors distal to the ampulla of Vater, the proximal duodenum was mobilized from the pancreas and resected to a level just far enough proximal to the ampulla that it could be safely closed at that level. Most of our MEN 1 patients have had more than one duodenal gastrinoma, although they were not always apparent until after a careful search has been made. The standard duodenotomy is closed in two layers in a vertical direction in which it was performed. When one or more duodenal tumors has been found, all parapancreatic lymph nodes on both surfaces of the pancreatic head are excised as are those along the common bile duct, portal vein, and hepatic artery to the celiac axis. On completion of these procedures, a Jackson-Pratt drain is placed near the pancreatic stump and brought out in the midline above the level of the transverse incision (Fig. 81-4). During the 17-year period from 1978 to 1995,25 MEN 1 patients with ZES without liver metastases underwent

FIGURE 81-4. Operation for multiple endocrine neoplasia type l-Zollinger-Ellison syndrome: (1) distal pancreatectomy; (2) enucleation of neuroendocrine (NE) tumors (head, uncinate); (3) duodenotomy, excision ofNE tumors; (4) regional lymph node dissection.

exploration with intent to "cure" their disease. The first 17 patients were reported elsewhere, with a follow-up ranging from 2 to 16 years.f Sixty-five percent had normal basal gastrin levels, were asymptomatic, and required no drug therapy. The remaining 35% had a decrease in serum gastrin levels, symptoms, and drug requirements. With longer follow-up, the incidence of eugastrinemia has decreased to about 30% with approximately half having been symptom free for 10 years or longer and one for 25 years. Only one of our MEN 1-ZES patients (n = 44) has developed a single liver metastasis. This was recently treated by right liver lobectomy and he is currently eugastrinemic. Several other patients have been re-explored for recurrences in lymph nodes or apparently new duodenal gastrinomas. No patient has developed, as best as we can determine, either a local recurrence in either the pancreatic head or duodenum after an enucleation. Gastrinomas were found in the duodenum in 76% of patients and in both duodenum and pancreas in 35%. Approximately half of the duodenal gastrinomas were malignant, as proven by excision of peripancreatic metastatic lymph nodes. All patients were found to have at least one microscopic neuroendocrine tumor involving the distal pancreas, two of which were gastrinomas as determined by immunohistochemical staining.

Insulinomas Approximately 5% of all insulinomas occur in MEN 1 patients, and an estimated 10% to 15% of MEN 1 patients acquire insulinomas as the only functional component of their pancreatic disease.'·2,22.27,30,42,47 Insulinomas in MEN 1 are commonly multiple or are associated with other pancreatic neuroendocrine tumors. Only by immunohistochemical

Pancreatic Surgery for Endocrine Tumors - - 743

staining subsequent to their excision can these tumors be specifically classified. The only localization study we currently use in MEN 1 patients with a confirmed diagnosis of insulinoma is EUS of the head and uncinate process of the pancreas. A serum gastrin level is also obtained to rule out concomitant preclinical gastrinoma and the possible need for a duodenotomy. The operative procedure we now perform routinely is a distal pancreatectomy and enucleation of any tumors in the head or uncinate process." At least two or more insulinomas have been found in the eight MEN 1 patients with hypoglycemia that we have treated during a 20-year period. A duodenotomy is performed only when the serum gastrin level is elevated and a secretin test is positive. Extrapancreaticinsulinomas have not been reported in MEN 1 patients. A peripancreatic lymphatic dissection is performed only in those patients with concomitant duodenal gastrinomas and in the rare patient with a malignant insulinoma arising from the pancreas. Only one of our patients, a 27-year-old man, was found to have a 7-cm malignant insulinoma arising from the neck of the pancreas as well as additional neuroendocrine tumors in the body and tail. Although one lymph node contained a metastasis, there has been no evidence of recurrence during a 12-year follow-up. All other patients are also euglycemic after follow-upperiods ranging from 6 to 20 years.

Nonfunctional Tumors Most patients with functional tumors have other nonfunctional tumors or those secreting hormones that produce no identifiable syndrome, most commonly arising in the distal pancreas. Most of these are found before their malignant potential is evident and before a functional syndrome has developed. Their presence is one of the primary reasons for recommending a distal pancreatectomy in all MEN l-ZES and insulinoma patients. 30,44 Approximately 5% to 10% of MEN 1 patients acquire neuroendocrine tumors, producing symptoms related entirely to their size, local invasion, or hepatic metastases, These patients may present with weight loss, abdominal pain, jaundice, an abdominal mass, or gastrointestinal hemorrhage. In those with large tumors of the head but without hepatic metastases, Whipple's procedure may be curative. Even when the superior mesenteric vein is involved by a neuroendocrine tumor, resection and vein replacement are indicated whenever such involvement is the only factor preventing total excision of the tumor. Tumors localized to the neck or uncinate involving the superior mesenteric vein or artery may cause portal hypertension with bleeding varices or visceral ischemia, respectively. Surgical resection and revascularization may offer significant palliation, if not cure, and should be considered. Finally, size alone does not always imply local invasion or metastatic disease, and we have resected three neuroendocrine tumors in MEN 1 patients that were 10 em or larger that showed no features of malignancy or subsequent recurrence.

REFERENCES I. Rothmund M, Angelini L, Brunt M, et al. Surgery for benign insulinoma: An international review. World J Surg 1990;14:393.

2. Service FJ, McMahon MM, O'Brien PC, Ballard OJ. Functioning insulinoma: Incidence, recurrence and long-term survival of patients: A 60-year study. Mayo Clin Proc 1991;66:711. 3. Pasieka JL, McLeod MK, Thompson NW, Burney RE. Surgical approach to insulinomas: Assessing the need for preoperative localization. Arch Surg 1992;127:442. 4. Udelsman R, Yeo CJ, Hruban RH, et al. Pancreaticoduodenectomy for selected pancreatic endocrine tumors. Surg Gynecol Obstet 1993;177:269. 5. Hamess JK, Geelhoed GW, Thompson NW, et al. Nesidioblastosis in adults. Arch Surg 1981;116:575. 6. Thompson NW, Czako PF, Fritts LL, et al. Role of endoscopic ultrasonography in the localization of insulinomas and gastrinomas. Surgery 1995;116:1131. 7. Doppman JL, Miller DL, Chang R, et al. Intraarterial calcium stimulation test for detection of insulinoma. World J Surg 1993;17:439. 8. Norton JA, Cromack DT, Shawker TH, et al. Intraoperative ultrasonographic localization of islet-cell tumors: A prospective comparison to palpation. Ann Surg 1988;207:160. 9. van Heerden JA, Grant CS, Czako P, et al. Occult functioning insulinomas: Which localizing studies are indicated? Surgery 1992;112:1010. 10. Pipeleers-Marichal M, Donow C, Heitz OV, Kloppel G. Pathologic aspects of gastrinomas in patients with Zollinger-Ellison syndrome with and without multiple endocrine neoplasia type I. World J Surg 1993;17:481. 11. Delcore R, Herumreck AS, Friesen SR. Selective surgical management of correctable hypergastrinemia. Surgery 1989;106:1094. 12. Thompson NW, Vinik AI, Eckhauser FE. Microgastrinomas of the duodenum: A cause of failed operations for the Zollinger-Ellison syndrome. Ann Surg 1989;209:396. 13. Sugg SL, Norton JA, Fraker DL, et al. A prospective study of intraoperative methods to diagnose and resect duodenal gastrinomas. Ann Surg 1963;218:138. 14. Thompson NW, Pasieka J, Fukuuchi A. Duodenal gastrinomas, duodenotomy and duodenal exploration in the surgical management of Zollinger-Ellison syndrome. World J Surg 1993;17:455. 15. Declore R Jr, Cheung LS, Friesen SR. Characteristics of duodenal wall gastrinomas. Ann J Surg 1990;160:621. 16. Thorn AK, Norton JA, Axiotis CA, Jensen RT. Location, incidence, and malignant potential of duodenal gastrinomas. Surgery 1991;110:1086. 17. Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasound. N Engl J Med 1992; 326:1721. 18. Vinik AI, Moattari AR, Cho K, Thompson NW. Transhepatic portal vein catheterization for localization of sporadic and MEN gastrinomas: A ten-year experience. Surgery 1990;107:246. 19. Imamura M, Takahashi K, Adachi H, et al. Usefulness of selective arterial secretin injection test for localization of gastrinoma in the Zollinger-Ellison syndrome. Ann Surg 1987;205:230. 20. Imamura M, Takahashi K, Isobe Y, et al. Curative resections of multiple gastrinoma aided by selective arterial secretin injection test and intraoperative secretin test. Ann Surg 1989;210:710. 21. Grant CS. Surgical management of malignant islet cell tumors. World J Surg 1993;17:498. 22. Norton JA. Neuroendocrine tumors of the pancreas and duodenum. Curr Probl Surg 1994;31:77. 23. Thompson NW, Eckhauser FE. Malignant islet cell tumors of the pancreas. World J Surg 1984;8:1. 24. Lamberts SWJ, Krenning EP, Reubi Je. The role of somatostatin and its analogs in the diagnosisand treatmentof tumors.Endocr Rev 1991;12:400. 25. Maton PN. Use of octreotide acetate for control of symptoms in patients with islet cell tumors. World J Surg 1993;17:504. 26. Eckhauser FE, Cheung PS, Vinik AI, et al. Nonfunctioning malignant neuroendocrine tumors of the pancreas. Surgery 1986;100:978. 27. Mignon M, Ruszniewski P, Podevin P, et al. Current approach to the management of gastrinoma and insulinoma in adults with multiple endocrine neoplasia type I. World J Surg 1993;17:489. 28. Shepherd J, Challis DR, Davies FF, et al. Multiple endocrine neoplasia, type I: Gastrinoma, pancreatic neoplasms, microcarcinoids, ZollingerEllison syndrome, lymph nodes, and hepatic metastases. Arch Surg 1993;128:1133. 29. Thompson NW. The surgical treatment of the endocrine pancreas and the Zollinger-Ellison syndrome in the MEN I syndrome. Henry Ford Hospital Med J 1992;40:112.

744 - - Endocrine Pancreas 30. Akerstrom G, Johansson H, Grama D. Surgical treatment of endocrine pancreatic lesions in MEN I. Acta OncoI1991;30:542. 31. van Heerden JA, Smith SL, Miller L. Management of the ZollingerEllison syndrome in patients with multiple endocrine neoplasia type I. Surgery 1986;100:871. 32. Tisell LE, Ahlman H, Jansson S, Grimelius L. Total pancreatectomy in the MEN I syndrome. Br J Surg 1988;75:154. 33. Thompson NW, Bondeson AG, Bondeson L, Vinik AI. The surgical treatment of gastrinoma in MEN I syndrome patients. Surgery 1989; 106:1081. 34. Sheppard BC, Norton JA, Doppmann JL, et al. Management of isletcell tumors in patients with multiple endocrine neoplasia: A prospective study. Surgery 1989;106:1108. 35. Norton JA. Advances in the management of Zollinger-Ellison syndrome. Adv Surg 1994;27:129. 36. Norton JA, Jensen RT. Unresolved surgical issues in the management of patients with Zollinger-Ellison syndrome. World J Surg 1991;15:151. 37. Pipeleers-Marichal M, Somers G, Willems C, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type I and the Zollinger-Ellison syndrome. N Engl J Med 1990;322:723. 38. Delcore R, Friesen SR. The role of pancreatic duodenectomy of primary duodenal wall gastrinomas in patients with the Zollinger-Ellison syndrome. Surgery 1992;112:1. 39. Cherevu JA, Sawyers JL. Benefits of resection of metastatic gastrinomas in multiple endocrine neoplasia type I. Gastroenterology1992; 102:1049.

40. Solcia E, Capella C, Fiocca R, et al. Gastric argyrophilic carcinoidosis in patients with Zollinger-Ellison syndrome due to type I multiple endocrine neoplasia. Am J Surg PathoI1990;14:503. 41. Thompson NW, Lloyd RV, Nishiyama RH, et al. MEN I pancreas: A histological and immunohistochemical study. World J Surg 1984;8:561. 42. Kloppel G, Willemer S, Stamm B, et al. Pancreatic lesions and hormonal profile of pancreatic tumors in multiple endocrine neoplasia type I: An immunocytochemical study of nine patients. Cancer 1986;56:1824. 43. Donow C, Pipeleers-Marichal M, Schroder S. Surgical pathology of gastrinoma: Site, size, multicentricity, association with multiple neoplasia type I and malignancy. Cancer 1991;68:1329. 44. Thompson NW. The surgical management of hyperparathyroidism and endocrine disease of the pancreas in the multiple endocrine neoplasia type I patient. J Intern Med 1995;238:1. 45. Imamura M, Kanda M, Takahashi K, et al. Clinicopathological characteristics of duodenal microgastrinomas. World J Surg 1992;16:702. 46. Zimmer T, Stolsel V, Bader M, et al. A duodenal gastrinoma in a patient with diarrhea and normal serum gastrin concentrations. N Engl J Med 1995;333:634. 47. O'Riordain DS, O'Brien T, van Heerden JA, et al. Surgical management of insulinoma associated with multiple endocrine neoplasia type I. World J Surg 1994;18:488.

Gastrinoma Stuart D. Wilson, MD

A gastrinoma is an endocrine tumor that elaborates the hormone gastrin. The consequences of the hypergastrinemia are gastric acid hypersecretion and related complications. Before the identification ofthe hormone gastrin as the gastric secretagogue, the tumors were called "ulcerogenic tumors of the pancreas."1,2 Zollinger-Ellison syndrome, or Z-E syndrome, is used frequently in the medical literature in place of the term gastrinoma.' Gastrinoma patients should be classified as having either sporadic or familial gastrinoma. This distinction is important because the pathophysiology, natural history, and medical or surgical management of sporadic and familial gastrinoma patients are different. Sporadic gastrinomas are not inherited and are only rarely associated with other endocrinopathies. Familial gastrinomas are those that develop in individuals who have inherited the genetic trait for multiple endocrine neoplasia type 1 (MEN 1).4 The eponym for the MEN 1 syndrome is Wermer's syndrome.' The term multiple endocrine adenopathy type 1 (MEA-I) is preferred to MEN 1 by some authors.v' In this chapter sporadic gastrinomas are discussed, Familial gastrinomas, occurring in patients with MEN I, are discussed in Chapter 76.

peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. They suggested a diagnostic triad for a new clinical syndrome': 1. The presence of primary ulcerations in unusual locations, that is, second or third portions of the duodenum or upper jejunum, or recurrent stomal ulcers after any type of gastric surgery short of total gastrectomy (TG) 2. Gastric hypersecretion of gigantic proportions persisting despite adequate conventional medical, surgical, or irradiation therapy 3. The identification of nonspecific islet cell tumors of the pancreas (an "ulcerogenic tumor factor of pancreatic islet origin" was postulated) The subsequent reports detailing the early descriptions of patients with ulcerogenic tumors, the discovery of a potent gastric secretagogue in the tumor tissue and the sera of Z-E syndrome patients, the identification of gastrin as the responsible hormone, and the development of radioimmunoassay (RIA) methods to measure physiologic and supranormal gastrin concentrations all make fascinating reading. This history has been recorded by Zollinger and Coleman."

Brief History and Evolution of the Zollinger-Ellison Syndrome

Pathophysiology and Symptoms

The history behind the identification and characterization of the Z-E syndrome is fascinating. Four decades of investigating the pathophysiology and natural history, searching for drugs to inhibit the marked gastric acid hypersecretion, developing new technologies to diagnose and locate the tumors, and searching for the preferred treatment for patients with Z-E syndrome have captivated many physicianscientists, some of whom could appropriately be dubbed "Z-E watchers." Some Z-E watchers have made the study of this disease entity a focus of their research and clinical practice. Their contributionshave altered our approach to the diagnosis, management, and treatment of this disease. 1,7-28 In 1955, at the annual meeting of the American Surgical Association, Robert M. Zollinger and Edwin H. Ellison reported the clinical histories of two patients with primary

The altered physiology of patients with Z-E syndrome is due to the effects of high concentrations of gastrin in the circulation. The primary effects of the hypergastrinemia are gastric acid hypersecretion and parietal cell hyperplasia (Fig. 82-1). Gastrin acts directly on specific receptors of the parietal cell to promote gastric acid secretion. Because gastrin is also a trophic hormone, chronic hypergastrinemia causes an absolute increase in the number of parietal cells, thus increasing gastric acid hypersecretion even more." Pancreatic volume and bicarbonate output are similarly increased by a combination of increased duodenal acid load and a direct trophic effect of gastrin on pancreatic acinar cells." The patient's response to the marked gastric acid hypersecretion is variable (see Fig. 82-1). Complications such as bleeding, perforation, and outlet obstruction may occur. Some patients with Z-E syndrome appear to have more than

745

746 - -

Endocrine Pancreas

EFFECTSOF HYPERGASTRINEMIA 1. gastric acid hypersecretion

2. parietal cell hyperplasia 3. pancreatic hypersecretion

~

PATIENTRESPONSE TO ACID-VARIABLE ~bleed

gastric } hypersecretion

/

ulceratlon _ perforate ............ obstruction / ' " hypokalemia

FIGURE 82-1. Pathophysiology of the ZollingerEllison syndrome and tumor locations. Gastrinomas may be (a) submucosal in duodenal wall; (b) pedunculated, arising from pancreatic surface; (c) in parapancreatic lymph nodes; (d) in pancreatic parenchyma; (e) liver metastases. (From Wilson S. Gastrinoma. In: Howard lM, Jordan GLJR, Reber HA reds], Surgical Diseases of the Pancreas. Philadelphia, Lea & Febiger, 1987.)

' " diarrhee _electrolyte imbalance ............ steetorrhea

Tumor locations

the usual duodenal and gastric mucosal resistance to peptic ulceration and initially may not experience peptic ulceration. In these patients, the combination of the increased gastric and pancreatic secretions may overwhelm the normal absorptive capacity of the intestine, and a watery "overflow" diarrhea may be the initial complaint." Erosive duodenitis and jejunitis can usually be documented in these patients by endoscopy." Seven diagnostic clues suggest the presence of a gastrinoma: 1. Diarrhea in a patient with peptic ulcer disease 2. Peptic ulcers persisting after therapy with H2 receptor antagonists or omeprazole 3. Recurrent ulcer after an adequate ulcer operation 4. Pathognomonic jejunal ulcers 5. Large gastric rugal folds, often associated with duodenitis, jejunitis, and rapid transit 6. Multiple atypical peptic ulcers 7. Marked gastric acid hypersecretion (>15 mEq/hour) Although these clues suggest the presence of a gastrinoma, the clinician should remember that most patients with Z-E syndrome present with signs and symptoms similar to those seen in patients with ordinary acid peptic ulcer disease. Most Z-E syndrome patients (approximately 70%) present with pain related to acid peptic disease. Cramping pains associated with diarrhea are not uncommon (20% to 30%), and in some patients (about 10%) diarrhea may be the only complaint. Symptoms have been present longer than a year in four of five patients. Gastric acid hypersecretion can produce a characteristic gastrointestinal radiologic picture (i.e., atypical ulcers, large gastric folds, rapid transit, and flocculation of barium); however, three of four patients exhibit ulceration in the usual duodenal ulcer locations.v-" Nearly one third of Z-E syndrome patients have had symptoms for 5 years before presenting to a physician, and four of five patients have radiologic findings of an ordinary duodenal ulcer. 34 ,35

Pathology Gastrinomas are composed of cells that resemble the G cells of the gastric antrum and duodenum." Variability in tumor histology, extrapancreatic sites, and multiplicity of lesions are characteristics of Z-E syndrome (see Fig, 82-1). Although first called pancreatic islet cell

tumors, many gastrinomas are located outside the pancreas, with sites in the duodenal wall, stomach, jejunum, peri pancreatic tissue, ovaries, and liver. In some series, fewer than 50% of Z-E syndrome patients have a histologically documented pancreatic primary tumor. The existence of primary (i.e., nonmetastatic) gastrinoma in a lymph node as a cause of Z-E syndrome is controversial, but numerous patients have been cured by removing one or more lymph nodes. 37-39 At least 60% of gastrinomas are malignant. Even tumors that appear histologically benign may be associated with metastases. I consider all gastrinomas to be potentially malignant neoplasms. However, gastrinomas may have an indolent course, and Z-E syndrome patients with proven lymph node metastases may live for several decades without apparent tumor progression.F'" The first gastrinomas were described as "noninsulinproducing islet-cell tumors" by Zollinger and Ellison because the tumors appeared to be islet cell lesions histologically, they produced a hormone, and conventional staining techniques indicated an absence of beta granules in the cytoplasm of the tumor cells. Islet cell tumor is a misnomer because these gastrin-producing neuroendocrine tumors probably do not develop from pancreatic islet cells directly. Current theory is that these tumors develop from pluripotential neuroendocrine stem cells located within the duct epithelium of the exocrine pancreas and gastrointestinal tract. 4 1,42 The morphologic appearance of gastrinomas is similar to that of carcinoid tumors and other neuroendocrine tumors of the pancreas. The arrangement of the tumor cells is variable; the common patterns are ribbon, rosette, follicular, and solid sheets of small, uniform, and usually well-differentiated cells separated by trabeculae. Distinction between a benign and a malignant tumor usually cannot be made on the basis of histology alone. 43,44 Immunohistochemical staining techniques, using specific antibodies, can identify gastrin granules within cytoplasm of the gastrinoma cells. Chromogranin A, neuron-specific enolase, and synaptophysin are proteins that can also be found in gastrinomas by these techniques, further characterizing these tumors as neuroendocrine in nature."

Gastrinoma - -

Etiology of Sporadic Gastrinoma Syndrome The etiology of the sporadic gastrinoma syndrome has not been defined, nor has a specific gene defect been identified. Studies by 1. Thompson's group were unable to document mutations of the p53 and ras genes in gastrinomas, but they did find amplification of HER-2/neu, a protooncogene related to the epidermal growth factor receptor." A gene defect has been localized to the long arm of chromosome 11 in patients with MEN 1, some of whom acquire gastrinomas, but patients with sporadic gastrinomas do not appear to have this defect." Chronic alcohol abuse may be an important risk factor in the genesis of some gastrinomas of the sporadic type. A history of excessive alcohol intake (>50 g/day) that antedated the Z-E syndrome in 23 of 36 (64%) sporadic gastrinoma patients admitted to our clinical research center could be documented over a 30-year period. Gastrinomas in the duodenal wall and in lymph nodes were a common finding in this group of patients, whereas primary pancreatic gastrinomas were rare. Death from progressive tumor growth has been infrequent. These observations suggest that the Z-E syndrome is not a single disease process but that several subgroups exist."

Evaluation of Patients: Suspected Zollinger-Ellison Syndrome The introduction of pharmacologic agents that inhibit gastric acid hypersecretion now allows the luxury of a safe and unhurried evaluation of patients, including diagnostic testing and tumor localization before an operation. Before the introduction ofthe H 2 receptor antagonists in 1978 and more recently the substituted benzimidazoles (omeprazole), most Z-E syndrome patients suffered complications of gastric acid hypersecretion before a surgeon was consulted. 18,49.50 Urgent operations, not planned elective procedures, were the norm." More problematic was the surgeon's inability to inhibit gastric acid hypersecretion after operating on a Z-E syndrome patient. Indeed, from 1955 to 1965, the decade after Zollinger and Ellison's historic presentation, nearly one half of deaths of Z-E syndrome patients occurred within 30 days after an operation, usually because the surgeon had not removed all of the gastrin-producing tumor or had not performed a TG.52 The hospital can still be a dangerous place for the gastrinoma patient. Great care should be taken to ensure that the excessive gastric acid secretion is shut down in patients during evaluation and testing periods. Before any tumor-localizing studies or operation, the following steps are recommendedv: 1. Document pharmacologic control of gastric acid hypersecretion. First, the dose of omeprazole required to reduce acid secretion adequately may vary from 20 to 120 mg/day and needs to be titrated to the individual.P Second, gastric acid secretion should be reduced to less than 5 mEq/hour during the hour preceding the

747

next dose.53 Third, a somatostatin analogue (octreotide) might be helpful to reduce acid secretion further in difficult cases during the perioperative period when intravenous infusion of H 2 antagonists is required.54-57 2. Document healing of peptic ulcers by endoscopy. The absence of symptoms does not indicate the adequacy of pharmacologic antisecretory control."

Diagnosis The diagnosis of Z-E syndrome is established by documenting gastric acid hypersecretion and hypergastrinemia. With rare exception, a basal acid output (BAO) greater than 15 mEq/ hour and a fasting serum gastrin greater than 500 pg/mL are diagnostic. There may be some overlap in the values of gastric acid output in a few patients with ordinary peptic ulcer disease and patients with gastrinoma, but when a fasting serum gastrin is measured, the diagnosis is generally clear." If the fasting serum gastrin is normal or in the equivocal range (100 to 500 pg/mL), a secretin injection test for gastrin response should identify the patients who harbor a gastrinoma.t? GASTRIC ANALYSIS

Marked gastric acid hypersecretion is the hallmark of the Z-E syndrome. The following gastric acid secretory criteria are characteristic:34.35.58.60.61 1. Nocturnal (12 hours) gastric acid secretion greater than 1000 mL and 100 mEq of hydrochloric acid 2. One-hour BAO greater than 15 mEq 3. BAO greater than 60% maximal acid output (MAO) (BAOIMAO ratio) 4. Basal acid concentration (BAC) greater than 60% of the maximal acid concentration (MAC) (BACIMAC ratio) A gastric analysis documents a BAO of greater than 15 mEq/ hour in nearly every Z-E syndrome patient, and more than 50% of Z-E patients have a BAO greater than 30 mEq/hour. The MAO and peak acid output (PAO) are also greater in Z-E syndrome patients because of an increase in parietal cells secondary to the trophic effect of gastrin. The MAO and PAO are indirect measurements of parietal cell mass. The BAOIMAO ratio is greater than 0.6 in most Z-E syndrome patients because hypergastrinemia is stimulating the parietal cells to near-maximal output.

Evaluation of Hypergastrinemia An understanding of gastrin physiology is necessary when evaluating a patient with hypergastrinemia. Gastrin is a peptide hormone, normally produced in the G cells of the antral mucosa. Gastrin release is stimulated by food in the stomach, and the amount of gastrin released is modulated by the surface pH of the antral mucosa. Gastrin (from the antrum) and acid (from the fundus) represent the positive and negative limbs of a feedback loop. When gastrin is released into the blood, the acid-producing parietal cells in the gastric fundus are stimulated to secrete more acid; the pH of the antral mucosal surface is lowered, and release of gastrin from the G cells is inhibited. This negative feedback loop modulating system maintains the serum gastrin in a normal physiologic range." Z-E syndrome patients harbor a gastrinoma, which produces

748 - - Endocrine Pancreas excess gastrin, causing gastric acid hypersecretion. These gastrinoma G cells are outside the negative feedback loop and are not "turned off" by the excess gastric acid, resulting in a chronic hypergastrinemic state. Serum gastrin concentrations can be precisely measured using RIA techniques.f Normal fasting serum gastrin averages between 10 and 150 pg/mL. Laboratories may use different assay methods, and normal values vary; interpretation of serum gastrin should take into account these differences. Hypergastrinemia can be caused by conditions other than the Z-E syndrome.35,48,53 A complete history and gastric analysis clarify the diagnosis in most situations (Table 82-1). Antral G-cell hyperfunction can cause hypergastrinemia and gastric acid hypersecretion. Antral G-cell hyperplasia and pseudo-Z-E are other terms used for this condition. BAO and serum gastrin are less than in gastrinoma patients, but there may be some overlap in values. Short bowel syndrome, gastric outlet obstruction, renal failure, and Helicobacter pylori gastritis can also be associated with an increase in serum gastrin. The clinical picture and a secretin provocative test rule out gastrinoma. A retained gastric antrum, after Billroth II gastrectomy, can mimic Z-E syndrome. The G cells in the retained antrum are not exposed to acid inhibition, so they release more gastrin than normal. A secretin provocative test distinguishes a patient with a retained antrum because gastrin release is not increased by intravenous secretin as observed in Z-E syndrome patients. Removal of the retained antrum returns the gastrin to normal and cures the ulcer disease in these patients. Patients with pernicious anemia or chronic gastritis have been referred to our institution with a diagnosis of Z-E syndrome because of an elevated serum gastrin, often greater than 1000 pg/mL. Because of the achlorhydria or hypochlorhydria inherent in these disorders, the usual acid inhibition of antral gastrin release is diminished or lost. Chronic atrophic gastritis and gastric ulcers can also be associated with an elevated serum gastrin by a similar mechanism. A patient with a vagotomy may have an increase in fasting serum gastrin, probably because of the loss of vagal and acid inhibition of antral gastrin production. Even if a gastric analysis cannot be obtained, an untreated gastric content pH greater than 3.5 rules out acid hypersecretion, and Z-E syndrome is excluded."

Provocative Diagnostic Tests Three provocativetests have been used to clarify the diagnosis of gastrinoma when the serum gastrin and gastric analysis are not definitive. The current recommendation is to use only the secretin injection test because of its simplicity, lack of side effects, and better discrimination. 1. Standardized test meal: A patient with duodenal ulcer or antral G-cell hyperplasia (pseudo-Z-E syndrome) may show an augmented gastrin response to a test meal, whereas the Z-E syndrome patient usually does not have a significant increase over basal gastrin. 62,63 2. Calcium infusion: Intravenous calcium is a stimulus for gastrin release from a gastrinoma as well as antral G cells. The Z-E patient usually has a more immediate and pronounced gastrin response than patients with other hypergastrinemic conditions. 14,64 3. Secretin injection test (Fig. 82-2): Intravenous secretin infusion produces a paradoxical increase in both serum gastrin and gastric acid secretion." This paradoxical response is unique to the Z-E syndrome patient. 59,66

Preoperative Tumor-Localizing Techniques Tumor-localizing techniques for gastrinoma have continued to evolve since Zollinger and Ellison's first report.' Their first two Z-E syndrome patients had only barium swallows, demonstrating mucosal changes in the stomach and small bowel related to excess acid. In Ellison's 1956 report, the first reported "series" of ulcerogenic tumor patients, no tumors were identified preoperatively by any imaging technique, and the concept of preoperative localizing was not even mentioned. Abdominal plain films and barium studies

500

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300

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FIGURE 82-2. Serum gastrin concentrations before and after the intravenous injection of secretin (2 Ulkg body weight). The test was performed before (circles) and after (triangles) resection of a 5-mrn submucosal duodenal wall gastrinoma from a patient with near-normal serum gastrin concentration.

Gastrinoma - - 749

are not helpful unless there is a large, bulky tumor or calcification in a pancreatic islet cell tumor. Sensitivities for preoperative gastrinoma-localizing modalities are given in Table 82-2. Practical steps for ordering preoperative localizing studies are listed in Table 82-3. Abdominal ultrasonography (US) has a low detection rate (20% to 25%) for gastrinomas but is relatively inexpensive and does not involve the risks associated with intravenous contrast material and radiation exposure that accompany computed tomography. Tumors smaller than I em are generally not detected, and only 15% of lesions I to 3 em in size are detected. Tumors larger than 3 em are usually seen. 67 Despite its poor sensitivity, US may improve the overall sensitivity for detecting a tumor if it is used in conjunction with other studies."

Computed tomography (CT) overshadowed abdominal angiography during the 1980s and became a popular gastrinoma-localizing technique. Early reports enthusiastically suggested that CT of the upper abdomen would detect nearly 70% of islet cell tumors found at laparotomy.'" However, even with the new-generation CT scanners and improved techniques, most modem studies indicate that CT identifies a gastrinoma in fewer than half of all Z-E patients." CT rarely detects tumors smaller than 1 em and finds less than 50% of 2-cm lesions. Preoperative CT has been important, however, to identify liver metastases. Two-phase helical CT scans abdominal organs in both the arterial and parenchymal phase after intravenous contrast. In a 1995 report, 9 of 11 islet cell tumors were identified (82% sensitivity), including a 4-mm gastrinorna.P This new technique could improve detection of gastrinomas. Magnetic resonance (MR) imaging has not demonstrated great sensitivity for localizing primary gastrinomas. Advantages of MR include the ability to obtain coronal and sagittal images and to identify liver metastases. A 1993 study from the National Institutes of Health (NIH) group that prospectively compared MR with US, CT, and angiography in 32 gastrinoma patients showed sensitivities of only 25%, 19%,28%, and 59%, respectively." However, for the 18 patients in the study with metastatic gastrinoma in the liver, MR imaging had a sensitivity of 83%, whereas the sensitivities of US, CT, and angiography were 50%, 56%, and 61%, respectively. The combination of MR, US, and CT was the same as MR alone. They concluded that MR is the imaging study of choice to assess metastatic pancreatic endocrine tumors in the liver. In contrast, the detection of primary tumors by MR imaging had not improved; therefore, they also recommended that angiography remain the study of choice for localizing primary tumors. MR imaging technology is improving, and, with reduced scanning times, image resolution may equal or exceed that of CT. Somatostatin receptor scintigraphy (SRS) is a new technique to localize gastrointestinal endocrine tumors. Because many of these tumors possess high-affinity somatostatin receptors, it is possible with the stable indium-Ill-labeled somatostatin analogue pentetreotide, which binds to these receptors, to detect somatostatin receptor-positive tumors scintigraphically. Several studies suggest that SRS is helpful in the preoperative localization of gastrointestinal endocrine tumors. n. 73 One study detected gastrinomas at a rate of 100% compared with 60% each for CT, MR, and percutaneous abdominal US.74 Endoscopic ultrasonography (EUS) has been shown to image the pancreas accurately and to be highly sensitive for small pancreatic adenocarcinomas." The University of Michigan group reported that EUS correctly identified and localized 7 of 10 insulinomas, all in the pancreas, but only 1 of 5 gastrinomas. Three "missed" gastrinomas, 3 to 6 mm, were found at operation in the duodenal wall. They concluded that a negative EUS study in Z-E syndrome patients excluded a pancreatic gastrinoma, indicating a small duodenal or extrapancreatic lesion." A subsequent prospective study from Paris showed that EUS alone localized gastrinomas in 41 % of 22 Z-E syndrome patients." Sensitivity of EUS was 50% for duodenal wall tumors (conventional endoscopy, 40%), 75% for pancreatic tumors (CT scan,

750 - - Endocrine Pancreas 25%), and 62.5% for tumoral lymph nodes (CT scan, 0%). They concluded that EUS should be considered as a firstchoice imaging technique for preoperative detection of gastrinomas, and, although small duodenal gastrinomas are still obviously difficult to detect, an accurate exploration of the pancreatic area was provided by this technique. Both the Michigan and Paris groups suggested that laparotomy could be performed in most Z-E syndrome patients after only two imaging studies: CT scan and EUS. Sensitivity of EUS is related not only to tumor size but also to the experience of the endoscopist and radiologist performing EUS. There is a learning curve, and 100 cases may be needed to become proficient. 76 Selective abdominal angiography was first used to detect a pancreatic islet cell tumor (an insulinoma) in 1963.78 The sensitivity of angiography in detecting gastrinoma has been considerably less than that for insulinoma, even with the new ancillary techniques that improve sensitivity, such as superselective vessel injection, magnification, and digital subtraction angiography. Selective angiography has proved to be the best imaging study to identify primary and metastatic gastrinoma compared with US, CT, and MRI.28 However, in this study, angiography rarely identified duodenal wall tumor or lymph node metastases. Portal venous sampling (PVS) is a fluoroscopically guided, percutaneous transhepatic catheterization procedure that obtains venous samples for gastrin from several different veins draining the pancreas or other areas of interest. Gradients in gastrin concentration "regionalize" the tumor locatiou.?? This test requires considerable expertise and has significant complications. PVS has now been replaced by the selective arterial secretin injection (SASI) test because the latter is more sensitive and patients experience fewer cornplications.s" The SASI test was developed by Imamura and colleagues to localize preoperatively gastrinomas that could not be seen by conventional imaging techniques." The principle of the SASI test is based on the observation that secretin injection induces a prompt release of gastrin from gastrinoma cells. 65 An arterial catheter is selectively inserted into one of three peripancreatic arteries: gastroduodenal, superior mesenteric, or splenic artery. The gastroduodenal artery feeds the upper half of the pancreatic head and upper duodenum. The splenic artery supplies the body and tail of the pancreas. The superior mesenteric artery feeds the lower half of the pancreatic head and the lower duodenum. A second catheter is placed in the right hepatic vein to collect venous samples for gastrin. Secretin is injected into the selected artery, and the hepatic venous blood samples are collected for gastrin measurement before and then 20, 40, 60, 90, and 120 seconds after each secretin injection. Gastrin concentration in the hepatic vein samples obtained after secretin injection into the selected artery supplying the area of duodenum or pancreas containing the gastrinoma peaks earlier and higher than when injected into an artery feeding an area without gastrinoma (Fig. 82-3). In a report by Imamura and Takahashi, the SASI test localized gastrinomas in 12 of 12 Z-E syndrome patients studied, whereas CT and transhepatic PVS had a positive predictability of less than 10%. Selective arteriography identified tumors in only 5 of 12 patients.P"?

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FIGURE 82-3. Results of selective arterial secretin injection test in a patient with Zollinger-Ellison syndrome with a gastrinoma in the second portion of duodenum. The chart shows hepatic vein serum gastrin concentrations after arterial secretin injection (25 U) into three different arteries supplying the pancreas and duodenum. A positive gradient occurred 20 seconds after injection into the superior mesenteric artery (SMA). This vessel supplies the blood to the second portion of the duodenum through the inferior pancreaticoduodenal arteries.

Medical Management versus Operation Optimum treatment recommendations for patients with Z-E syndrome have undergone continuing change during the 40 years since Zollinger and Ellison reported on their first two patients, both of whom required a TG to control the complications of recurring peptic ulcer disease. These changes in Z-E syndrome management have come with a better understanding of the natural history and pathophysiology of Z-E syndrome, the RIA for gastrin, new imaging technologies that preoperatively and intraoperatively localize gastrinomas, and, perhaps most important, new drugs that inhibit gastric acid secretion."

Medical Management Inhibition of gastric acid secretion in many Z-E syndrome patients was made possible with the introduction of the H2 receptor antagonist cimetidine." Previously, TG had been necessary to achieve long-term survival of patients with Z-E syndrome. After cimetidine became available in 1977, some argued for medical management alone, claiming that the mortality for TG was inordinately high and finding and removing all gastrinoma tissue were unlikely.'" However, there were failures of medical management and antiandrogen side effects at high cimetidine doses (>4.8 g/day), such as breast tenderness, gynecomastia, and impotence in men, which continued to fuel the controversy. Some surgeons still favored TG when not all tumor could be removed." The introduction of two new H2 blockers, ranitidine and famotidine, which inhibited gastric acid secretion more effectively and did not have antiandrogen side effects, made medical therapy even more attractive.

Gastrinoma - - 751 Then another important advance in medical therapy came with the advent of a new class of antisecretory drugs: the substituted benzimidazoles (omeprazolej.tv" The mechanism of action of these drugs is different from that of the Hz receptor antagonists in that they bind to a unique enzyme responsible for acid secretion at the apical (luminal) aspect of the gastric parietal cell: the hydrogen-potassium adenosine triphosphatase proton pump enzyme. In most Z-E syndrome patients, gastric acid hypersecretion can be treated effectively with a once-daily dose of omeprazole, although about 10% to 25% of patients require a dose every 12 hours. 50,53 Tachyphylaxis does not occur, and the dose can be decreased over time in some patients. The Z-E syndrome patient must continue to take omeprazole indefinitely unless cured surgically. Repeated gastroduodenal endoscopy is necessary to evaluate the dose of anti secretory medication adequately.P>' There has been concern that long-term complete acid inhibition with achlorhydria might increase the risk of gastric carcinoids because these tumors can be so induced in rats." However, studies report that in Z-E syndrome patients there is no increase in occurrence of gastric carcinoids as a result of omeprazole." Omeprazole is now the drug of choice for long-term antisecretory therapy in Z-E syndrome patients because of its potency, long duration of action, and ease of use. Long-term prospective studies of antisecretory therapy for the Z-E syndrome by the group at the NIH outline the most effective methods to control gastric acid hypersecretion.v-"

Operative Management: Sporadic Gastrinoma Laparotomy is now recommended for most patients with evidence of gastrinoma (sporadic type) to define the extent of disease and then to achieve curative resection when possible. The rationale for this approach is based on several factors. First, although gastrinomas may have histologic characteristics that appear benign, most have malignant potential, and, although frequently indolent in nature, these tumors can grow, metastasize, and cause death. Second, using improved preoperative imaging modalities and aggressive exploratory techniques to find the tumor, modem studies suggest that 20% to 50% of Z-E syndrome patients may be cured by early exploration and excision of the gastrinoma.F''" Early laparotomy and tumor extirpation, even with incomplete excision of all gastrinoma tissue, appears to alter favorably the natural history of this syndrome. 96.98

Operative Management: Familial Gastrinoma Controversy continues among Z-E watchers regarding the advisability of early operation for the MEN I patient with hypergastrinemia. Most MEN 1 patients present with primary hyperparathyroidism before there is evidence of a gastrinoma, and it is agreed that parathyroidectomy should be performed before a laparotomy to explore for gastrinoma because gastric acid hypersecretion and serum gastrin are often reduced when parathyroidectomy returns serum calcium to normal. The controversy centers on the question of whether to explore the young, asymptomatic, hypergastrinemic

MEN I patient (acid secretion controlled) early or to wait until a gastrinoma can be seen on an imaging study,zz.99 Surgeons from Ohio State University, NIH, Mayo Clinic, and Paris reported few, if any, cures after exploration for gastrinoma in MEN I patients. Z6,Z7,lOO,101 A cure is defined by the return of serum gastrin to normal after removing one or more gastrinomas. Gastrinomas in MEN I patients are invariably multiple and usually not large enough to be localized preoperatively, so one is less likely to find and remove all gastrinoma tissue than when one is operating for gastrinoma of the sporadic type. IOZ.103 For these reasons, some authorities recommend antisecretory therapy without surgery for the patient with familial gastrinoma unless tumor can be identified on localizing studies. Z7,IOO,lOl,l04 However, Thompson's group at the University of Michigan suggested that some MEN 1 patients with gastrinomas can be cured if PVS is used to regionalize the location of the gastrinomas. ZZ,79,99 The NIH group't" also used the preoperative PVS technique but failed to cure any patient even though each patient had an islet cell tumor removed from the exact area of the pancreas implicated by PVS. This topic of familial gastrinoma in the MEN I syndrome is discussed in more detail in Chapter 76.

Intraoperative Steps to Find the Gastrinoma Gastrinomas may be single or multiple and are often duodenal and extrapancreatic. Frequently, the only gastrinoma found is in paraduodenal-pancreatic lymph nodes, without a primary site identified.P-" Gastrinomas in the duodenal wall may be submucosal and smaller than 5 mm 95,106,107 (Figs. 82-4 and 82-5). Several intraoperative maneuvers to find gastrinomas have been recommended for three decades 35,48,108: 1. Perform a thorough abdominal exploration, including search for tumor in the liver. 2. Open the lesser sac, inspect, and perform bimanual palpation of the body and tail of the pancreas. 3. Perform a Kocher maneuver with inspection and palpation of the head of the pancreas; tumor nodes are frequently found behind the uncinate portion of the pancreas. 4. Look for small duodenal wall, submucosal tumors. Palpation and inspection through a duodenotomy may be necessary.

5. Multiple lymph node biopsies, with emphasis on excision of paraduodenal and pancreatic capsule "nodules," are most important. Histologic examination of several dozen lymph nodes and suspicious duodenal wall nodes is often necessary to obtain a tissue diagnosis. 6. Do not terminate the search after finding a single positive node because numerous patients have been "cured" only after removing several lymph nodes. The routine use of duodenotomy as well as the newer innovations of intraoperative US and endoscopic transillumination to search for duodenal wall tumors has resulted in the detection of a gastrinoma in more than 90% of patients explored.Tv'"

752 - - Endocrine Pancreas

FIGURE 82-4. Intraoperative maneuvers to search for gastrinomas. Endoscopy with transillumination, duodenotomy, and palpation for duodenal wall tumors increase the surgeon's chances to find tumor. Intraoperative ultrasonography of the mobilized pancreas helps to find pancreatic body and tail lesions.

A review of the pathology reports from "failed" Z-E syndrome operations (i.e., those in which a gastrinoma was not found) usually shows that few biopsy specimens were taken by the surgeon.'? The greater the number of lymph nodes examined, the more likely it is that gastrinomas will be found. A search in the area of the "gastrinoma triangle" can be most rewarding. A gastrinoma can be found in 9 of 10 cases in this anatomic triangle, whose apices are the cystic duct-common bile duct junction, the border of the second and third portion of the duodenum, and the junction of the neck and body of the pancreas."

Operative Procedure of Choice: Sporadic Gastrinoma The choice of operation depends on the character and extent of the tumor identified by the surgeon. Ideally, all gastrinoma

FIGURE 82-5. Benign-appearing submucosal duodenal wall gastrinoma that was excised along with two adjacent lymph nodes containing metastases. Immunocytochemically, all three lesions stained positive for gastrin. The patient, now eugastrinemic, is presumably cured.

tissue should be removed to avoid the problems associated with tumor growth as well as the excess gastric acid. TG is rarely warranted now that gastric acid can be effectively inhibited. Tumor staging can predict the biologic behavior and long-term outcome, suggesting optimum operative strategies. 1. Duodenal wall tumor: The most common disease encountered by the surgeon during exploration of the Z-E syndrome patient in modem series has been duodenal wall tumors, often with metastatic gastrinoma in paraduodenal lymph nodes. The steps outlined in intraoperative maneuvers should be carefully followed. 2. Lymph nodes contain tumor and no apparent primary tumor found: The surgeon should remove as many lymph nodes as possible and search for primary and liver metastases. Excision of only one or more lymph nodes containing tumor has resulted in cure. 3. Liver metastases: Diffuse liver metastases indicate that complete tumor excision is unlikely, and lifelong antisecretory therapy is required. Single liver lesions should be excised because cures have been reported, even when a primary was not found. 4. Pancreatic tumors: Gastrinomas in the body and tail are best managed by distal pancreatectomy. Some wellencapsulated lesions might be enucleated; however, distal pancreatectomy is preferred because of the concept that gastrinomas originating in the pancreas to the left (splenic side) of the mesenteric vessels have a more aggressive biologic behavior. 110 Pancreatic head gastrinomas can be enucleated in some patients. For large pancreatic head tumors not amenable to enucleation, pancreaticoduodenectomy is favored by some authorities.92.94.111 Pancreaticoduodenectomy is usually not advisable when not all gastrinoma tissue can be excised. 5. Other extrapancreatic gastrinomas: Gastrinomas have been reported in the ovary, stomach wall, small bowel wall, omentum, and bowel mesentery, usually in lymph nodes. Excision may cure or improve longterm survival.

Gastrinoma - - 753 6. Total gastrectomy: In special situations, TG may still be the operation of choice. Z-E syndrome patients who are noncompliant, do not take their omeprazole, and have recurrent ulcer complications might benefit from TG.

Assessment of Cure and Follow-up Several reports suggest that at least one half of all Z-E syndrome patients explored, with the expectation to extirpate tumor and cure, continue to have hypergastrinemia postoperatively.84,96 Typically, a small duodenal gastrinoma or lymph node containing tumor has been excised, but an elevated serum gastrin level indicates that more tumor remains. A follow-up plan is needed for such patients. Should such a patient be re-explored or monitored? Should re-exploration be done only when localizing studies indicate the site of tumor? A prospective study by the NIH group to assess and predict long-term cure in Z-E syndrome patients provides insight into these questions.l'? Eighty-one consecutive Z-E syndrome patients who had undergone surgical exploration for gastrinoma resection were studied. Fasting gastrin and secretin provocative tests were the first to become positive in patients with recurrence, whereas the calcium provocative test and imaging studies were less sensitive. Fifty-two percent of the patients were disease free immediately after surgery, 44% at 3 to 6 months, 42% at I year, and the number of "cured" patients was down to 35% by 5 years. This careful study indicates that in some Z-E syndrome patients who have a normal serum gastrin level immediately postoperatively and who appear to have been cured, hypergastrinemia recurs with time, indicating recurrent tumor. After removal of a gastrinoma, I recommend a serum gastrin measurement before the patient is discharged from the hospital and then at 3-month intervals for the first year. Hypergastrinemia indicates residual gastrinoma tissue. A normal gastrin level may indicate a surgical cure, but a positive secretin provocative test for gastrin response unmasks some patients who still harbor gastrinomas. A secretin provocative test should be performed 3 months postoperatively and then annually for all normogastrinemic patients who have undergone "curative" gastrinoma resection. Patients previously operated on for gastrinoma but with progression of hypergastrinemia should also be evaluated periodically to search for a gastrinoma that might be amenable to curative excision because these tumors can grow and cause death. A CT scan and selective abdominal angiography might be done at 1- to 2-year intervals in selected patients. I have successfully excised a large extrapancreatic gastrinoma from a Z-E syndrome patient who presented with a new abdominal mass and a serum gastrin level of 1.5 million pg/mL 20 years after a TG. At the first operation, a duodenal wall gastrinoma was removed along with a TG, which was done to control bleeding ulcers, The patient was in good health during the 20 years since her TG until the discovery of an abdominal mass. After successful removal of the gastrinoma, the patient's serum gastrin and secretin provocative tests have been normal for 5 years. This case illustrates that some Z-E syndrome patients may

be cured by an operation, many years after incomplete tumor excision. Lifelong follow-up is required.

Follow-up of Zollinger-Ellison Syndrome Patients with Total Gastrectomy Although TG is now done infrequently, there are numerous living patients who have had TG. Some may have had gastrinomas removed at the time of TG, but many still have hypergastrinemia and residual tumor. Although these patients are no longer at risk for complications of excess gastric acid, they still need periodic evaluation to assess for tumor progression as well as nutrition-related problems. Evaluation of patients is recommended at 6-month intervals. Vitamin B 12 injections are given monthly, and most patients can administer their B 12 injections at home. Folic acid, calcium, and iron supplements are advisable. Many Z-E syndrome patients are noncompliant, particularly when there is a history of alcohol abuse/" TG also places the patient at risk for cholelithiasis. Nearly all Z-E syndrome patients who have undergone TG acquire gallstones if they live long enough.J':' I recommend that cholecystectomy be done at the time of TG.33

Treatment of Metastatic Gastrinoma Appropriate treatment for unresectable metastatic gastrinoma is not well defined, although there is general agreement about certain groups of Z-E syndrome patients with metastatic disease. For example, Z-E syndrome patients who have a duodenal wall tumor and a positive lymph node excised at operation and who still have hypergastrinemia postoperatively most certainly have metastatic disease remaining. However, there is no evidence that chemotherapy is indicated for these patients. In fact, survival in this group of Z-E syndrome patients is not significantly different from survival in patients who are rendered eugastrinemic and presumably cured after a similar operation. Survival is greater than 90% at 10 years. 93.98,114 On the other end of the spectrum is the group of Z-E syndrome patients who present with liver metastases; they have only a 20% 5-year survival rate. 37,93 Chemotherapy is not recommended for the Z-E syndrome patient with metastatic disease confined to regional lymph nodes but is reserved for the patient with metastatic disease in the liver or more distal sites. Tumor response to chemotherapy regimens varies from 6% to 69%.115 The combination of streptozocin and doxorubicin appears to be more effective than streptozocin and 5-fluorouracil or chlorozotocin alone (69% response versus 45% and 30%, respectively) in terms of decreasing tumor size and also in terms of survival.!" Cytoreductive surgery for functioning unresectable gastrinoma may be helpful in selected cases. ll7,118 Treatment with interferon has been disappointing. I 19 Somatostatin analogues decrease metastatic pancreatic endocrine tumor size in about 10% of cases,54,55 but their usefulness for controlling tumor growth and prolonging survival is unproved.F? Hepatic artery embolization, with or without chemotherapy, has been tried in selected patients. Hepatic transplantation

754 - - Endocrine Pancreas has also been carried out in a few Z-E syndrome patients, but improved survival has not been documented.!" The reader is referred to Chapter 88 for detailed information regarding chemotherapy.

Staging A staging system has been proposed by Ellison 114 to develop predictive survival curves. Analysis of Z-E syndrome patients diagnosed at Ohio State University during a 40-year period indicated three determinants of survival: primary tumor size, presence of liver metastases, and complete resection of tumor. Factors with no effect on survival were age at diagnosis, sex, presence of lymph node metastases, and associated MEN. The expected lO-year survival for resected stage I tumors (primary < 2 em, no liver metastases) was 94% to 96%; stage II (primary> 2 em, no liver metastases), 86% to 91%; and stage III (liver metastases), 65% to 90%. When tumor was not resected, survival for stage I was 68% to 82%; stage II, 40% to 55%; and stage III, 7% to 50%. A report by the NIH group analyzing 185 consecutive Z-E syndrome patients who were observed prospectively showed that survival was determined primarily by the presence of liver metastases at the time of admission." Liver metastases correlated with the size of the primary tumor and occurred more often with pancreatic than duodenal tumors. The lO-year survival rate was not significantly different between patients with gastrinoma found only in lymph nodes and patients with duodenal gastrinomas (100% and 94%, respectively); however, both groups had significantly better survival than the 59% survival rate of all patients with pancreatic gastrinomas. This report supports the concept that there are two distinct clinical forms of gastrinoma: benign and malignant.!"

Summary Gastrinomas may be sporadic or familial and solitary or multiple. A gastrinoma should be considered in patients with (1) peptic ulcer disease and diarrhea, (2) persistent peptic ulcer disease despite treatment with H2 receptor antagonists or omeprazole, (3) recurrent ulcers after peptic ulcer surgery, (4) marked gastric hypersecretion (~15 mEq/L) , (5) multiple or jejunal ulcers, and (6) large gastric surgical folds. The diagnosis is established by documenting hypergastrinemia in patients with gastric hypersecretion and by a paradoxical rise in response to intravenous secretion. Laparotomy is indicated for virtually all patients with sporadic gastrinoma, whereas controversy exists regarding the surgical management of patients with familial disease. Tumor size, liver metastases, and resectability influence long-term survival.

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2. EIlison EH. The ulcerogenic tumor of the pancreas. Surgery 1956;40: 147. 3. Eiseman B, Maynard RM. A non-insulin producing islet cell adenoma associated with progressive peptic ulceration. Gastroenterology 1956;31:296. 4. Wilson SO. Multiple endocrine adenopathy type I (MEA-I): Wermer's syndrome. In: Friesen SR, Thompson NW (eds), Surgical Endocrinology. Clinical Syndrome. Philadelphia, JB Lippincott, 1990, p 339. 5. Wermer P. Genetic aspects of adenomatosis of endocrine glands. Am J Med 1954;16:363. 6. Welbourn RE. Multiple endocrine adenopathy and paraendocrine syndromes. In: Welbourn RB (ed), The History of Endocrine Surgery. New York, Praeger, 1990, p 269. 7. Oberhelman HA Jr, Nelsen TS, Johnson AN Jr, et al. Ulcerogenic tumors of the duodenum. Ann Surg 1961;153:214. 8. Oberhelman HA Jr. Excisional therapy for ulcerogenic tumors of the duodenum: Long-term results. Arch Surg 1972;104:447. 9. Gregory RA, Grossman MI, Tracy HJ, et al. Nature of the gastric secretagogue in Zollinger-Ellison tumors. Lancet 1967;2:543. 10. Friesen SR, Tracy JH. Mechanism of the gastric hypersecretion in the Z-E syndrome: Successful extraction of gastrin-like activity from metastatic and primary pancreaticoduodenal islet cell carcinoma. Ann Surg 1962;155:167. II. Friesen SR. A gastric factor in the pathogenesis of the Zollinger-Ellison syndrome. Ann Surg 1968;168:483. 12. Wilson SO. Z-E tumor registry (available from Medical College of Wisconsin, 9200 W Wisconsin Avenue, Milwaukee, WI 53226). 13. McGuigan JE, Trudeau WL. Immunochemical measurement of elevated levels of gastrin in the serum of patients with pancreatic tumors of the Zollinger-EIlison variety. N Engl J Med 1968;278:1308. 14. Passaro E Jr, Basso N, Walsh JH. Calcium challenge in the ZollingerEIlison syndrome. Surgery 1972;72:60. 15. Passaro E Jr, Stabile BE, Howard TJ. Contributions of the ZoIlingerEllison syndrome. Am J Surg 1991;161:203. 16. Deveney CW, Deveney KS, Way LW. The Zollinger-Ellison syndrome-23 years later. Ann Surg 1978;188:384. 17. Deveney CW, Deveney KS, Stark 0, et al. Resection of gastrinomas. Ann Surg 1983;198:546. 18. McCarthy OM. Report on the United States experience with cimetidine in the Zollinger-Ellison syndrome and other hypersecretory states. Gastroenterology 1978;74:453. 19. Bonfils S, Mignon M, Gratton J. Cimetidine treatment of acute and chronic Zollinger-EIlison syndrome. World J Surg 1979;3:597. 20. Bonfils S, Landor JH, Mignon M, et al. Results of surgical management in 92 consecutive patients with Zollinger-EIlison syndrome. Ann Surg 1981;194:692. 21. Thompson JC, Lewis BG, Wiener I, et al. The role of surgery in the Zollinger-EIlison syndrome. Ann Surg 1983;197:594. 22. Thompson NW, Bondeson AG, Bondeson L, et al. The surgical management of gastrinoma in MEN I syndrome patients. Surgery 1989;106:1O8l. 23. Stabile BE, Morrow OJ, Passaro E. The gastrinoma triangle: Operative implications. Am J Surg 1984;147:25. 24. Lamers CBHW. Gastrinoma in multiple endocrine neoplasia type I. Acta OncoI1991;30:489. 25. Mignon M, Benhamou G. Which diagnostic test and therapeutic approach to the Zollinger-Ellison syndrome should be adopted in 1990? Acta Chir Belg 1991;91:88. 26. Mignon M, Ruszniewski P, Podevin P, et al. Current approach to the management of gastrinoma and insulinoma in adults with multiple endocrine neoplasia type l. World J Surg 1993;17:489. 27. Van Heerden JA, Smith SL, Miller U. Management of the ZollingerEIlison syndrome in patients with multiple endocrine neoplasia type I. Surgery 1986;100:97l. 28. Norton JA. Neuroendocrine tumors of the pancreas and duodenum. In: Wells SA Jr (ed), Current Problems in Surgery. St. Louis, CV Mosby, 1994, p 77. 29. ZoIlinger RM, Coleman OW. The Influence of Pancreatic Tumors on the Stomach. Springfield, Ill, Charles C Thomas, 1974. 30. Polacek MA, Ellison EH. Parietal cell mass and gastric acid secretion in the Zollinger-Ellison syndrome. Surgery 1966;60:606. 31. Dreiling DA, Greenstein A. Pancreatic function in patients with Zollinger-Ellison syndrome: Observations concerning acid-bicarbonate secretion ratios. Am J Gastroenterol 1972;58:66.

Gastrinoma - - 755 32. Soergel KH. Mechanism of diarrhea in the Zollinger-Ellison syndrome. In: Demling L, Ottenjan R (eds), Non-Insulin Producing Tumors of the Pancreas. Stuttgart, Georg Thieme Verlag, 1969, p 152. 33. Raufman JP, Collins SM, Pandol SJ, et al. Reliability of symptoms in assessing control of gastric acid secretion in patients in ZollingerEllison syndrome. Gastroenterology 1983;84:108. 34. Ellison EH, Wilson SD. The Zollinger-Ellison syndrome: Reappraisal and evaluation of 260 registered cases. Ann Surg 1964;160:512. 35. Wilson SD. Ulcerogenic tumors of the pancreas: The Zollinger-Ellison syndrome. In: Carey LC (ed), The Pancreas. SI. Louis, CV Mosby, 1973, P 295. 36. McGuigan JE, Greider MH. Correlative immunochemical and light microscopic studies of the gastrin cell of the antral mucosa. Gastroenterology 1971;60:223. 37. Fox PS, Hofmann JW, Decosse JJ, et al. The influence of total gastrectomy on survival in malignant Zollinger-Ellison tumors. Ann Surg 1974;180:558. 38. Arnold WS, Fraker DL, Alexander HR, et al. Apparent lymph node primary gastrinoma. Surgery 1994;116:1123. 39. Perrier ND, Batts KP, Thompson GB, et al. An immunohistochemical survey for neuroendocrine cells in regional pancreatic lymph nodes: A plausible explanation for primary nodal gastrinomas? Surgery 1995; 118:957. 40. Wilson SD. Zollinger-Ellison syndrome in children: A 25-year follow up. Surgery 1991;110:696. 41. Andrews A. Gut and pancreatic amine precursor uptake and decarboxylation cells are not neural crest derivatives. Gastroenterology 1983;84:429. 42. Kloppel G, Heitz PU. Pancreatic endocrine tumors. Pathol Res Pract 1988;183:155. 43. Creutzfeldt W, Arnold R, Creutzfeldt C, et al. Pathomorphologic, biochemical and diagnostic aspects of gastrinomas (Zollinger-Ellison syndrome). Hum PathoI1975;6:47. 44. Solcia E, Capella C, Buffa R, et al: Pathology of the Zollinger-Ellison syndrome. In: Fenoglio CM, Wolf M (eds), Progress in Surgical Pathology, Vol 1. New York, Masson, 1980, p 119. 45. Metz DC. Diagnosis and treatment of pancreatic neuroendocrine tumors. Semin Gastrointest Dis 1995;6:67. 46. Evers BM, Rady PL, Sandoval K, et al. Gastrinomas demonstrate amplification of the HER-2/neu proto-oncogene. Ann Surg 1994; 219:596. 47. Larsson C, Skogseid B, Oberg K, et al. Multiple endocrine neoplasia type 1 maps to chromosome II and is lost in insulinoma. Nature 1988; 332:85. 48. Wilson SD. Gastrinoma (Zollinger-Ellison syndrome, ulcerogenic tumor of the pancreas). In: Howard JM, Jordan GL Jr, Reber HA (eds), Surgical Diseases of the Pancreas. Philadelphia, Lea & Febiger, 1987, P 829. 49. Metz DC, Strader DB, Orbuch M, et al. Use of omeprazole in Zollinger-Ellison: A prospective nine-year study of efficacy and safety. Aliment Pharmacol Ther 1993;7:597. 50. Metz DC, Pisegna JR, Fishbeyn VA, et al. Control of gastric acid hypersecretion in the management of patients with Zollinger-Ellison syndrome. World J Surg 1993;17:468. 51. Ellison EH, Wilson SD. ZoE syndrome updated. Surg Clin North Am 1967;47:1115. 52. Wilson SD, Ellison EH. Survival in patients with the Zollinger-Ellison syndrome treated by total gastrectomy. Arn J Surg 1966;111:787. 53. Hirschowitz BI. Pathobiology and management of hypergastrinemia and the Zollinger-Ellison syndrome. Yale J Bioi Med 1992;65:659. 54. Maton PN, Frucht H, Vinayek R, et al. Medical management of patients with Zollinger-Ellison syndrome who have had previous gastric surgery: A prospective study. Gastroenterology 1988;94:294. 55. Maton PN. Octreotide acetate and islet cell tumors. Med Clin North Am 1989;18:897. 56. Maton PN, Gardner JD, Jensen RT. Use of the long-acting somatostatin analogue SMS201-995 in patients with pancreatic islet cell tumors. Dig Dis Sci 1989;34(SuppI3):28S. 57. Mozell E, Woltering EA, O'Dorisio TM, et al. Effect of somatostatin analog on peptide release and tumor growth in the Zollinger-Ellison syndrome. Surg Gynecol Obstet 1990;170:476. 58. Collen MJ, Jensen RT. Idiopathic gastric acid hypersecretion: Comparison with Zollinger-Ellison syndrome. Dig Dis Sci 1994;39:1434.

59. McGuigan JE, Wolfe MM. Secretin injection test in the diagnosis of gastrinoma. Gastroenterology 1980;79: 1324. 60. Aoyagi T, Summerskill WHl Gastric secretion with ulcerogenic islet cell tumor. Arch Intern Med 1966;117:667. 61. Malagelada JR, Davis CS, O'Fallon WM, et al. Laboratory diagnosis of gastrinoma. Mayo Clin Proc 1982;57:211. 62. Berson SA, Yalow RS: Progress in gastroenterology: Radioimmunoassay in gastroenterology. Gastroenterology 1972; 62:1061. 63. Friesen SR, Tomita T. Pseudo-Zollinger-Ellison syndrome: Hypergastrinemia, hyperchlorhydria without tumor. Ann Surg 1981;194:481. 64. Basso N, Passaro E Jr. Calcium-stimulated gastric secretion in the Zollinger-Ellison syndrome. Arch Surg 1970;101:399. 65. Isenberg Jl, Walsh JH, Passaro E, et al. Unusual effect of secretin on serum gastrin, serum calcium, and gastric acid secretion in a patient with suspected Zollinger-Ellison syndrome. Gastroenterology 1972;62:626. 66. Frucht H, Howard JM, Siaff Jl, et al. Secretin and calcium provocative test in the Zollinger-Ellison syndrome: A prospective study. Ann Intern Med 1989;9:713. 67. London JF, Shawker TH, Doppman JL, et al. Zollinger-Ellison syndrome: Prospective assessment of abdominal US in the localization of gastrinomas. Radiology 1991;178:763. 68. Orbuch M, Doppman JL, Jensen RT. Localization of pancreatic endocrine tumors. Semin Gastrointest Dis 1995;6:90. 69. Stark DD, Moss AA, Goldberg Hl, et al. CT of pancreatic islet-cell tumors. Radiology 1984;150:491. 70. Van Hoe L, Gryspeerdt S, Marchal G, et al. Helical CT for the preoperative localization of islet cell tumors of the pancreas: Value of arterial and parenchymal phase images. AJR Am J Roentgenol 1995;165:1437. 71. Pisegna JR, Doppman JL, Norton JA, et al. Prospective comparative study of ability of MR imaging and other imaging modalities to localize tumors in patients with the Zollinger-Ellison syndrome. Dig Dis Sci 1993;38: 1318. 72. Weinel RJ, Neuhaus C, Stopp J, et al. Preoperative localization of gastrointestinal endocrine tumors using somatostatin-receptor scintigraphy. Ann Surg 1993;218:640. 73. Schirmer WJ, Melvin WS, Rush RM, et al. Indium-Ill-pentetreotide scanning versus conventional imaging techniques for the localization of gastrinoma. Surgery 1995; II 8:1105. 74. Lamberts SWJ, Chayvialle JA, Krenning EP. The visualization of gastroenteropancreatic endocrine tumors. Digestion 1993;54:92. 75. Rosch T, Lorenz R, Braig C, et al. Endoscopic ultrasound in pancreatic tumor diagnosis. Gastrointest Endosc 1991;37:347. 76. Thompson NW, Czako PF, Fritts LL, et al. Role of endoscopic ultrasonography in the localization of insulinomas and gastrinomas. Surgery 1994;116:113. 77. Ruszniewski P, Amouyal P, Amouyal G, et al. Localization of gastrinomas by endoscopic ultrasonography in patients with the Zollinger-Ellison syndrome. Surgery 1995;117:629. 78. Olsson O. Angiographic diagnosis of an islet-cell tumor of the pancreas. Acta Chir Scand 1963;126:346. 79. Vinik A, Moattari R, Cho K, et al. Transhepatic portal venous catheterization for localization for sporadic and MEN gastrinomas. Surgery 1990;107:240. 80. Thorn AK, Norton JA, Doppman JL, et al. Prospective study of the use of intra-arterial secretin injection and portal venous sampling to localize duodenal gastrinomas. Surgery 1992;112:1002. 81. Imamura M, Takahashi K. Adachi H, et aI. Usefulness of selective arterial secretin injection test for localization of gastrinoma in the ZollingerEllison syndrome. Ann Surg 1987;205:230. 82. Imamura M, Takahashi K. Use of selective arterial secretin injection test to guide surgery in patients with Zollinger-Ellison syndrome. World J Surg 1993;17:433. 83. Jensen RT, Gardner JD. Gastrinoma. In: Go VLW, DiMagno EP, Gardner JD, et al (eds), The Pancreas: Biology, Pathobiology and Diseases, 2nd ed. New York, Raven Press, 1993, p 931. 84. Norton JA, Doppman JL, Collen MJ. Prospective study of gastrinoma localization and resection in patients with Zollinger-Ellison syndrome. Surgery 1986;204:468. 85. Wise SR, Johnson J, Sparks J, et al. Gastrinoma: The predictive value of preoperative localization. Surgery 1989;106:1087.

756 - - Endocrine Pancreas 86. Roche A, Raisonnier A, Gillon-Savouret MC. Pancreatic venous sampling and arteriography in localizing insulinomas and gastrinomas: Procedure and results in 55 cases. Radiology 1982;145:621. 87. Cherner JA, Doppman JL, Norton JA, et al. Prospective assessment of selective venous sampling for gastrin to localize gastrinomas. Ann Intern Med 1986;105:841. 88. Landor J. The Zollinger Ellison syndrome. In: Landor J (ed), Problems in General Surgery. Philadelphia, JB Lippincott, 1990, p489. 89. McCarthy DM. The place of surgery in the Zollinger-Ellison syndrome. N Engl J Med 1980;302:1844. 90. Frucht H, Maton PN, Jensen RT. Use of omeprazole in patients with the Zollinger-Ellison syndrome. Dig Dis Sci 1991;36:394. 91. Hakanson R, Sundler F. Mechanisms for the development of gastric carcinoids. Digestion 1986;35(Suppl 1): 1. 92. Howard TJ, Zinner MJ, Stabile BE, et al. Gastrinoma excision for cure: A prospective analysis. Ann Surg 1990;211:9. 93. Norton JA, Doppman JL, Jensen RT. Curative resection in ZollingerEllison syndrome: Results of a 10 year prospective study. Ann Surg 1992;215:8. 94. Stadil F, Bardram L, Gustafsen J, et aI. Surgical treatment of the Zollinger-Ellison syndrome. World J Surg 1993;17:46. 95. Thompson NW, Vinik AI, Eckhauser FE. Microgastrinomas of the duodenum. Ann Surg 1989;209:396. 96. Fraker DL, Norton JA, Alexander HR, et al. Surgery in ZollingerEllison syndrome alters the natural history of gastrinoma. Ann Surg 1994;220:320. 97. Ellison EC. Forty-year appraisal of gastrinoma. Ann Surg 1995;222:511. 98. Weber HC, Venzon DJ, Lin IT, et al. Determinates of metastatic rate and survival in patients with Zollinger-Ellison syndrome: A prospective long-term study. Gastroenterology 1995;108:1637. 99. Thompson NW. Surgical treatment of the endocrine pancreas and Zollinger-Ellison syndrome in the MEN-l syndrome. Henry Ford Hosp Med J 1992;40: 19j. 100. Melvin WS, Johnson JA, Sparks J, et al. Long term prognosis of Zollinger-Ellison syndrome in multiple endocrine neoplasia. Surgery 1993;114:1183. 101. MacFarlane MP, Fraker DL, Alexander HR, et al. Prospective study of surgical resection of duodenal and pancreatic gastrinomas in multiple endocrine neoplasia type 1. Surgery 1995;118:973. 102. Pipeleers-Marichal M, Somers G, Willems G, et aI. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type I and the Zollinger-Ellison syndrome. N Engl J Med 1990;322:723. 103. Ruszniewski P, Poderin P, Cadiot G, et aI. Clinical, anatomical and evolutive features of patients with the Zollinger-Ellison syndrome combined with type I multiple endocrine neoplasia. Pancreas 1993;8:295.

104. Norton JA, Jensen RT. Unresolved surgical issues in the management of patients with the Zollinger-Ellison syndrome. World J Surg 1991;15:151. 105. Sheppard BC, Norton JA, Doppman JL, et aI. Management of islet cell tumors in patients with multiple endocrine neoplasia. Surgery 1989;106:1108. 106. Hofmann JW, Fox PS, Wilson SD. Duodenal wall tumors and the Zollinger-Ellison syndrome. Arch Surg 1973;107:334. 107. Thorn AK, Norton JA, Axiotis CA, et aI. Location, incidence and malignant potential of duodenal gastrinomas. Surgery 1991;110:1086. 108. Ellison EH, Wilson SD. Ulcerogenic tumor of the pancreas. In: Ariel 1M (ed), Progress in Clinical Cancer. New York, Grone & Stratton, 1966, p 225. 109. Sugg SL, Norton JA, Fraker DL, et al. A prospective study of intraoperative methods to diagnose and resect duodenal gastrinomas. Ann Surg 1993;218:138. 110. Howard TJ, Zinner MJ, Stabile BE, et al. Gastrinoma excision for cure. Ann Surg 1990;211:9. 111. Delcore R, Hermeck AS, Friesen SR. Selective surgical management of correctable hypergastrinemia. Surgery 1989;106: 1094. 112. Fishbeyn VA, Norton JA, Benya RV,et al. Assessment and prediction of long-term cure in patients with the Zollinger-Ellison syndrome: The best approach. Ann Intern Med 1993;119:199. 113. Catty RP, Wilson SD. Cholelithiasis follows total gastrectomy in Zollinger-Ellison. Surgery 1989;106: 1070. 114. Ellison EC. Forty-year appraisal of gastrinoma. Ann Surg 1995;222:511. 115. Gibril F, Doppman JL, Jensen RT. Recent advances in the treatment of metastatic pancreatic endocrine tumors. Semin Gastrointest Dis 1995;6:114. 116. Moertel CG, Lefkoponlo M, Lipsitz S, et al. Streptozotocin-doxorubicin, streptozotocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992;326:563. 117. Carty SE, Jensen RT, Norton JA. Prospective study of aggressive resection of metastatic pancreatic endocrine tumors. Surgery 1992; 112:1024. 118. Nagorney DM, Que FG. Cytoreductive hepatic surgery for metastatic gastrointestinal neuroendocrine tumors. In: Mignon M, Jensen RT (eds), Frontiers in Gastrointestinal Research. Basel, Karger, 1995, p 416. 119. Pisegna JR, Slimak GG, Doppman JL, et aI. An evaluation of human recombinant alpha interferon in patients with metastatic gastrinoma. Gastroenterology 1993;105:1179. 120. Arnold R, Neuhaus C, Benning R, et al. Somatostatin analogue sandostatin and inhibition of tumor growth in patients with metastatic endocrine gastroenteropancreatic tumors. World J Surg 1993;17:511. 121. Stabile BE, Passaro E Jr. Benign and malignant gastrinoma. Am J Surg 1985;49:144.

Multiple Endocrine Neoplasia Type 2B Craig A. Miller, MD • E. Christopher Ellison, MD

Multiple endocrine neoplasia (MEN) includes three distinct clinical entities characterized by patterns of hyperplastic, adenomatous, or neoplastic change arising in functionally and anatomically discrete endocrine tissues. MEN 1 and 2A are discussed elsewhere in this text. MEN 2B is the focus of the present chapter. Attention is directed at the pathogenesis, clinical presentation, and surgical treatment of the manifestations of this syndrome. MEN 2A and 2B are characterized by the presence of medullary thyroid carcinoma and pheochromocytomas. MEN 2B, however, is also distinguished by a characteristic phenotype consisting of multiple mucosal neuromas and a distinctive marfanoid body habitus. Skeletal and ophthalmic abnormalities as well as multiple gastrointestinal ganglioneuromas may also be present. Parathyroid hyperplasia, a common finding in MEN 2A, is not a feature of MEN2B. MEN 2B is generally the most virulent of the MEN syndromes; the natural history of the disease is dominated by the clinical course of an aggressive species of medullary thyroid carcinoma. MEN 2B may arise de novo sporadically or, more commonly, as a genetically transmitted syndrome of autosomal dominant inheritance. Studies have begun to elucidate the genetic derangements underlying the pathogenesis of this complex disorder.

Historical Considerations Most endocrine tumors are solitary, occurring in single organs without concomitant disease in other endocrine tissues. The first known report of neoplasia arising in multiple endocrine organs in the same individual appeared in 1903, when Erdheim described an acromegalic patient noted on autopsy to have tumors of both the pituitary and parathyroid glands. I Thereafter, only similar sporadic reports of multiple

endocrine tumors appeared in the literature until 1954, when Wermer first described a familial clustering of anterior pituitary, parathyroid, and pancreatic islet cell neoplasia, which he termed endocrine adenomatosis? This report, which described the pattern of endocrine tumors now known as MEN 1, established the existence of heritable endocrine tumor syndromes. The presence of other related multiple endocrine adenomatoses became apparent over the next several years. In 1959, medullary thyroid carcinoma was defined as a histopathologically distinct tumor (characterized, unlike other thyroid tumors, by the presence of stromal amyloid) by Hazard and associates.' Subsequent studies in the 1960s demonstrated the cell of origin of this tumor to be the thyroid parafollicular C cell, the source of calcitonin. In 1961, Sipple" described an association between thyroid carcinoma and pheochromocytoma, a concordance further defined 4 years later when Williams 5 and Schimke and colleagues" noted that the involved thyroid tumor was medullary carcinoma. In 1968, Steiner and coworkers 7 coined the term MEN 2, to describe the familial association of medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. The authors also suggested that the syndrome described by Wermer be termed MEN 1. In 1966, Williams and Pollack reported two patients with concurrent medullary thyroid carcinoma, pheochromocytomas, and mucosal neuromas of the mouth and eyes, describing an apparent variant of von Recklinghausen's disease.! In 1968, both Gorlin.? Schimke.!? and their colleagues subsequently defined this pattern as a distinct clinicopathologic syndrome of endocrine disease, and in a 1975 review of medullary carcinoma of the thyroid, Chong and coworkers!' applied the term MEN 2B to the syndrome, which emphasized both the similarities and differences between this and the other more common MEN syndromes.

757

758 - - Endocrine Pancreas

Pathogenesis The patterns of organ involvement and familial clustering of the MEN syndromes suggest an autosomal dominant mode of inherited transmission in each, with essentially complete penetrance but a varying degree of expression. In the 1960s, the observation that both thyroid parafollicular C cells (the cells of origin of medullary thyroid carcinoma) and cells of the adrenal medulla (which give rise to pheochromocytomas) derive from the embryonic neural crest and are of the amine precursor uptake and decarboxylation (APUD) variety of neuroendocrine cells led to speculation that a single defect in development of tissues of this origin and nature might underlie the disease. Although attractive at first glance, this hypothesis was understood to be oversimplified in that it failed to adequately account for both the clinicopathologic differences between the MEN syndromes and, in particular, the derangements found in these diseases among cells not possessing APUD characteristics and tissues not derived from the neural crest (e.g., the parathyroid hyperplasia of MEN 2A). Nevertheless, the two syndromes were clearly variations on a common theme of genetic endocrine derangement. In the late 1980s, several DNA concordance studies definitively mapped the inherited defects of the MEN 2 syndromes (as well as a familial variant of medullary thyroid carcinoma) to the pericentromeric region of chromosome 10.12, 13 Further work in the early 1990s making use of the advancing DNA technology has shed considerable light on the specific genetic alterations underlying the different phenotypes of these related but distinct diseases. The ret protooncogene is a segment of the human genome on chromosome 10 that encodes a specific cell surface receptor complex. This receptor, homologous to the well-characterized epidermal growth factor receptor, possesses a large extracellular domain, a single membrane-spanning segment, and an intracellular tyrosine kinase domain putatively involved in signal transduction. Receptors of this kind are believed to play a significant role in the regulation of cell growth and differentiation. The specific ligand and physiologic function of this receptor are, however, unknown. It has been demonstrated that mutations in the segment of the ret proto-oncogene coding for the extracellular domain of the receptor protein are responsible for producing the MEN 2A phenotype as well as sporadic and familial cases of medullary thyroid carcinoma. Studies by Hofstra, 14 Carlson," and their colleagues, in which they used single-strand polymorphism analysis to examine the DNA from MEN 2B patients, have clearly shown that a single point mutation in the segment of ret encoding the intracellular tyrosine kinase catalytic domain of the protein product is responsible for MEN 2B (Figs. 83-1 and 83-2). This mutation, which alters ret codon 918 from ATG to ACG and thus results in a substitution of threonine for methionine in the receptor catalytic segment, was found in both inherited and sporadic cases of the syndrome. In addition, the mutation was noted in the genetic material of all MEN 2B patients examined. It remains for further study to elucidate the mechanism by which this specific mutation affects ligand binding or, more likely, signal transduction to produce the MEN 2B phenotype. Recent studies have characterized gene expression induced by RET with MEN 2A or 2B mutation. Watanabe and

N= GTT AAA TGG ATG GCA ATT Val Lys Trp Met Ala lie 918 M= GTT AAA TGG ACG GCA An Thr FIGURE 83-1. The point mutation in the tyrosine kinase domain ret protooncogene, which gives rise to the multiple endocrine neoplasia (MEN) 2B phenotype, DNA sequence analysis of polymerase chain reaction amplification products from genomic DNA of unaffected parents (unshaded square and circle) and daughter with MEN 2B (half-shaded circle) from family-coded GK-7. DNA and corresponding amino acid sequences appear beneath the sequencing ladders, Both parents possess the normal sequence (ATG coding for methionine) for each allele, whereas the daughter has one normal and mutant allele, the mutation being a C for a T substitution at position 918 (asterisk). This produces the codon ACG, which replaces methionine with threonine. (From Carlson K, Dou S, Chi D, et al. Single missense mutation in the tyrosine kinase catalytic domain of the ret proto-oncogene is associated with multiple endocrine neoplasia type 2B, Proc Nat! Sci USA 1994;91:1579.)

coworkers identified 10 genes induced by RET-MEN 2 or RET-MEN 2B mutant proteins." The inducible genes included cyclin D1, cathepsins Band L, and coflin-all known to be involved with cell growth tumor progression and invasion. The repressed genes included type I collagen, lysyl oxidase, annexin I, and tissue inhibitor of matrix metalloproteinase 3-all known to be implicated in tumor suppression. The fact that MEN 2A and 2B arise from separate mutations affecting different domains of a single receptor may also help explain the observed similarities and differences between these entities. Moreover, the observation that the ret protooncogene is expressed in the progenitors of parathyroid cells may provide an explanation for the alterations found in the MEN 2A phenotype among these cells, which are neither of the APUD type nor derived from the neural crest.

Clinical and Pathologic Characteristics Although it may arise sporadically, MEN 2B more frequently occurs as a familial disorder inherited in an autosomal dominant fashion. MEN 2B is less common than MEN 2A.

Multiple Endocrine Neoplasia Type 2B - -

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FIGURE 83-2. A diagram of the ret protooncogene demonstrating both highly conserved elements and sites of mutation known to be responsible for sporadic and familial medullary thyroid carcinoma (MTC) as well as the multiple endocrine neoplasia (MEN) 2 syndromes. Vertical bars within the diagram indicate sites of cysteine codons. Cysteine codon mutations in the juxtamembrane extracellular domain (609, 611, 618, 620, 634) are responsible for familial MTC as well as the MEN 2A syndrome. Mutation at 630 (underlined) gives rise to sporadic MTC. Segments 1 to 4 in the tyrosine kinase domain represent highly conserved elements, whereas asterisks denote possible sites for tyrosine autophosphorylation. The substitution of threonine for methionine in position 918 produces the MEN 2B phenotype. LB = ligand-binding segment; TM = transmembrane domain; TK = tyrosine kinase; CT = carboxyterminus; ATP = site of adenosine triphosphate binding. (From Carlson K, Dou S, Chi D, et al. Single missense mutation in the tyrosine kinase catalytic domain of the ret proto-oncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Sci USA 1994;91:1580.)

For example, a multicenter study by Modigliani and associates identified 300 MEN 2 patients with pheochromocytoma. There were only 26 (<10%) with MEN 2BP Significantly, disease that arises de novo is also subsequently transmitted to descendant generations in an autosomal dominant fashion." Penetrance is believed to be nearly 100%, but expressivity is variable. As a result, all the manifestations of the syndrome may not be present in a given afflicted patient. Whereas medullary thyroid cancer, mucosal neuromas, and a marfanoid habitus are essentially universal among MEN 2B patients, pheochromocytoma is found in only about one half. 19 The sexes are apparently affected equally.P Families in which the diagnosis of MEN 2B has been made seldom persist beyond a few generations, owing to the aggressive nature of the neoplasia involved.

Although found most frequently in the gastrointestinal tract, the neuromas of MEN 2B may be present in any organ possessing a submucosa, including the bronchi and urinary bladder. These neuromas have been described as hamartomatous proliferations of Schwann cells, nerve fibers, and, less frequently, ganglion cells." When present in the gut, they predispose the patient to significant gastrointestinal symptoms, especially constipation or diarrhea, which may constitute the presenting complaint.

Neuromas and Habitus The outstanding clinical features of MEN 2B comprise the near-pathognomonic physical appearance (Figs. 83-3 and 83-4). Patients afflicted with this syndrome possess a tall, slender, "marfanoid" habitus with varying degrees of muscle wasting. The face is generally elongated; neuromas cause enlarged and nodular lips as well as thickened eyelids. Slit-lamp examination may reveal thickening of corneal nerves. Skeletal abnormalities are also characteristic and may include genu valgum, pes cavus, and kyphoscoliosis. Significantly, these characteristic physical features are often recognizable in infancy or even at birth, affording the careful clinician the opportunity to diagnose the disorder before the thyroid and adrenal neoplasia have become clinically manifest.

FIGURE 83-3. Ganglioneuromatosis of the lips and tongue in a patient afflicted with multiple endocrine neoplasm 2B. Note the thickened lips as well as multiple submucosal nodules. (From Dodd G. The radiologic features of multiple endocrine neoplasia types 2A and 2B. Semin Roentgenol1985;20:79.)

760 - - Endocrine Pancreas

FIGURE 83-4. Marfanoid habitus of a patient with multiple

endocrine neoplasia 2B. Note the disproportionately long limbs, muscle wasting, and joint deformities. (FromDodd G. The radiologic features of multiple endocrine neoplasia types 2A and 2B. SeminRoentgenol 1985;20:81.)

Medullary Thyroid Carcinoma Medullary carcinoma of the thyroid, a tumor of the calcitoninproducing parafollicular C cells, is an invariable feature of MEN 2B. If early diagnosis based on phenotype is not made, this tumor is generally the ftrst abnormality discovered. Classically, the clinical course of this tumor in the context of MEN 2B has been characterized as being more virulent than when it appears in MEN 2A or in an isolated form, with a more ominous metastatic potential. This perception, however, is evolving. Studies have suggested that the natural histories of these tumors in MEN 2A and 2B may, in fact, be comparable. The major difference appears to be that medullary thyroid cancer develops in MEN 2B at a signiftcantly earlier age (in one study, diagnosis of medullary thyroid carcinoma in MEN 2B occurred at a mean age of 22 years vs. a mean age of 38 years in MEN 2A).22 However, a review of the German Medullary Thyroid Carcinoma Registry demonstrated a signiftcantly decreased survival rate in patients with this disease in the context of MEN 2B in comparison to those with the tumor in MEN 2A (survival rates in patients with sporadic medullary thyroid cancer were similar to those in MEN 2B patients) (see Fig. 83-6).23 A measure of the aggressive nature of this neoplasm in MEN 2B may be derived from a review of the syndrome in which 100% of symptomatic patients had metastases at the time of surgery.-" Medullary thyroid carcinoma in MEN 2A and 2B is almost invariably bilateral and multicentric and is preceded by a focal or diffuse proliferation of parafollicular calcitoninproducing cells termed C-cell hyperplasia. By contrast, sporadically arising medullary thyroid cancer is typically unilateral and, classically, is not preceded by a premalignant proliferation. Therefore, bilateral disease, multicentricity,

and presence of C-cell hyperplasia have all been considered to be evidence for familial rather than de novo disease. However, several authors have described the presence of C-cell hyperplasia in nonhereditary medullary thyroid cancer as well as benign thyroid disease and, moreover, its absence in medullary cancer in the setting of known MEN 2A, suggesting that the identiftcation of this pathologic entity may be of less value than previously thought. 25,26 In fact, aside from the suggestive evidence of multicentricity and bilaterality, there are no microscopic differences between sporadically arising and hereditary medullary thyroid cancer that can be detected by histopathologic means at this time. Medullary thyroid cancer is typically found in the superior portion of the gland, where the greatest concentration of C cells exists. The tumor presents clinically as a thyroid mass or nodule, most often noted incidentally on physical examination, which may appear unilateral or bilateral to palpation. Fine-needle aspiration biopsy may provide cytologic evidence of the disease, which is subject to conftrmation by immunocytochemical staining for calcitonin. The gross pathologic appearance is of whitish brown, wellcircumscribed nodules. Microscopically, the lesion appears as nests of polygonal or round, uniform cells surrounded by a ftbrous and vascular stroma in which material with the staining properties of amyloid frequently resides (Fig. 83-5). This material consists of a calcitonin prohormone secreted by the tumor cells. The tumor cells of medullary thyroid carcinoma actively secrete a number of peptide hormone products. Foremost is calcitonin, the serum level of which is markedly increased in the presence of the tumor. Levels of calcitonin greater than 1000 pg/mL in the presence of elevated carcinoembryonic antigen are said to be diagnostic of the disease, and persistently elevated calcitonin after surgical resection suggests residual or recurrent tumor.F Provocative tests in which

FIGURE 83-5. The microscopic appearance of medullary thyroid carcinoma. Compressed nestsof smallround and polygonal tumor C cells amid stromal amyloid. Normal follicles are seen peripherally. (FromDodd G. The radiologic features of multiple endocrine neoplasia types 2A and 2B. Semin Roentgenol 1985;20:81.)

Multiple Endocrine Neoplasia Type 2B - -

pentagastrin (either alone or in combination with calcium) is injected to stimulate calcitonin release (analogous to the secretin stimulation test in gastrinoma diagnosis) have also been advocated. Elevations of calcitonin higher than 300 pg/mL on provocation are considered diagnostic of C-cell hyperplasia or medullary thyroid cancer," Other peptides elaborated by the medullary thyroid cancer cells include calcitonin gene-related peptide, somatostatin, corticotropin, and chromogranin A.29 Paraneoplastic syndromes (particularly Cushing's syndrome from excessive corticotropin) occur but are unusual. Diarrhea, presumably from an unidentified humoral source, arises in approximately 30% of patients with this tumor and is amenable to conservative therapy. The most distinctive feature of medullary carcinoma of the thyroid in the setting of MEN 2B is the ominous potential for early metastases. These appear first in the regional cervical or mediastinal lymph nodes, with distant metastases arising later in the lung, liver, and bone, Patients presenting with advanced local disease may manifest hoarseness or dysphagia, whereas distant metastases may be suggested by symptoms referable to the systems involved. Relatively little controversy attends the question of the preferred method of treating medullary thyroid cancer. Because this tumor is not responsive to present conventional chemotherapeutic or radiologic treatment regimens, surgical therapy is the only option. Most authorities recommend total thyroidectomy once the diagnosis has been made, whether this diagnosis is based on clinical evidence or biochemical screening tests. Imaging studies are of little use because localization of the tumor within the thyroid is of academic interest only. Advocacy of total thyroidectomy is particularly sensible in the case of MEN 2B in light of the understanding that medullary thyroid cancer is frequently bilateral as well as unusually aggressive in the setting of this syndrome. Central neck compartment lymph nodes should be dissected in all patients in an effort to achieve local control of disease. Thyroid replacement therapy must, of course, be initiated in the postoperative period. Data from the German Medullary Thyroid Carcinoma Registry indicate a 5-year (after diagnosis) survival rate of 82.5% in MEN 2B patients (Fig. 83-6). By 10 years after diagnosis, the survival rate decreased to 66.0%.23The major prognostic factor in this study appeared to be tumor stage at diagnosis. Previous reports have noted improved survival in patients whose thyroid tumors were detected by biochemical means over those first diagnosed on the basis of clinical grounds.P

Pheochromocytoma Pheochromocytoma arises in approximately 50% of individuals with MEN 2B. The predisposition of pheochromocytoma in MEN 2 may be related to mutations in glial cell line-derived neurotrophic factor (GDNF). Some studies suggest that allelic variation at the GDNF locus may modify the susceptibility to pheochromocytoma." Although its histologic appearance in this familial setting is indistinguishable from that of the sporadically occurring tumor, bilateral involvement (which is unusual in de novo disease) occurs in more than half of MEN 2B patients.F These tumors are rarely the initial presenting feature of MEN 2B; their presence is

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months FIGURE 83-6. Comparison of survival rates between medullary thyroid carcinoma (MTC) patients in whom the disease arose in the absence of other endocrine neoplasias, as part of the multiple endocrine neoplasia (MEN) 2A syndrome, and as part of the MEN 2B syndrome. Data from 741 cases are entered in the German Medullary Thyroid Carcinoma Registry. (From Raue F, FrankRaue K, Grauer A. Multiple endocrine neoplasia type 2: Clinical features and screening. Endocrinol Metab Clin North Am 1994;23:137.)

most often detected either after the existence of medullary thyroid carcinoma has been established or concurrently with the diagnosis of thyroid involvement, when suspicion of MEN 2B has been aroused. A multicenter center by Modigliani and colleagues showed pheochromocytoma presented first in 25% of 300 cases (274 MEN 2A and 26 MEN 2B) after medullary thyroid cancer diagnosis in 40% and in a synchronous manner in 35%. Hyperplasia of the adrenal medulla precedes pheochromocytoma in MEN 2A and 2B. This hyperplasia is analogous to the C-cell hyperplasia that precedes medullary thyroid cancer in these patients. As in the thyroid disease in MEN 2, a spectrum of adrenal involvement may be encountered, including nodular or diffuse hyperplasia, multiple small pheochromocytomas, and thickening of the entire adrenal medulla. Most pheochromocytomas in this syndrome are benign. As with the sporadic form, pheochromocytoma in MEN 2B may be either asymptomatic or associated with varying degrees of symptomatology referable to the catecholamines produced by these tumors. Symptoms include episodic diaphoresis, headaches, anxiety, and palpitations. Hypertension may be present and may be minimal or marked. The definitive diagnosis of pheochromocytoma may be made via biochemical means (e.g., elevated amounts of urinary catecholamines), abdominal computed tomographic (CT) or magnetic resonance imaging (MRI) scans, or metaiodobenzylguanidine (MIBG) scintigraphy. In MEN 2B, diagnosis of pheochromocytoma should be followed by exploration and excision of the affected tissue. Bilateral disease requires bilateral adrenalectomy. Controversy has arisen, however, over the proper surgical treatment of unilateral pheochromocytoma in this setting. Some authorities maintain that bilateral adrenalectomy is indicated owing to the likelihood of eventual contralateral involvement. Others, however, have proposed that unilateral

762 - - Endocrine Pancreas excision with close follow-up is sufficient. Proponents of the latter view note that this approach avoids both lifelong glucocorticoid-mineralocorticoid replacement therapy and the persistent risk of addisonian crisis. If both medullary thyroid cancer and pheochromocytoma exist concurrently, adrenalectomy must be performed first followed by thyroidectomy. This order must be observed to avoid the potential of intraoperative hypertensive crisis during thyroid resection, and it underscores the importance of screening for pheochromocytoma when MEN is suspected.

Screening and Diagnosis Screening for MEN 2B should be reserved for a few welldefined populations: (1) family members of known MEN 2B patients, (2) patients newly diagnosed with medullary thyroid carcinoma or pheochromocytoma, and (3) individuals exhibiting the characteristic phenotype of marfanoid habitus and mucosal neuromas. Screening is mandatory in these patients to maximize the opportunity to perform curative thyroidectomy or adrenalectomy, or both, before metastasis of the endocrine tumors. Screening of family members of affected individuals should consist of biochemical tests of thyroid C cell and adrenal medullary function as well as imaging studies where indicated. A 1991 consensus statement of the European Community Concerted Action: Medullary Thyroid Carcinoma group recommended annual basal and pentagastrin- or calcium-provoked serum calcitonin determinations in this group of patients, beginning at age 3 years and continuing until age 35 years, after which the frequency could be decreased owing to greatly diminished yield.P The criteria for diagnosis on the basis of serum calcitonin elevation were discussed previously. Confusion may be noted in attempts to diagnose medullary thyroid carcinoma biochemically in children because serum calcitonin levels could be high in the young in the absence of disease.l" Currently, individuals suspected of MEN 2B are tested for zet mutation; if they have the zet mutation, prophylactic total thyroidectomy is recommended.v-" To detect pheochromocytomas, annual assays of urinary catecholamines and catecholamine metabolites (epinephrine, norepinephrine, vanillylmandelic acid, and metanephrines) are also recommended. Some authors advocate annual or semiannual abdominal imaging studies, including MIBG, because these may detect pheochromocytomas before elevation of urinary catecholamines. However, the wisdom of repetitive dosing with ionizing radiation or radioiodinated compounds has been called into question, especially in light of the generally benign course of these tumors in MEN 2B. For screening purposes, MRI may be preferable. With identification of the genetic defect responsible for MEN 2B, in the future it is likely that these biochemical, radiologic, and nuclear screening tests will be reserved for those individuals known to possess the mutant allele. As noted, the characteristic facies and habitus of these patients may be present from birth. In this setting, in the absence of a family history, the phenotype may provide a clue to the presence of the disorder before the tumors become clinically manifest, allowing definitive surgical

therapy to be performed with excellent potential for cure. Thus, children with multiple mucosal neuromas should also undergo biochemical screening. These individuals may also be tested for the presence of the MEN 2B ret mutation and treated appropriately. If, in de novo disease, the presence of neuromas is not appreciated or the phenotype is incompletely expressed and thus unremarkable, MEN 2B usually presents as a thyroid mass incidentally identified on physical examination. Histopathologic examination of tissue obtained by fineneedle aspiration biopsy then identifies the disease process through appreciation of the characteristic tissue architecture and amyloid as well as positive tumor cell staining for calcitonin. The diagnosis of medullary thyroid carcinoma should alert the physician to the possible presence of MEN 2A or 2B and the potential for concurrent or metachronous appearance of pheochromocytoma or (in MEN 2A) parathyroid disease, or both. Appropriate screening for these entities should then proceed. Occasionally, the catecholamine-induced symptomatology of pheochromocytoma may constitute the presenting complaints in de novo MEN 2B. The presence of elevated urinary catecholamines or characteristic abnormalities on abdominal CT, MRI, or MIBG scans then confirms the presence of the tumor. The diagnosis of pheochromocytoma should always arouse suspicion of the presence of a multiple endocrine disease syndrome.

Summary MEN 2B is a syndrome in which the phenotype of a marfanoid body habitus with multiple mucosal neuromas is found in combination with medullary carcinoma of the thyroid and, frequently, pheochromocytomas. The syndrome may arise sporadically but is more often genetically transmitted in an autosomal dominant fashion. The genetic defect appears to be a single missense mutation in a segment of the ret protooncogene of chromosome 10. The ret protooncogene encodes for a cell surface receptor, the function of which is poorly characterized. The mutation found in MEN 2B lies in a segment of ret that codes for the intracellular tyrosine kinase domain of this receptor. Although the exact mechanism by which this mutation produces the MEN 2B phenotype is unknown, the receptor encoded by ret bears considerable structural resemblance to the epidermal growth factor receptor, which is involved in transduction of signals regulating cellular growth and differentiation. Other well-characterized mutations in ret give rise to the related MEN 2A syndrome. The marfanoid habitus and multiple mucosal neuromas present in MEN 2B produce a characteristic appearance and symptomatology among affected patients. Large, nodular lips, thickened eyelids, skeletal abnormalities, and constipation or diarrhea from gastrointestinal ganglioneuromas are common. These signs and symptoms may lead to diagnosis of MEN 2B in the first years of life. The clinical course of patients afflicted with MEN 2B is largely dependent on intervention in the natural history of the medullary thyroid carcinoma, which is invariably present. In individuals with a positive family history, screening for zet

Multiple Endocrine Neoplasia Type 2B - -

protooncogene mutation is indicated. If there is no family history, this cancer is most often found incidentally on physical examination. The species of this neoplasm found in MEN 2B is thought to be particularly aggressive, although this supposition has been called into question. The treatment is total thyroidectomy, with dissection of local lymph nodes. Patients who have not undergone thyroidectomy before metastasis of this tumor rarely survive beyond 40 years. Pheochromocytomas are found in approximately 50% of MEN 2B patients. They are generally bilateral and benign. Rarely the source of the presenting complaint, they may be clinically silent or frankly symptomatic. Bilateral adrenalectomy is advocated by many authorities when even unilateral involvement is established owing to the likelihood of contralateral disease.

REFERENCES 1. Erdheim J. Zur normalen und pathologischen Histologie der Glandula thyroidea, parathyroidea, und hypophysis. Beitr Pathol Anat Allg PathoI1903;33:158. 2. Wermer P. Genetic aspects of adenomatosis of endocrine glands. Am J Med 1954;16:363. 3. Hazard JB, Hawk WA, Crile G Jr. Medullary (solid) carcinoma of the thyroid: A clinico-pathologic entity. J Clin Endocrinol Metab 1959;19:152. 4. Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961;31:163. 5. Williams ED. A review of 17 cases of carcinoma of the thyroid and pheochromocytoma. J Clin PathoI1965;18:288. 6. Schimke RN, Hartmann WHo Familial amyloid-producing medullary thyroid carcinoma and pheochromocytoma: A distinct genetic entity. Ann Intern Med 1965;63:102. 7. Steiner AL, Goodman AD, Powers SR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism, and Cushing's disease: MUltiple endocrine neoplasia type 2. Medicine 1968;17:371. 8. Williams ED, Pollack DJ. Multiple mucosal neuromata with endocrine tumours: A syndrome allied to von Recklinghausen's disease. J Pathol BacterioI1966;19:114. 9. Gorlin RI, Sedano HO, Vickers RA, et aI. Multiple mucosal neuroma, pheochromocytoma, and medullary carcinoma of the thyroid: A syndrome. Cancer 1968;22:293. 10. Schimke RN, Hartmann WH, Prout TE, et al. Syndrome of bilateral pheochromocytoma, medullary thyroid carcinoma, and multiple neuromas. N Engl J Med 1968;279:1. 11. Chong GC, Beahrs OH, Sizemore GW, et al. Medullary carcinoma of the thyroid gland. Cancer 1975;35:695. 12. Mathew CGP, Chin KS, Easton DF, et aI. A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10. Nature 1987;328:527. 13. Simpson NE, Kidd KK, Goodfellow PN, et al. Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature 1987;328:528. 14. Hofstra RMW, Landsvater RM, Cecchirini I, et aI. A mutation in the RET protooncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994; 367:375. 15. Carlson K, Dou S, Chi D, et al, Single missense mutation in the tyrosine kinase catalytic domain of the ret protooncogene is associated

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28. 29. 30. 31. 32. 33. 34. 35. 36.

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with multiple endocrine neoplasia type 2B. Proc Nat! Acad Sci USA 1994;91:1579. Watanabe T, Ichihara M, Hashimota M, et aI. Characterization of gene expression induced by RET with MEN 2A or MEN 2B mutation. Am J PathoI2002;16:249. Modigliani E, Vasen HM, Raue K, et aI. Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. J Intern Med 1995;238:363. Jackson CE, Norum RA: Genetics of the multiple endocrine neoplasia type 2B syndrome. Henry Ford Hosp Med J 1992;40:3. Grun R, Eberle F. Multiple endocrine neoplasia, type II (MEN II). Ergeb Inn Med Kinderheilkd 1981;46:151. Khairi MRA, Dexter RN, Burzynski NJ, et aI. Mucosal neuroma, pheochromocytoma, and medullary thyroid carcinoma: Multiple endocrine neoplasia type 3. Medicine (Baltimore) 1975;54:85. Padberg BC, Holl K, Schroder S. Pathology of multiple endocrine neoplasias 2A and 2B: A review. Horm Res 1992;38(Suppl 2):24. Carney JA, Sizemore GW, Lovestedt SA. Mucosal ganglioneuromatosis, medullary thyroid carcinoma, and pheochromocytoma: Multiple endocrine neoplasia type 2B. Oral Surg 1976;41:739. Vasen HFA, van der Feltz M, Raue F, et al. The natural course of multiple endocrine neoplasia type lIb: A study of 18 cases. Arch Intern Med 1992;15:1250. Raue F, Kotzerke J, Reinwein D, et aI. Prognostic factors in medullary thyroid carcinoma: Evaluation of 741 patients from the German Medullary Thyroid Carcinoma Register. Clin Invest 1993;71:7. Ulbright TM, Kraus FT, O'Neal LW. C-cell hyperplasia developing in residual thyroid following resection of sporadic medullary carcinoma. Cancer 1981;48:2076. Rosenberg-Bourgin M, Gardet P, de Sahb R, et al. Comparison of sporadic and hereditary forms of medullary thyroid carcinoma. Henry Ford Hosp Med J 1989;37: 141. Tashjian AH, Howland BG, Melvin KEW, et al. Immunoassay of human calcitonin: Clinical measurement, relation to serum calcium, and studies in patients with medullary thyroid cancer. N Engl J Med 1970;283:890. Raue F, Frank-Raue K, Grauer A. Multiple endocrine neoplasia type 2: Clinical features and screening. Endocrinol Metab Clin North Am 1994;23:137. Nelkin BD, Ball DW, Baylin SB. Molecular abnormalities in tumors associated with multiple endocrine neoplasia type 2. Endocrinol Metab Clin NorthAm 1994;23:187. Wells SA Jr, Baylin SB, Gann SD, et al. Medullary thyroid carcinoma: Relationship of method of diagnosis to pathologic staging. Ann Surg 1978;188:377. Woodward ER, Eng C, McMahan R, et al. Genetic predisposition to phaeochromocytoma: Analysis of candidate genes GDNF, RET, and VHL. Hum Mol Genet 1997;6:1051. Evans DB, Lee JE, Merrell RC, et al. Adrenal medullary disease in multiple endocrine neoplasia type 2: Appropriate management. Endocrinol Metab Clin North Am 1994;23:167. Calmettes C, Ponder BAJ, Fischer JA, et aI. Early diagnosis of the multiple endocrine neoplasia type 2 syndrome: Consensus statement. Eur J Clin Invest 1992;22:755. Saaman NA, Draznin MB, Halpin RE, et aI. Multiple endocrine syndrome type lIb in early childhood. Cancer 1991;68: 1832. Leboulleux S, Travagli JP, Caillou B, et aI. Medullary thyroid carcinoma as part of a multiple endocrine neoplasia type 2B syndrome: Influence of the stage on the clinical course. Cancer 2002;94:44. Yip L, Cote OJ, Shapiro SE, et aI. MUltiple endocrine neoplasia type 2: Evaluation of the genotype-phenotype relationship. Arch Surg 2003;138:409.

Somatostatinoma and Rare Pancreatic Endocrine Tumors Jeffrey A. Norton, MD

General Comments The overall prevalence of functional pancreatic endocrine tumors is low, approximately I to 10 per million in the population. I,2 Gastrinoma and insulinoma are the most common functional neuroendocrine tumors and account for approximately 70% to 90% of all functional pancreatic neuroendocrine tumors.? Thus, somatostatinoma and other functional neuroendocrine tumors are rare, and no endocrine surgeon has vast experience with them. Patients with these rare tumors present with either a specific syndrome or symptoms related to the malignant nature of the tumor. Therefore, therapeutic strategies designed to treat these patients need to control the tumoral process and ameliorate the syndrome associated with it. Obviously, if the tumoral process can be completely controlled by surgical resection, the characteristic syndrome resolves. However, in many individuals with these rare tumors, the extent of the disease limits the effectiveness of surgery in completely controlling the tumor. For these patients, effective medical treatments for controlling symptoms may be available and must be considered. This chapter also describes the medical therapy that may be useful in preparing the patient for surgery or controlling symptoms in the long term.

Pathology Pancreatic endocrine tumors are commonly termed neuroendocrine tumors. However, some researchers indicate that it is unclear whether these tumors originate from the pancreatic islets.' Pancreatic endocrine tumors may contain ductular structures; may produce hormones that are not produced by the normal pancreas, including gastrin and vasoactive intestinal polypeptide (VIP); and may produce more than one hormone.t" These findings suggest that pancreatic endocrine tumors originate from dedifferentiation of an immature

764

pancreatic stem cell. 4 The finding of ductular structures in these tumors has led to the suggestion that these tumors are ductular in origin." Further, these tumors may appear to be papillary and cystic in structure." It has also been proposed that pancreatic endocrine tumors originate from cells that are part of the diffuse neuroendocrine system: amine precursor uptake and decarboxylation tumors (APUDomas).8-1O These tumor cells contain dense secretory granules, may produce multiple peptides, and usually stain positive for neuron-specificenolase, chromograninA, and synaptophysin.Vv! APUDomas comprise many neuroendocrine tumors, including carcinoids, medullary thyroid carcinoma, and pbeochromocytomas.s!" Microscopically, pancreatic endocrine tumors are composed of sheets of small, round cells with uniform nuclei and cytoplasm (Fig. 84-1). Mitotic figures are rare, and the precise determination of malignancy cannot be made on the basis of histologic appearance.S'? Studies suggest that there is an aggressive and a nonaggressive form of pancreatic neuroendocrine tumor. The aggressive form comprises glucagonoma, somatostatinoma, and most nonfunctional tumors. It is more common in patients without multiple endocrine neoplasia type I (MEN I). It is characterized by a short disease duration, large pancreatic tumors, liver metastases, and a long-term survival rate as low as 20% to 50%. This may also apply to liver metastases. Some liver neuroendocrine tumors demonstrate slow growth and progression, whereas others grow rapidly. Those with rapid growth are associated with decreased survival. Studies have shown a number of clinical and tumoral factors that are predictors of aggressive growth (Table 84-1). These include liver metastases, lymph node metastases, local invasion, large primary tumor size, nonfunctional tumor, and incomplete tumor resection. The further definition of other factors is likely to have a significant impact on the surgical management of pancreatic neuroendocrine tumors; that is, aggressive tumors will require more aggressive surgery.

Somatostatinoma and Rare Pancreatic Endocrine Tumors - -

FIGURE 84-1. Duodenal somatostatinoma. Sheets of uniformappearing, small, round cells with rare mitotic activity are present within this tumor, which occurs in the submucosal layer of the duodenum. This tumor stained positively for somatostatin by immunocytochemistry. It was detected by palpation of the duodenum at the time of cholecystectomy.

The molecular pathogenesis of pancreatic neuroendocrine tumors is just being elucidated and holds promise for the identification of important parameters. Studies have demonstrated that alterations in the tumor suppressor gene DPC4 located on 18q21 are involved in tumorigenesis.P Unfortunately, at present, no gene alteration sufficiently predicts aggressive behavior to allow a different, more aggressive treatment strategy to be implemented. Determination of malignancy is best made by either radiographic or surgical pathologic documentation of metastases to either regional lymph nodes or the liver.

765

Pancreatic endocrine tumors are classified according to the functional syndrome they produce (Table 84-2). Every type of pancreatic endocrine tumor may be associated with MEN 1, and it is important to recognize this association because these patients generally have multiple tumors and a more indolent natural history. 14 Several studies suggest that, in addition to MEN 1, pancreatic neuroendocrine tumors are found in higher frequency in patients with von Recklinghausen's disease, 15-17 von Hippel-Lindau disease," and tuberous sclerosis. 19 In patients with von Recklinghausen's disease, duodenal somatostatinoma and gastrinoma have been reported. 15-17 Of patients with von Hippel-Lindau disease, 17% had pancreatic endocrine tumors, including both adenomas and carcinomas. However, it is unusual for these tumors to be functional, and few patients have a clinical hormonal syndrome. Patients with tuberous sclerosis may have a higher incidence of insulinoma and nonfunctional pancreatic neuroendocrine tumors.

Multiple Endocrine Neoplasia Type 1 MEN 1 is a well-established inherited endocrine disorder characterized by parathyroid hyperplasia, pituitary adenoma, and pancreatic neuroendocrine tumors. Studies indicate that the genetic defect in patients with MEN 1 is localized to the long arm of chromosome 11 and linked to the skeletal muscle glycogen phosphorylase gene. 20 •21 Evidence from these studies suggests that the development of endocrine tumors in patients with MEN 1 conforms to Knudson's twohit model of neoplasm formation with an inherited mutation in one chromosome unmasked by a somatic deletion or mutation of the other normal chromosome, thereby removing the suppressor effects of the normal gene." In contrast, in sporadic patients with pancreatic neuroendocrine tumors,

766 - - Endocrine Pancreas tumors do not appear to develop by homozygous inactivation of the same gene." Furthermore, growth factors have been identified in the plasma of patients with MEN I. A circulating blood factor that was mitogenic for parathyroid cells in tissue culture has been identified.P and a subsequent study demonstrated that the factor was similar to fibroblast growth factor." In addition, patients with MEN 1 are susceptible to other tumors, including bronchial, thymic, and intestinal carcinoid tumors; thyroid adenomas; adrenal adenomas; and multiple lipomas. 14 Thus, the complete pathogenesis of the multiple endocrine tumors in MEN 1 patients is not completely understood. In patients with MEN I, primary hyperparathyroidism is the most common clinical condition, occurring in approximately 95% of individuals. 14 Functional pancreatic neuroendocrine tumors are the next most common condition, occurring in approximately 80% of patients." Finally, approximately 35% of individuals with MEN 1 develop a pituitary adenoma, most commonly a prolactinoma.!" Gastrinoma and insulinoma are the most common functional neuroendocrine pancreatic tumors in MEN 1 patients, accounting for approximately 50% and 20% of the neuroendocrine tumor syndromes, respectively.P Nonfunctional pancreatic endocrine tumors and pancreatic polypeptide (PP)-producing tumors (PPomas) may be the most common pancreatic neuroendocrine tumors in MEN 1 patients because these tumors are almost always identified on careful histologic studies of the pancreas.P-" Of the rare pancreatic neuroendocrine tumors, MEN 1 is present in approximately 3% of patients with glucagonoma, 1% of patients with VIPoma, 33% of patients with tumors that secrete growth hormonereleasing factor (GRF) (GRFoma), and 5% of patients with somatostatinoma.!" Essentially, any pancreatic neuroendocrine tumor may occur in individuals with MEN I; therefore, when evaluating a patient with a known neuroendocrine tumor, the possibility of unrecognized MEN 1 should be considered. The best way to determine the presence of MEN I is to question the patient carefully about family history, search for lipomas, and measure serum levels of calcium, gastrin, glucose, PP, and prolactin, If MEN 1 is present, multiple neuroendocrine tumors are identified within the pancreas.v-" and resection of the neuroendocrine tumor and the portion of pancreas near it is indicated. Somatostatinomas and other rare pancreatic neuroendocrine tumors, unlike insulinomas, are almost always malignant.v>' Therefore, in patients with localized, potentially curable disease, pancreatic resection--either Whipple's procedure for pancreatic head tumors or subtotal pancreatectomy for pancreatic body and tail tumors-is indicated,

Surgical Principles The goal of the surgical operation in a patient with an islet cell tumor is to identify accurately, stage, and remove the tumor. The surgeon should remove all tumor in a manner that allows the mortality and morbidity of surgery to be less than those in the natural history of the tumor. The surgeon needs to know the natural history and pathology of the neuroendocrine tumor, the expected outcome of the surgical

procedure, the expected survival with the tumor resected, the immediate and long-term complication rate, and the availability of alternative medical treatments to manage the disease.F-" Most experts recommend that patients with neuroendocrine tumors undergo surgery because any neuroendocrine tumor may be malignant, medical management can only control the signs and symptoms, and tumor resection is the only potentially curative treatment. Therefore, each patient with biochemical evidence of a neuroendocrine tumor should undergo complete radiologic assessment of the extent of disease to determine the feasibility of surgery. During the radiologic evaluation, medical management should be used to ameliorate symptoms secondary to excessive hormone secretion. It is clear that in some neuroendocrine tumors (such as VIPoma) advances in medical control of the hormone production have improved the surgical outcome and reduced the operative complication rate. 34 Many variables associated with an individual patient have an impact on the surgical outcome. These include the extent of disease on preoperative imaging studies, whether the primary tumor is within the pancreas or duodenum, the exact area of the pancreas involved (head, body, or tail), the presence of liver or other distant metastases and whether they are resectable, the occurrence of the neuroendocrine tumor in a familial or a sporadic setting, and the simultaneous occurrence of other medical conditions that may limit the ability of a patient to undergo major surgery. Success need not be defined as cure of the hormonal syndrome. It may be a decreased medication requirement, decreased symptoms, and increased length of survival. In each patient, it is clear that neuroendocrine tumors may be malignant, that surgery is an effective way of accurately staging the true extent of disease, and that surgery may be curative, even in the patient with metastatic neuroendocrine tumor. 34 -38

Somatostatinoma Somatostatinomas are rare endocrine tumors of the pancreas or duodenum that secrete excessive amounts of somatostatin. Somatostatin excess causes a syndrome characterized by steatorrhea, mild diabetes, and cholelithiasis, Somatostatin is an inhibitory hormone originally discovered in the hypothalamus in 1973. It was discovered by its ability to inhibit growth hormone and thus was called somatotropin release-inhibiting hormone. In 1977, Lans-Inge Larsson and P. O. Ganda and their colleagues reported the first two cases of somatostatinoma.v-" Initially, the somatostatinoma syndrome included diabetes, cholelithiasis, weight loss, and anemia. Subsequently, diarrhea, steatorrhea, and hypochlorhydria were added." Somatostatin inhibits the release of most other hormones. It decreases many gastrointestinal functions, including acid secretion, pancreatic enzyme secretion, and intestinal absorption. It reduces gut motility and transit time. Patients with pancreatic or intestinal somatostatinoma are generally about 50 years old. There is an equal proportion of males and females." Initial symptoms are diabetes, gallbladder disease, and steatorrhea (Table 84-3). Diabetes mellitus and glucose intolerance are reported to occur in

Somatostatinoma and Rare Pancreatic Endocrine Tumors - - 767

60% of patients. Gallstones occur in 70% of patients. Diarrhea and steatorrhea are reported in 30% to 68% of patients. In some, the severity of the diarrhea and steatorrhea correlates with the size and degree of metastatic spread of the tumor, and it improves with tumor resection. Hypochlorhydria has been found in approximately 33% to 53% of patients. It arises more commonly with pancreatic somatostatinoma, occurring in 86% of patients with pancreatic somatostatinoma and in 17% of patients with intestinal somatostatinoma. The weight loss may be secondary to diarrhea and malabsorption. In most instances, somatostatinomas have been found by accident. The tumor is usually found at the time of cholecystectomy or during routine imaging studies. Imaging studies have been performed because of abdominal pain, bleeding, or diarrhea. Once discovered, the tumor is identified as somatostatinoma either by a demonstration of elevated tissue concentrations of somatostatin or by the documentation of increased plasma levels of somatostatin. The early diagnosis of somatostatinoma may be possible with greater awareness of its existence and reliable assays for the determination of somatostatin in blood. Current assays are complicated by the need for extraction of the plasma. Most somatostatinomas are solitary and located within the pancreatic head or duodenum. A high proportion of these tumors are malignant. If the tumor is localized and not widely metastatic, surgical resection is the treatment of choice. This usually necessitates a Whipple pancreaticoduodenectomy. Surgical debulking of metastatic disease has been advocated, but patients are few and clear benefits have not been demonstrated. '

VIPoma VIPomas are generally located within the pancreas. They secrete excessive amounts of VIP, which causes a distinct syndrome. Patients have a very large volume diarrhea, severe hypokalemia with muscle weakness, hypercalcemia, and hypochlorhydria (Table 84-4). VIPoma typically occurs in adults. However, it has been reported in two children with severe diarrhea.f It was originally called the Verner-Morrison syndrome" because these two authors first described pancreatic cholera and the watery diarrhea, hypokalemia, and achlorhydria syndrome in 1958.421\vo patients were described

who died from watery diarrhea, hypokalemia, and nephropathy associated with a non-insulin-secreting pancreatic neuroendocrine tumor.P The diarrhea was so severe that despite intravenous fluids both patients experienced renal failure and death secondary to dehydration. The diarrhea is characteristically large in volume (>5 L/day). It is secretory, which means that it persists despite fasting.44,45 Hypokalemia is present in nearly every patient and is caused by excessive potassium losses in the diarrheal fluid. 46,47 The hypokalemia causes severe muscle weakness, which is also a common symptom in these patients, and some are bedridden. Hypochlorhydria is found in 75% of patients with VIPoma and is due to inhibition of gastric acid secretion by VIP.45,48 Flushing, which occurs in a minority of patients, is probably caused by the vasodilatory effects of VIP.45 Hyperglycemia occurs in 25% to 50% of patients and is caused by overconversion of glycogen to glucose. VIP is a glycogenolytic hormone.f Hypercalcemia is present in a significant proportion of patients with VIPoma. The diagnosis of VIPoma requires the triad of severe secretory diarrhea, elevated fasting serum levels of VIP, and the presence of a pancreatic neuroendocrine tumor. In most patients, stool output is greater than 5 L/day, and the diagnosis is excluded when it is less than 700 mL/day. The normal fasting plasma VIP concentration should be determined when diarrhea is present. The mean fasting plasma level of VIP in 29 published patients with VIPoma was 956 pg/mL (range, 225 to 11,850 pg/mL).44,45 After the diagnosis has been established, all patients with VIPoma need correction of dehydration, hypokalemia, and other metabolic abnormalities (see Table 84-4). Before the long-acting somatostatin analog octreotide was introduced, complete correction of the electrolyte and volume derangements was impossible because the voluminous diarrhea persisted. However, octreotide therapy dramatically reduces serum levels of VIP; stops the diarrhea, dehydration, and hypokalemia; and allows rapid restoration of total body potassium (Fig. 84_2).49,50 Octreotide therapy has dramatically advanced the preoperative electrolyte management of patients with VIPoma. Patients with biochemical evidence of VIPoma should undergo imaging studies to localize the tumor. Computed tomographic (CT) scanning identifies tumor in nearly every

768 - - Endocrine Pancreas

FIGURE 84-2. Use of octreotide in a patient with vasoactive intestinal polypeptide tumor (VIPoma). Serum potassium level, potassium replacement requirement, and stool output in patient with VIPoma are shown. The patient had a low serum level of potassium, a high potassium replacement requirement, and a high stool output. After initiating octreotide therapy at 150 ug subcutaneously every 8 hours (450 Ilg/day), the serum level of potassium became normal and the potassium replacement requirement and stool output dramatically lessened. This drug is useful in preparing patients with VIPoma for surgery.

patient with VIPoma. VIPomas can be well imaged by magnetic resonance imaging. Pancreatic masses are best shown on a Tl-weighted fat-suppressed image as a low-signal-intensity mass. Liver metastases from VIPoma show intense peripheral ring enhancement on postgadolinium spoiled gradient echo images. 51,52 Octreoscan is useful in selected individuals whose imaging studies are equivocal. After octreotide therapy to restore circulating volume and potassium, all patients who have localized tumors should undergo surgical exploration. Tumors may be malignant, and careful evaluation of regional lymph nodes and the liver is necessary. In the case of a malignant VIPoma with hepatic metastases, debulking surgery may be indicated to decrease plasma VIP concentrations and facilitate medical management of the diarrhea. 53 Long-term management of the diarrhea in patients with disseminated VIPoma has been successfully achieved with octreotide. 49,50,54,55 However, not all patients respond to octreotide, and patients who initially respond may become refractory to it. An 86-year-old woman with a metastatic VIPoma initially responded well to octreotide acetate (Sandostatin LAR) but subsequently became refractory to it, requiring higher and higher doses. Eventually, control was impossible and she died from dehydration.56

Glucagonoma Glucagonoma is an endocrine tumor of the pancreas that secretes excessive amounts of glucagon and results in a characteristic syndrome that includes a skin rash, diabetes mellitus, malnutrition, weight loss, thrombophlebitis,

glossitis, and anemia (Table 84-5).57 Glucagon itself is responsible for most of the signs and symptoms, and its induction of hypoaminoacidemia is thought to be responsible for the skin rash. Liver disease and zinc deficiency may also contribute in some cases." Unlike some other islet cell tumors, glucagonomas are almost always malignant. Tumorrelated deaths occur in most patients after about 5 years of follow-up. Unless the tumor can be removed surgically, there is no other potentially curative treatment." In 1963, Roger Unger first isolated glucagon by extraction from neuroendocrine tumors. McGavran and colleagues, in 1966, first reported a patient with diabetes mellitus, a skin rash, anemia, and a pancreatic carcinoma with liver metastases/" Subsequently, the patient was found to have high plasma levels of glucagon. Mallison and others associated glucagonoma with a specific skin rash subsequently labeled necrolytic migratory erythema and described a large series of patients with dermatitis, diabetes mellitus, weight loss, hypoarninoacidemia, anemia, and a glucagon-producing tumor of the pancreas.57 We demonstrated that in one patient the rash was due to markedly decreased plasma levels of amino acid, which could be completely reversed with total parenteral nutrition.f When the intravenous feeding corrected the hypoaminoacidemia, the rash completely resolved (Fig. 84-3). However, others have reported that infusion of peripheral amino acids did resolve the rash but not the serum amino acid levels." Patients with glucagonoma are between 50 and 60 years of age. The skin rash is migratory, red, and scaling and is associated with intense pruritus, It commonly occurs in the groin and lower extremities. The rash is pathognomonic of the tumor. 59,60,61 Hypoaminoacidemia occurs in most p~tients, and l~vels vary with the plasma level of glucagon. Diabetes mellitus and glucose intolerance are among the most frequent findings in patients. However, some patients (20%) do not have hyperglycemia.f Weight loss and cachexia are common and may be profound. Thromboembolic symptoms occur more commonly in patients with glucagonoma.f Both deep venous thrombosis and pulmonary emboli may ultimately cause death. Patients have presented with a dilated cardiomyopathy reversibly associated with glucagonoma.v' Diagnosis is made by measuring elevated plasma levels of glucagon. In all patients with glucagonoma, the plasma

Somatostatinoma and Rare Pancreatic Endocrine Tumors - -

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FIGURE 84-3. Plasma concentrations of amino acids in a patient with glucagonoma and skin rash. Seventeen individual plasma amino acid levels were determined in this patient. Normal levels are indicated by the dashed line (100%). Notice that each plasma amino acid level is reduced. After peripheral amino acid infusion (3.5% amino acids), there was no change in plasma amino acid levels and no change in the rash. After institution of total parenteral nutrition (TPN, 25% dextrose, 4.25% FreAmine II), there was a normalization of most plasma amino acid levels and a complete resolution of the rash. Zinc was not added to the TPN solution, and zinc blood levels were unchanged. When TPN was stopped, the rash recurred. This study suggested that the skin rash in this patient with glucagonoma (NME) is caused by hypoaminoacidemia, which is corrected and ameliorated by TPN. (From Norton JA, Kahn CR, Schieberger R, et al. Amino acid deficiency and skin rash associated with glucagonoma. Ann Intern Med 1979;91:213.)

glucagon concentration is elevated (>150 pg/mL). Plasma levels of glucagon greater than 1000 pg/mL are diagnostic of glucagonoma. Preoperative preparation of patients with glucagonoma involves controlling the diabetes, treating any complications of venous thrombosis, and improving the nutritional status with total parenteral nutrition, which usually corrects and heals the rash (see Fig. 84-3). Octreotide has been used, and it reduces plasma levels of glucagon, improves nutritional status, and ameliorates the rash.> Glucagonomas are usually found within the body and tail of the pancreas and rarely in the pancreatic head.62,64 Glucagonomas are usually large, malignant neuroendocrine tumors (>4 em) and are readily apparent on a CT scan. Studies should also evaluate the liver because 70% of patients with glucagonoma have liver metastases at diagnosis. Surgical procedures are indicated to remove all tumor for potential cure and to debulk tumor mass for improvement of symptoms. Primary tumors within the pancreas are generally removed by resection (subtotal pancreatectomysplenectomy) because of the high probability of malignancy. Resection may be used for liver metastases. Other options include hepatic artery embolization, chemotherapy with streptozotocin and 5-fluorouracil, long-term octreotide for symptoms, and transplantation of the liver and pancreas. Metastatic disease tends to progress slowly, and patients may survive for years without treatment.f

GRFoma GRFomas, first described in 1982,66,67 are neuroendocrine tumors that secrete excessive amounts of GRF. Patients with

these tumors have acromegaly. GRF is a peptide that is similar to VIP.66.67 GRFomas can occur (in order of decreasing frequency) in the lung (bronchus), pancreas, jejunum, adrenal, and retroperitoneum.P" Patients with GRFoma commonly have a large pancreatic neuroendocrine tumor (>6 em) that is metastatic in one third of cases at diagnosis. Approximately 50% of patients with GRFomas also have Zollinger-Ellison syndrome and 33% have MEN 1 (Table 84-6). GRFoma is anticipated when a patient has acromegaly and a pancreatic mass. Liver metastases and peptic ulcer disease should also be considered. 66-68 The diagnosis can be confirmed by performing a plasma assay for GRF and a CT scan of the abdomen to identify a pancreatic or liver tumor. Octreotide therapy can relieve the signs and symptoms of acromegaly. Surgical resection should be attempted in these patients because complete resection may be curative, and debulking may decrease symptoms and prolong survival.

Corticotropin-Producing Tumor Cushing's syndrome associated with a pancreatic neuroendocrine tumor that secretes corticotropin usually occurs in patients with neuroendocrine tumors that secrete another peptide and cause another syndrome." Malignant neuroendocrine tumors commonly secrete more than one peptide. Excessive production of corticotropin by a pituitary tumor may occur in patients with MEN 1 but is usually mild and clinically insignificant." Cushing's syndrome has also been reported in 5% of patients with Zollinger-Ellison syndrome.55 In these patients, Cushing's syndrome is severe, and they usually have metastatic disease. Cushing's syndrome is due

770 - - Endocrine Pancreas

to ectopic production of corticotropin by the neuroendocrine tumor.s? These patients seldom respond to chemotherapy and have a poor prognosis. In our experience, patients with corticotropin-producing pancreatic neuroendocrine tumors are usually unable to be rendered surgically free from disease. Medical management of the hypercortisolism in these patients is usually inadequate. Therefore, either debulking surgery or bilateral adrenalectomy may be indicated to control the severe signs and symptoms of hypercortisolism/"

Tumor Releasing Parathyroid Hormone-Related Protein Severe hypercalcemia has been reported to be due to a pancreatic neuroendocrine tumor releasing parathyroid hormonerelated protein (PTHrP).70,71 Hypercalcemia associated with pancreatic neuroendocrine tumors has also been reported to be due to the release of other substances such as VIP. In most cases, the pancreatic tumor is malignant and has spread to the liver by the time of diagnosis,

Neurotensinoma Pancreatic neuroendocrine tumors that secrete neurotensin have been reported.F" Neurotensin is a peptide that is present in the brain and the gastrointestinal tract." Neurotensin can cause hypotension, tachycardia, cyanosis, pancreatic secretion, intestinal motility, and small intestinal secretion.F Patients with neurotensinomas have diarrhea with hypokalemia, weight loss, diabetes, cyanosis, hypotension, and flushing. Patients may be cured by tumor resection, and others have responded to chemotherapy. 72,73 Some have questioned whether a separate neurotensinoma exists. Patients with VIPoma and gastrinoma have been found to have elevated plasma levels of neurotensin. At present, it is unclear whether a separate syndrome exists.

Ghrelinoma Ghrelin is a novel gastrointestinal hormone that exerts a wide range of metabolic functions. It promotes growth hormone release. It is an important regulator of energy balance. It has been demonstrated to increase appetite and food intake and modulate insulin secretion. It has significant homology with motilin and it stimulates gastric contractility

and acid secretion. A study demonstrated that one patient with an apparently nonfunctional pancreatic neuroendocrine tumor had markedly elevated serum levels of ghrelin. Further, immunohistochemistry of tumor showed intense focal cytoplasmic positivity for ghrelin. This study suggested that the patient had a tumor that secreted ghrelin, a so-called ghrelinoma. This had not been previously described. The authors examined many other carcinoid and pancreatic neuroendocrine tumors and no other tumor had detectable levels of ghrelin or stained positive for ghrelin."

PPoma and Nonfunctioning Neuroendocrine Tumor PPomas secrete pancreatic polypeptide, but this hormone does not appear to cause symptoms in men and this tumor is considered nonfunctional. PPomas and nonfunctioning pancreatic neuroendocrine tumors are tumors that have no functional syndrome. Dopamine agonists have been shown to decrease circulating levels of PP and chromogranin A in patients with large unresectable islet cell tumors." PPomas produce symptoms by tumor mass effects. This tumor is diagnosed because the patient has cachexia, abdominal pain, intestinal bleeding, blockage, or hepatomegaly. Patients with these tumors have also presented with clinical signs and symptoms of pancreatitis.v?? Patients commonly have locally advanced or metastatic neuroendocrine tumor by the time of diagnosis. Nonfunctioning pancreatic neuroendocrine tumors or PPomas usually cannot be differentiated from other malignant tumors of the pancreas before biopsy. Preliminary studies suggested that plasma marker 7B2 may be a good indicator of nonfunctional pancreatic neuroendocrine tumors." However, this has not been the case, and serum levels of chromogranin A or PP have been the best markers. Tumors can be found incidentally during any operative procedure.f Patients with a long survival (>5 years) and with suspected metastatic pancreatic adenocarcinoma may have a nonfunctioning neuroendocrine tumor or PPoma rather than an exocrine carcinoma. Typically, these tumors are large when diagnosed (>5 em), and almost all are malignant (70% to 92%).80 Nonfunctioning pancreatic endocrine tumors are differentiated from PPomas on the basis of results of the serum PP assay. At present, there are no data that suggest that PPomas or nonfunctioning pancreatic endocrine tumors differ in biologic behavior from malignant functioning neuroendocrine tumors. 81,82 However, recognizing that a tumor is a PPoma may be clinically important in that serum

Somatostatinoma and RarePancreaticEndocrine Tumors - - 771 PP levels may be used to monitor the results of antitumor therapies such as surgical resection or chemotherapy.

Summary Unusual neuroendocrine tumors of the pancreas and duodenum as well as nonfunctional tumors are more typically malignant than either gastrinoma or insulinoma. Despite this fact, patients with these tumors may have a better prognosis than those with other intra-abdominal solid malignancies. Therefore, if the entire extent of tumor can be resected and the patient is otherwise healthy, major operative procedures (e.g., a Whipple pancreaticoduodenectomy, liver lobectomy, subtotal pancreatectomy-splenectomy) may be indicated.v" Furthermore, in patients with some rare tumors associated with severe symptoms that are poorly controlled medically, such as somatostatinoma, glucagonoma, PTHrP-releasing tumor, and corticotropin-secreting tumor, major surgery to debulk tumor or to remove end organs (adrenal in patients with corticotropin-secreting tumor) may be necessary. Therefore, aggressive surgery has an important role in the therapy of these patients and is the only potentially curative treatment.

REFERENCES 1. Buchanan KD, Johnston CF, O'Hare MMT, et aI. Neuroendocrine tumors: A European view. Am J Med 1986;81(SuppI68):14. 2. Erickson B, Oberg K, Skogseid B. Neuroendocrine pancreatic tumors. Acta OncoI1989;28:433. 3. Kloppel G, Heitz PU. Pancreatic endocrine tumors. Pathol Res Pract 1988;183:155. 4. Creutzfeldt W, Amold R, Creutzfeldt C, Track NS. Pathomorphological, biochemical and diagnostic aspects of gastrinomas (Zollinger-Ellison syndrome). Hum PathoI1975;6:47. 5. Heitz PU, Kasper M, Polak JM, Kloppel G. Pancreatic endocrine tumors: Immunocytochemical analysis of 125 tumors. Hum Pathol 1982;13:263. 6. Jensen RT, Norton JA. Endocrine tumors of the pancreas in gastrointestinal disease. In: Sieisenger MH, Fordtran JS (eds), Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. Philadelphia, WB Saunders, 1993, p 1695. 7. Pareja-Megia MJ, Rios-Martin 11, Garcia-Escudero A, GonzalezCampora R. Papillary and cystic insulinoma of the pancreas. Histopathology 2002;40:483. 8. Bolande RP. The neurocrestopathies: A unifying concept of disease arising from neural crest maldevelopment. Hum PathoI1974;5:409. 9. Pearse AGE, TaborTT. Embryology of the diffuse neuroendocrine system and its relationship to the common peptides. Fed Proc 1979;38:2288. 10. Pearse HGE. The APUD concept and hormone production. Clin Endocrinol Metab 1980;9:211. II. Lloyd RV, Mervak T, Schidt K, et al. Immunohistochemical detection of chromogranin and neurospecific enolase in pancreatic endocrine tumors. Am J Surg Pathol 1984;8:607. 12. Norton JA, Levin B, Jensen RT. Cancer of the endocrine system. In: Devita VT, Hellman S, Rosenberg SA (eds), Cancer: Principles and Practice of Oncology. Philadelphia, JB Lippincott, 1993, p 1333. 13. Bartsch D, Hahn SA, Danichevski KD, et al. Mutations of the DPC41 Smad4 gene in endocrine pancreatic tumors. Oncogene 1999;18:2367. 14. Friedman EM, Larsson C, Amorosi A, et aI. Multiple endocrine neoplasia type I pathology, pathophysiology, molecular genetics and differential diagnosis. In: Bilezikian JP, Levine MA, Marcus R (eds), The Parathyroids. New York, Raven Press, 1994, p 647. 15. Burke AO, Sobin LH, Federspiel BH, et al. Carcinoid tumors of the duodenum. Arch Pathol Lab Med 1990;114:700. 16. Burke AP, Sobin LH, Shekitka KM, et aI. Somatostatin-producing duodenal carcinoids in patients with von Recklinghausen's neurofibromatosis: A predilection for black patients. Cancer 1990;65:1591.

17. Chagnon JP, Barge J, Hienin D, Blanc D. Recklinghausen's disease with digestive localizations associated with gastric acid hypersecretion suggesting Zollinger-Ellison syndrome. Gastroenterol Clin BioI 1985;9:65. 18. Binkovitz LA, Johnson CD, Stephens DH. Islet cell tumors in HippelLindau disease, increased prevalence and relationship to multiple endocrine neoplasia. AJR Am J Roentgenol 1990;155:501. 19. Davoren PM, Epstein MT. Insulinoma complicating tuberous sclerosis. J Neurol Neurosurg Psychiatry 1992;55:1509. 20. Oberg K, Skogseid B, Ericksson N. Multiple endocrine neoplasia type I. Acta Oncol 1989;28:383. 21. Bale AE, Norton JA, Wong EL, et al. Allelic loss on chromosome II in hereditary and sporadic tumors related to familial multiple endocrine neoplasia type 1. Cancer Res 1991;51:1154. 22. Knudson AG. Mutation and cancer: Statistical study of retinoblastoma. Proc Nat! Acad Sci USA 1971;68:820. 23. Brandi MI, Aurbach GD, Fitzpatrick LA, et al. Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type I. N Engl J Med 1986;314:1287. 24. Zimmering MB, Brandi MI, de Grange DA, et aI. Circulating fibroblast growth factor-like substance in familial multiple endocrine neoplasiatype I. J Clin Endocrinol Metab 1990;70:149. 25. Sheppard BC, Norton JA, Doppman JL, et al. Management of islet cell tumors in patients with multiple endocrine neoplasia: A prospective study. Surgery 1989;106:1108. 26. Thompson NW, Lloyd RV, Nishiyama RH, et aI. MEN-I pancreas: A histological and immunohistochemical study. World J Surg 1984; 8:561. 27. Kloppel G, Willemar S, Stamm B, et al. Pancreatic lesions and hormonal profile in pancreatic tumors in multiple endocrine neoplasia type I. Cancer 1986;57:1820. 28. Legaspi A, Brennan ME Management of islet cell carcinoma. Surgery 1988;104:1018. 29. Harris G, Tio F, Cruz A. Somatostatinoma: A case report and a review of the literature. J Surg OncoI1987;36:8. 30. Higgins GA. The glucagonoma syndrome: Surgically curable diabetes. AmJ Surg 1979;137:142. 31. Chastain MA. The glucagonoma syndrome: A review of its features and discussion of new perspectives. Am J Med 2001;321:306. 32. Mozell E, Stenzel P, Woltering EA, et al. Functional endocrine tumors of the pancreas: Clinical presentation, diagnosis, and treatment. Curr Probl Surg 1990;27:303. 33. Wermers RA, Fatourechi V, Wynne AG, et al. The glucagonoma syndrome: Clinical and pathological features in 21 patients. Medicine (Baltimore) 1996;75:53. 34. Norton JA. Neuroendocrine tumors of the pancreas and duodenum. Curr Probl Surg 1994;31:77. 35. Alexander EK, Robinson M, Staniec M, Dluhy R. Peripheral amino acid and fatty acid infusion for the treatment of necrolytic migratory erythema in the glucagonoma syndrome. Clin Endocrinol (Oxf) 2002;57:827. 36. Maton PN. The use of the long-acting somatostatin analogue, octreotide acetate, in patients with islet cell tumors. Gastroenterol Clin North Am 1989;18:897. 37. Fraker DL, Norton JA. The role of surgery in the management of islet cell tumors. Gastroenterol Clin North Am 1989;18:805. 38. Carty S, Jensen RT, Norton JA. Prospective study of aggressive resection of metastatic pancreatic endocrine tumors. Surgery 1992;112:1024. 39. Ganda PO, Weir GC, Soeldner JS, et al. Somatostatinoma: A somatostatin-containing tumor of the endocrine pancreas. N Engl J Med 1977;296:963. 40. Larsson LI, Hirsch MA, Holst J, et al. Pancreatic somatostatinoma: Clinical features and physiologic implications. Lancet 1977;1:666. 41. Krejs GJ, Orci L, Conlon M, et al. Somatostatinoma syndrome (biochemical, morphological, and clinical features). N Engl J Med 1979;301:285. 42. Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med 1958;29:529. 43. Marks IN, Bank S, Louw JH. Islet cell tumor of the pancreas with reversible watery diarrhea and achlorhydria. Gastroenterology 1967;52:695. 44. O'Dorisio TM, Mehkjian HS. VIPoma syndrome. In: Cohen S. Soloway RD (eds), Hormone Producing Tumors of the Pancreas. New York, Churchill Livingstone, 1985, p 101.

772 - - Endocrine Pancreas 45. O'Dorisio TM, Mehkjian HS, Gaginella TS. Medical therapy of VIPomas. Endocrinol Metab Clin North Am 1989;18:545. 46. Bloom SR, Long RG, Bryant MG, et al. Clinical, biochemical and pathological studies on 62 VIPomas. Gastroenterology 1980;78:1143. 47. Verner JV, Morrison AB. Non-B islet tumors and the syndrome of watery diarrhea, hypokalemia and hypochlorhydria. Clin Gastroenterol 1974;3:595. 48. Maton PN, O'Dorisio TM, Howe BA, et al. Effect of a long-acting somatostatin analogue (SMS 201-995) in a patient with pancreatic cholera. N Engl J Med 1985;312:17. 49. Maton PN, Gardner JD, Jensen RT. The use of the long acting somatostatin analogue 201-995 in patients with pancreatic endocrine tumors. Dig Dis Sci 1989;34:29. 50. Sofka CM, Semelka RC, Marcos HB, Woosley JT. MR imaging of metastatic pancreatic VIPoma. Magn Reson Imaging 1997;15:1205. 51. Mortele KJ, Oei A, Bauters W, et al. Dynamic gadolinium-enhanced MR imaging of pancreatic VIPoma in a patient with Verner-Morrison syndrome. Eur Radiol 2001;11:1952. 52. Nagorney DM, Bloom SR, Polak JM, Blumgart LM. Resolution of recurrent Verner-Morrison syndrome by resection of metastatic VIPoma. Surgery 1983;93:348. 53. Maton PN. Octreotide acetate and islet cell tumors. Med Clin North Am 1989;18:897. 54. Maton PN, Gardner JD, Jensen RT. The incidence and etiology of Cushing's syndrome in patients with the Zollinger-Ellison syndrome. N Engl J Med 1986;315:1. 55. Schoevaerdts D, Favet L, Zekry D, et al. VIPOMA: Effective treatment with octreotide in the oldest old. J Am Geriatric Soc 2001;49:496. 56. McGavran MH, Unger RH, Recant L, et al. A glucagon-secreting alpha-cell carcinoma of the pancreas. N Engl J Med 1966; 274:1408. 57. Mallison CN, Bloom SR, Warin AP, et al. A glucagonoma syndrome. Lancet 1974;2:1. 58. Norton JA, Kahn CR, Schieberger R, et al. Amino acid deficiency and skin rash associated with glucagonoma. Ann Intern Med 1979; 91:213. 59. Wilkinson DS. Necrolytic migratory erythema with carcinoma of the pancreas. Trans St John's Hosp Dermatol Soc 1973;59:244. 60. Kahan RS, Perez-Figaredo RA, Neimanis A. Necrolytic migratory erythema: Distinctive dermatosis of the glucagonoma syndrome. Arch Dermatol 1977;113:792. 61. Vinik AI, Moattari AR. Treatment of endocrine tumors. Endocrinol Metab Clin North Am 1989;18:483. 62. Stacpoole pw. The glucagonoma syndrome: Clinical features, diagnosis, and treatment. Endocr Rev 1981;2:347. 63. Chang-Cretien K, Chew IT, Judge DP. Reversible dilated cardiomyopathy associated with glucagonoma. Heart 2004;90: I. 64. Aldridge MC, Williamson RCN. Surgery of endocrine turnours of the pancreas. In: Lynn J, Bloom SR (eds), Surgical Endocrinology. New York, Butterworth, 1993, p 503. 65. Carty SE, Jensen RT, Norton JA. Prospective study of aggressive resection of metastatic pancreatic endocrine tumors. Surgery 1992;112:1024.

66. Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone-releasing factor from a human pancreatic islet cell tumour. Nature 1982;300:276. 67. Thorner MO, Perryman RL, Cronin MJ, et al. Somatotroph hyperplasia. J Clin Invest 1982;70:965. 68. Sano T, Asa SL, Kovacs K. Growth hormone releasing-producing tumors: Clinical, biochemical and morphological manifestations. Endocr Rev 1988;9:357. 69. Zeiger MA, Pass ill, Doppman JD, et al. Surgical strategy in the management of non-small cell ectopic adrenocorticotropic hormone syndrome. Surgery 1992;112:994. 70. Bresley L, Borssel P, Conroy T, Grosdidier J. Pancreatic islet cell carcinoma with hypercalcemia: Complete remission 5 years after surgical excision and chemotherapy. Am J Gastroenterol 1991;86:635. 71. Arps H, Dietel M, Schulz A, et al. Pancreatic endocrine carcinoma with ectopic PTH-production and paraneoplasia hypercalcaemia. Virchows Arch A Pathol Anat HistopathoI1986;408:497. 72. Blackburn AM, Bryant MG, Adrian TE, Bloom SR. Pancreatic tumors produce neurotensin. J Clin Endocrinol Metab 1981;52:820. 73. Shulkes A, Boden R, Cook I, et al. Characterization of a pancreatic tumor containing vasoactive intestinal peptide, neurotensin and pancreatic polypeptide. J Clin Endocrinol Metab 1984;58:41. 74. Corbetta S, Peracchi M, Capiello V, et al. Circulating ghrelin levels in patients with pancreatic and gastrointestinal neuroendocrine tumors; identification of one pancreatic ghrelinoma. J Clin Endocrinol Metab 2003;88:3117. 75. Pathak RD, Tran TH, Burshell AL. A case of dopamine agonists inhibiting pancreatic polypeptide secretion from an islet cell tumor. J Clin Endocrinol Metab 2004;89:581. 76. Grino P, Martinez J, Grino E, et al. Acute pancreatitis secondary to pancreatic neuroendocrine tumors. JOP 2003;4:104. 77. Ramsay D, Gibson P, Edmunds S, Mendelson R. Pancreatic islet cell tumours presenting as recurrent acute pancreatitis: Imaging features in three cases. Australas Radiol 200 1;45:520. 78. Iguchi H, Yasuda D, Yamada Y, et al. 7B2, a possible marker for nonfunctioning pancreatic islet cell tumor. Horm Metab Res 1991;23;486. 79. Kent RB, van Heerden JA, Weiland LH. Nonfunctioning islet cell tumors. Ann Surg 1981;193:185. 80. Eckhauser FE, Cheung PS, Vinik AI, et al. Nonfunctioning malignant neuroendocrine tumors of the pancreas. Surgery 1986;100:978. 81. VonKatesh S, Ordonoz NG, Ajani J, et al. Islet cell carcinoma of the pancreas: A study of 98 patients. Cancer 1990;65:354. 82. Lin TH, Zhu Y, Lui QI, et al. Nonfunctioning pancreatic endocrine tumors: An immunohistochemical and electron microscopic analysis of 26 cases. Pathol Res Pract 1992;188:191. 83. Danforth DN, Gorden P, Brennan ME Metastatic insulin secreting carcinoma of the pancreas: Clinical course and the role of surgery. Surgery 1984;96:1027. 84. Norton JA, Sugarbaker PH, Doppman JL, et al. Aggressive resection of metastatic disease in selected patients with malignant gastrinoma. Ann Surg 1986;203:352. 85. Bolden G. Insulinoma and glucagonoma. Semin OncoI1987;14:253.

Non-Multiple Endocrine Neoplasia Endocrine Syndromes Gary B. Talpos, MD

Multiple endocrine neoplasia (MEN) type 1 (MEN 1) and type 2 (MEN 2) syndromes have provided surgeons with most of their knowledge about hereditary endocrine disorders. Efficient screening, diagnostic, and postoperative surveillance algorithms have been established and used to better evaluate therapy. Less than 35 years after Sipple's initial description, the specific genetic abnormality in the ret protooncogene region of chromosome 10 has been identified in many MEN 2 families and allows accurate genetic testing as the sole diagnostic study before preemptive thyroidectomy. Ret testing also simplifies screening of family members at risk for familial medullary thyroid cancer,' Although less well known, several other hereditary syndromes involving the thyroid (Table 85-1), parathyroid, adrenal (Table 85-2), or pancreas (Table 85-3) have been described. Most syndromes, as in neurofibromatosis, involve nonendocrine as well as endocrine abnormalities. In some, such as the hereditary hyperparathyroidism-jaw tumor syndrome, a specific location has been documented on chromosome 1.1,2 In others, such as Li-Fraumeni syndrome, even more is known about the mutation.' The tumor suppressor gene p53 at chromosome 17p13 appears to be the location of the genetic abnormality.t-' Normally, this gene encodes a protein that binds a specific DNA sequence or transcription factor that blocks growth of abnormal cells in the G\ stage of cell replication of the cell cycle using apoptosis or inhibition of angiogenesis." A mutation at this location allows propagation or avoidance of blockage of propagation of abnormal genetic material, and one report indicated that the normal gene inhibits angiogenesis.' Frequently, clinical observations initiate a search using molecular biology and other techniques to recognize hereditary endocrine syndromes and lead to identification of the genetic abnormality. Thorough understanding of the mutation eventually guides attempts to correct or treat the disorder and even prevent the disorder through gene therapy in utero in

known kindreds. Most of the following clinical disorders represent syndromes with involvement of endocrine organs as well as nonendocrine tissue. Some represent discrete mutations that appear to affect only one step in the normal function of an endocrine organ if this defect has been recognized to be hereditary. Many defects that affect hormonal biosynthesis have already been identified. An individual need only consult testing algorithms for adrenal function in a major text to appreciate the many enzyme defects that have been well documented. Yet most abnormalities are not recognized as hereditary with transmission of the defect to subsequent generations. Undoubtedly, some of the "nontransmissible" defects could also have a genetic basis for the disorder with a recessive pattern of inheritance and irregular penetrance and are not recognized to be hereditary. Others are somatic mutations early in life, but not germline mutations, which could be inherited by other family members. Further study in this area will eventually illuminate the field more effectively. In this chapter I consider some of the more dramatic syndromes that involve the endocrine glands as a major component of the clinical disorder. In some instances, endocrine gland involvement is the only recognized component of the clinical syndrome because multiorgan involvement was not a criterion for inclusion in this chapter. Rather, genetic transmission or a hereditary basis for the clinical disorder was used as the major criterion for inclusion. This chapter is not exhaustive because new information and associations appear regularly. It is merely a stepping stone that delineates current knowledge and encourages the reader to improve the related body of science. Beckwith-Wiedemann syndrome is a disorder usually recognized at birth and characterized by a variable constellation of findings, including hemihypertrophy, macroglossia, gigantism, malrotation, and visceromegaly. 8 Islet cell hyperplasia with associated hypoglycemia, Wilms' tumor,

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adrenocortical abnormalities including carcinoma with associated Cushing's syndrome, gonadal hyperplasia, and liver abnormalities ranging from focal nodular hyperplasia to hepatoblastoma have also been described. Mental retardation has been noted in several patients with this disorder as well, although it is not clear whether it is related to the hypoglycemia associated with the nesidioblastosis and seen in more than half of these patients. Beckwith first described these patients in 1963 and pondered whether this was a discrete syndrome." Wiedemann reported on additional families shortly after and also suggested a new syndrome. to Irving labeled this disorder the EMG syndrome, for exomphalos, macroglossia, and gigantism. II Fraumeni and Miller also referenced case reports dating from 1935 linking hemihypertrophy and adrenocortical tumors (five malignant, one benign) in which the patients usually presented with precocious puberty (five) and Cushing's syndrome (twO).12.13 Undoubtedly, their review of 62 children with adrenocortical adenomas or carcinomas includes some children with the Beckwith-Wiedemann syndrome and also some with what has become known as the Li-Fraumeni syndrome.v-"

Clinically, patients with the Beckwith-Wiedemann syndrome are recognized in the newborn period with hemihypertrophy, macroglossia, and the other somatic manifestations of this disease.P-'" Palpation or radiologic evaluation of the abdomen frequently reveals a mass related to enlargement of the pancreas, adrenals, kidneys, or liver, which requires prompt evaluation and treatment. More urgently, however, normoglycemia needs to be ascertained in light of associated nesidioblastosis. In selected cases, subtotal pancreatectomy has proved essential in controlling the serum glucose and preventing the sequelae of profound hypoglycemia." It is also apparent that these children must be committed to an aggressive surveillance program because the development of adrenocortical abnormalities-usually malignant-ean be delayed until at least age 17 years, Genetic studies indicate an abnormality on chromosome 11 at the p l S locus in some patients with hemihypertrophy, 19 Eighty-five percent of these cases appear sporadic, although variable expression and reduced penetrance could mask a higher percentage of autosomal dominant transmission. This genetic abnormality could act as a true oncogene. The insulin-like growth factor (lGF2) gene is considered a candidate gene in light of its proximity at 11p15 and the hemihypertrophy and the fact that the product of the IGF2 gene is a fetal growth factor. Overexpression of the mutated gene could then have an impact on any somatic mutation, leading to multiple-organ involvement.'? Familial hyperinsulinemia has an incidence of 1 to 5 per 100,000 and is sometimes called the familial hyperproinsulinemia syndrome. It involves autosomal dominant transmission of a point mutation at l lpl S, which results in reduced insulin receptor binding and mild diabetes mellitus. It is rarely recognized and is noted only to link it to the BeckwithWiedemann syndrome with its similar genetic location. Treatment to reduce elevated insulin levels is not necessary because these patients do not demonstrate hypoglycemia.P The hereditary hyperparathyroidism-jaw tumor syndrome has been described over the past 15 years." Typically, this syndrome occurs in an autosomal dominant fashion, and these patients present as teenagers with hypercalcemia and are found to have single-gland parathyroid disease. The abnormal parathyroid is characterized by an adenomatousappearing gland that frequently, but not invariably, is cystic, Excision of this solitary gland and identification of

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normal-appearing glands usually result in a prompt return of normocalcemia. However, at least two individuals in the six described kindreds experienced recurrent single-gland parathyroid disease several years after their initial operation. At reoperation, only a single abnormal gland was found. Parathyroid cancer has also been described in two kindreds in younger individuals. This finding is supportive of Knudsen's two-hit hypothesis in which the first "hit" involves a germline mutation. The second hit represents a somatic mutation. A third hit, or additional somatic mutation, could then lead to development of a malignancy. Usually, these hereditary tumors are multicentric and occur in younger individuals. Jaw tumors associated with this condition are distinct from osteitis fibrosa cystica and "brown tumors." They have been characterized as ossifying fibromas. Typically, they arise in an asymptomatic fashion on dental radiographs or as tender intraoral nodules involving only the mandible or maxilla. In the six kindreds listed, at least 10 of the 31 individuals with parathyroid disease did not have jaw tumors at last report; thus, this feature of the syndrome does not appear to have complete penetrance or expressivity. Characteristically, these neoplasms occur much earlier than the fourth or fifth decade, when sporadic jaw tumors usually occur. Correction of the hypercalcemia also appears to have no relationship to development or progression of the tumors. Some tumors have been monitored with isotopic and plain film radiographs and appeared to stabilize independent of development or redevelopment of the clinical hyperparathyroidism. Wilms' tumor has also been seen in a single individual in three of the six known kindreds with hereditary hyperparathyroidism-jaw tumor syndrome, which suggests a striking coincidence or an unexplained genetic relationship.l,22,23 Extensive genetic studies have been performed on tissue from members of five kindreds affected with the syndrome. A candidate gene was mapped to chromosome Iq21-31 and labeled HRPT2. Furthermore, failure to identify loss of heterozygosity in affected tissue from eight individuals suggests that the responsible gene mutation for hereditary hyperparathyroidism-jaw tumor syndrome is a protooncogene analogous to the ret protooncogene responsible for MEN 2. An HRPT2 mutation has been identified in about 60% of sporadic parathyroid carcinomas.e' Currently, it is unknown whether the six involved kindreds with hereditary hyperparathyroidism-jaw tumor syndrome represent the true incidence of this syndrome or whether the syndrome involves more families but goes unrecognized. Several hereditary thyroid syndromes have been described. Most are associated with hypothyroidism and resultant goiter formation, although at least one syndrome is associated with hyperthyroidism. Pendred's syndrome is an autosomal recessive disorder seen approximately once in every 15,000 births.i" It represents a defect in the peroxidase-generating system with resultant hypothyroidism. Goiter usually results. Deafness is also seen in these patients. Chromosomal studies have not yet identified the specific mutation for this syndrome. Separate and distinct unnamed hereditary disorders have also been identified with iodide transport deficiency and iodotyrosine deiodinase deficiency, both of which result in hypothyroidism and goiter without other organ involvement.P

775

Both of these entities appear to be transmitted in an autosomal recessive fashion, although specific chromosomal abnormalities have not yet been identified. Because only one biochemical defect is noted in each disorder, these disorders might be particularly amenable to gene therapy in the future. Currently, thyroid replacement and thyroidectomy as necessary are indicated for Pendred's syndrome and patients with the latter two disorders. Hereditary hyperthyroidism is a rare disorder transmitted in an autosomal dominant fashion in which increased stimulation of thyrocytes occurs with resultant thyromegaly and autonomy" In some families, it has been thought mistakenly to represent a hereditary form of Graves' disease. No trials comparing therapy exist in this illness, although both radioiodine and surgery should be effective. Von Hippel-Lindau disease has a long history. The classical eye findings were first described by Collins in 1894; von Hippel recognized the familial pattern in 1904. Finally, in 1926 Lindau saw that the retinal and cerebellar hemangioblastomas were part of the larger syndrome.P Von Hippel-Lindau disease is now known to be an autosomal dominant disorder because of a mutation at chromosome 3p25-26. 26 This appears to encode a tumor suppressor locus and results in variable expression, with many organs potentially being affected. Classically, hemangioblastomas of the brain stem, retina, or kidney are seen. Renal cell carcinoma; pheochromocytoma, usually bilateral; epididymal cysts; and pancreatic abnormalities are also found, although there are marked interfamily differences with constant intrafamily involvement.27.28 Depending on the method of diagnosis, pheochromocytoma is reported in 20% to 80% of patients found to have von Rippel-Lindau disease, and it is usually the presenting sign of the disorder.i? Lack of family screening programs and the frequently dramatic occurrence of pheochromocytoma usually overshadow the more readily detectable retinal findings evidenced on funduscopic examination. Bilaterality of the pheochromocytomas has been seen but does not appear to be as constant a finding as in MEN 2 syndrome. When bilateral pheochromocytomas are detected, metachronous involvement seems to be the rule. It is not clear whether this is a legitimate observation or a reflection of diagnostic efforts. In addition, adrenal medullary hyperplasia has not been documented as a precursor lesion, although medullary hyperplasia was thought to represent the initial step in the development of pheochromocytoma in hereditary cases. Finally, extra-adrenal pheochromocytomas or paragangliomas have been reported in approximately 10% of patients. For this reason, transabdominal exploration is advocated for surgery for pheochromocytoma in this disorder," Pancreatic lesions have also been seen in 56% of patients with von Rippel-Lindau disease. Isolated pancreatic cysts accounted for two thirds of these lesions, whereas approximately 15% of the abnormalities were found to be islet cell tumors. Although immunoperoxidase staining occasionally identified specific hormones stored in these tumors, no clinical sequelae associated with the specific hormones have been identified. The remainder of the pancreatic lesions seen in von Hippel-Lindau disease were found to be indeterminate pancreatic masses or combinations of the just-mentioned syndromes.F-"

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Endocrine Pancreas

Although the genetic abnormality associated with von Hippel-Lindau disease has been localized to chromosome 3p, widespread genetic testing for this disorder is not yet available. A positive family history of pheochromocytoma remains the single most important fact that identifies the patient as having a hereditary disorder. Genetic testing and calcitonin measurements can usually detect individuals with pheochromocytomas associated with the MEN 2 syndrome. The individuals with pheochromocytoma associated with a phakomatosis can usually be identified by the cutaneous manifestation of the disorder whether it is neurofibromatosis, Sturge-Weber syndrome, or any other type of phakomatosis. The remainder of hereditary cases involving pheochromocytoma appear to be found in kindreds with familial pheochromocytoma or von Hippel-Lindau disease. A detailed family history searching for extra-adrenal manifestations of von Hippel-Lindau disease and careful funduscopic examination by an experienced ophthalmologist usually serve to distinguish these two disorders. Periodic screening of all individuals at risk in each kindred should also be performed because survival is related to the stage of tumor at diagnosis. Familial pheochromocytoma has also been reported in different forms. Hereditary bilateral adrenal pheochromocytoma,29,30 extra-adrenal pheochromocytoma," and bilateral multicentric pheochromocytoma associated with islet cell tumors (unrelated to von Hippel-Lindau diseasej-' have all been described as being transmitted in an autosomal dominant fashion with incomplete penetrance. The genetic aberrations in these disorders have yet to be determined, although each disorder has been detected in multiple unrelated kindreds. It is not known whether these distinct clinical entities represent separate hereditary disorders or whether they are different expressions of a common genetic mutation. A detailed family history remains the best means of determining the presence of a hereditary adrenal disorder. The increased incidence of multiple tumors, bilaterality with either synchronous or metachronous involvement, adrenal medullary hyperplasia, or an early age of onset should also heighten suspicion of a pheochromocytoma-associated syndrome. If it is found, regular screening should be instituted. Carney's complex represents a variable constellation of abnormalities, including myxomatous masses, spotty pigmented lesions of the skin, endocrine disorders, and psammomatous melanotic schwannomas.P'" The myxomas occur in the heart (most important clinically), the skin, and the breast. The pigmented skin lesions most commonly have been termed lentigines or blue nevi, whereas the endocrine disorders have consisted of a unique bilateral pigmented nodular adrenocortical abnormality, testicular tumors, and a growth hormone-producing pituitary adenoma. The characteristic schwannoma associated with Carney's complex is a rare melanotic peripheral nerve tumor that is usually benign, although malignancy has been seen and was fatal in 10% of cases. Cushing's syndrome occurs early, with a mean age of onset of 19 years. It is usually cured by bilateral adrenalectomy. Intraoperatively, the adrenal glands have been noted to be studded with small, dark nodules. Interestingly, Nelson's syndrome (postadrenalectomy pituitary tumor) has yet to be reported in patients with Carney's complex. Whether this is genuine or more a problem of recognition remains to be seen.

Cardiac myxomas were seen in approximately 75% of Carney's original series; more than half had multiple myxomas. Excision, frequently in a staged fashion, is the treatment of choice. Echocardiography remains the diagnostic tool of choice. 34 Testicular tumors are also seen in Carney's complex, affecting more than half of the male patients. They are usually bilateral and multicentric, occurring at a mean age of 11 years. Metastasis has not yet been reported. Histologically, the tumors have been characterized as large-cell calcifying Sertoli cell tumors or as a steroid-type tumor (either a Leydig cell tumor or a tumor of an adrenocortical rest). Pituitary adenomas are also a major component of this syndrome, affecting 10% of patients and usually occurring in the teenage years. Growth hormone has invariably been elevated. Hypophysectomy remains the treatment of choice. Psammomatous melanotic schwannoma is an uncommon tumor. Half of the cases have been reported in association with Carney's complex. Typically, the tumor involves the esophagus, stomach, or paravertebral sympathetic chains. Although most tumors have been characterized as benign, 10% were malignant and fatal." Patients with Carney's complex can usually be recognized by a positive family history and the spotty skin changes. Multiple myxomatous tumors of the skin or breast should also raise suspicion for this disorder." Screening protocols for cardiac myxomas should be instituted early because death from this entity has been reported as early as 4 years of age. Screening for adrenal abnormalities, pituitary tumors, and testicular tumors should also be started early because tumors were frequently seen before 10 years of age." Early age of onset, multicentricity, bilaterality, and familial tendency argue for a genetic mechanism for this syndrome, although none has been determined to date. Clinically, 32% of the patients reported by Carney were alive and well, whereas 30% died, usually from a cardiac myxoma. Another 30% were alive with sequelae of the syndrome, most commonly myxoma-related embolism. Gardner's syndrome, also termed familial adenomatous polyposis, was first described in 1951. 38 This syndrome of premalignant colonic polyposis, osteomas, and soft tissue tumors is transmitted in an autosomal dominant fashion and affects about 1 per million as opposed to just polyposis, which affects 1 per 8000. In 1959 Turcot documented two patients with familial adenomatous polyposis who also had malignant brain tumors. Gardner's syndrome has been traced to chromosome 5q21, as has adenomatous polyposis coli. Epidermoid cysts are commonly seen, although desmoid tumors are present in only about 10% of patients." Typically, these occur in young women and can recur locally after excision. Sulindac, tamoxifen, and interferon have all been reported to cause regression in some instances. Osteomas and pigmented eye lesions are also frequently reported. Malignant tumors are also seen in Gardner's syndrome." Colon cancer eventually occurs in all patients, whereas periampullary carcinoma, the next most common malignancy, is seen in 10% of cases." Papillary thyroid cancer is seen less frequently (about 2%) but at a reported incidence of more than 100 times the expected incidence in women younger than 35 years in the general population.'? The cancer is

Non-Multiple Endocrine Neoplasia Endocrine Syndromes - - 777

usually multicentric and frequently bilobar. It appears to be associated with both a germline APC mutation and a ret/PTC somatic mutation. Histologically, the papillary thyroid cancers have a unique cribriform pattern. Frequent physical examinations of the neck combined with liberal fine-needle aspiration of thyroid nodules should lead to curative total thyroidectomy in these patients. Preemptive suppression of thyroid function through the administration of oral thyroid medication to prevent tumorigenesis remains an attractive but unproven alternative. Several isolated reports of adrenocortical adenomas and adenocarcinomas complicating Gardner's syndrome also exist.39 Recognizing the relative scarcity of adrenal neoplasms, the coexistence of these with polyposis seems related. Only detailed autopsy studies or better understanding of the involved genetic mechanism is likely to explain this relationship. At this point, increased clinical awareness should lead to earlier recognition of a symptomatic patient because the incidence of adrenal tumors in Gardner's syndrome at this time appears too low to justify screening programs. Cowden's disease, also known as the multiple hamartoma syndrome, was named after Rachel Cowden, who, in 1963, was recognized as having a disorder involving mucocutaneous lesions and abnormalities of the breast and thyroid. Ten years later she died of the breast cancer associated with this syndrome, as did her mother/" In retrospect, patients presented by Costello in 1940 and by Witten and Kopf in 1957 were found to share the same physical features as well as the same histologic findings on biopsy." This genodermatosis is now recognized as an autosomal dominantly inherited complex that has variable expressivity. Major criteria for diagnosis are cutaneous facial papules and oral mucosal papillomatosis, whereas minor criteria are acral and palmoplantar keratoses. A definitive diagnosis requires (1) two major criteria, (2) one major and one minor criterion, (3) one major criterion and a positive family history, or (4) two minor criteria and a positive family history. These cutaneous lesions usually develop in the second or third decade of life. Other characteristic lesions develop in the breast in 76% of female patients. Aggressive fibrocystic change, papillomas, and vaginal hypertrophy have all been reported. Breast cancer is seen in approximately one third of women with this disorder. In light of this increased incidence, a more aggressive screening program for breast cancer in women with a confmned diagnosis of Cowden's disease is recommended. Thyroid disease is also commonly seen; about two thirds of both male and female patients are affected. Benign conditions predominate and include toxic as well as nontoxic goiter, follicular adenomas, and less commonly carcinoma.f These potential disorders should be sought and needle biopsy performed for any thyroid nodules in patients with Cowden's disease. Gastrointestinal hamartomatous polyps are also seen, although malignant degeneration is not thought to develop. Hundreds and, on occasion, thousands of small polyps carpet the entire gastrointestinal tract.f? Genitourinary, nervous system, and skeletal abnormalities occur frequently as well with varying degrees of disability. The major threats to the involved patient, however, are the malignancies that develop from the breast and thyroid disorders.

Noonan's syndrome has been recognized as a distinct entity since 1963, although a male patient with features compatible with this disorder was reported in 1883.43 The appearance is similar to that of Turner's syndrome because a webbed neck, hypertelorism, low-set ears, and short stature are seen in both. Turner's syndrome, however, involves only females because it represents an absence or an abnormality of the X chromosome. Noonan's syndrome is seen in both sexes, and the underlying genetic defect has been located on the long arm of chromosome 12.44 Autosomal dominant inheritance with variable expression is noted in approximately one half; sporadic cases represent the remainder. Most authors estimate the frequency to be 1 per 1000 to I per 2500 births. However, other estimates suggest a frequency of I per 1000 in the severely affected and 1 per 100 in the mildly affected patients." Neurofibromatosis I has also been seen in association with Noonan's syndrome, but genetic studies have not indicated any other abnormality on chromosome 17, the neurofibromatosis I chromosome.f Affected children have a typical facies, and 90% have a chest deformity such as pectus excavatum or pectus carinatum. Hyperextensible joints are also seen. A variety of cardiac defects have been noted in half of the patients with this disorder, and right heart outflow anomalies are most common.v Eye findings, including thickened corneal nerves, have been documented in 63% in one series. Deafness also occurs in about 40% of affected individuals. Undescended testicles are seen in more than one half of males, which results in decreased fertility. Pheochromocytomas have been described as well. It is not certain, however, that these individuals did not have accompanying neurofibromatosis 1.47,48 Newborns affected with Noonan's syndrome have been characterized as listless, poor feeders prone to episodes of vomiting. Despite sharing these features as well as thickened corneal nerves and hyperextensible joints with the MEN 2B syndrome, no genetic association has been identified between these two syndromes. The phakomatoses represent a group of disorders characterized by neuroectodermal findings, including an increased incidence of pheochromocytoma. Neurofibromatosis is now recognized as two conditions. Neurofibromatosis I includes von Recklinghausen's disease and is associated with hereditary pheochromocytomas, whereas neurofibromatosis II is considered the acoustic neuroma syndrome. Neurofibromatosis I affects I in 3500 live births and appears to have an autosomal dominant pattern of transmission. Criteria for diagnosis include two or more of the following: cafe au lait spots, neurofibromas, freckling in non-sun-exposed areas, optic glioma, Lisch nodules, distinctive bone lesions, and a first-degree relative with the disorder." A variety of mutations consisting primarily of deletions and insertions have been identified at chromosome 17q 11.2, which appears to cause disordered growth through a tumor suppressor mechanism involving neurofibromin." This gene product appears to be involved with regulation of cell proliferation and differentiation and is one of the guanine triphosphatases (GTPases).50 The classical appearance of von Recklinghausen's disease, or "elephant man's" disease, is usually seen. Pheochromocytomas, however, are less commonly detected, with a reported incidence of less than 1%.51 Whether this

778 - - Endocrine Pancreas reflects the true incidence is unclear because most screening programs for neurofibromatosis do not prospectively screen for adrenal abnormalities. Neurofibromatosis II does not appear to be related to adrenal involvement, and its mutational site appears to be on chromosome 22. Duodenal or periampullary carcinoids are also associated with neurofibromatosis disease, although it has not yet been determined whether they are seen in neurofibromatosis I, II, or both. The incidence is probably less than that reported for pheochromocytoma in this disorder.52 Tuberous sclerosis is an uncommon condition that is considered to be one of the phakomatoses or genodermatoses. Several studies suggest a prevalence of 1 case per 6000 to 9000 individuals. Autosomal dominant transmission has been recognized with variable penetrance and expressivity and a high spontaneous mutation rate. Hamartomas as well as true neoplasms are seen" Diagnostic criteria for tuberous sclerosis involve combinations of primary, secondary, and tertiary features. Multiple-organ involvement is usually seen, with skin and retina typically affected. Cardiac rhabdomyomas are seen in approximately two thirds of patients, as are renal cysts and angiomyolipomas. Brain involvement is frequently seen and manifested by seizures and mental retardation. Seen much less commonly are pulmonary involvement, adrenal pheochromocytomas, and islet cell tumors. 54.56 Survival is affected primarily by the cardiac disease and, to a lesser intent, the pulmonary involvement, which, although affecting only a small number of individuals, is usually fatal within 5 years. Two genetic variants of tuberous sclerosis are recognized, although phenotypic differences have not been seen. Tuberous sclerosis I (TSC 1) appears to involve a mutation at chromosome 9q33.34,57 whereas TSC 2 involves a mutation at chromosome 16p13.3.56 The TSC 2 gene appears to be involved with tuberin production and with polyadenylation affecting the GTPase-activating protein (GAP) (or rap-l GAP). Interestingly, neurofibromin, the product of the nfi gene, is homologous to ras-GAP. The ras gene is one of a group of GTPases that helps regulate all proliferation and differentiation. Birt-Hogg-Dube syndrome is a rare condition found in one Canadian family and described in 1977.57 This is an autosomal dominant condition consisting of multiple fibrofolliculomas with trichodiscomas and acrochordons, which affected 15 of 25 adults studied in the kindred. Medullary thyroid cancer was also found in 6 of 15 affected members.P

Summary These syndromes as well as others waiting to be described have endocrine features that require treatment. Earlier recognition of the syndromes and better surveillance for the different components of each syndrome should allow more effective treatment algorithms. Surgeons should be aware of these syndromes with endocrine involvement to better treat each individual patient and also to participate in family screening. Treating the preclinical stages of disease should allow the best possible outcome. Endocrine surgeons must remain involved if they are to keep intact their role as physician-teacher-researcher.

The findings from the human genome project are providing much useful information regarding genotype-phenotype relationships. These findings should lead to earlier diagnosis and more appropriate and effective therapies.

REFERENCES 1. Szabo J, Heath B, Hill VM, et al. Hereditary hyperparathyroidism-jaw tumor syndrome: The endocrine tumor gene HRPT2 maps to chromosome Iq21-q31. Am J Hum Genet 1995;56:944. 2. Phay JE, Moley JF, Lairmore TC. Multiple endocrine neoplasias. Surg OncoI2000;18:324. 3. Frebourg T, Barbier N, Van Y, et al. Germline p53 mutations in 15 families with Li-Fraumeni syndrome. Am J Hum Genet 1995;56:608. 4. Malkin D. p53 and the Li-Fraumeni syndrome. Cancer Genet Cytogenet 1993;66:83. 5. Ponz de Leon M. Li-Fraumeni syndrome. Recent Results Cancer Res 1994;136:275. 6. Knudson AG. Antioncogenes and human cancer. Proc Nat! Acad Sci USA 1993;90:10914. 7. Dameron KM, Volpert OV, Tainsky MA, Bouck N. The p53 tumor suppressor gene inhibits angiogenesis by stimulating the production of thrombospondin. Cold Spring Harbor Symp Quant Bioi 1994;59:483. 8. Beckwith JB. Macroglossia, omphalocele, adrenal cytomegaly, gigantism, and hyperplastic visceromegaly. Birth Defects 1969;5:188. 9. Beckwith JG. Extreme cytomegaly of adrenal fetal cortex, omphalocele, hyperplasia of kidneys and pancreas and Leydig cell hyperplasia: Another syndrome? Presented at the annual meeting of the Western Society for Pediatric Research, Los Angeles, November II, 1963. 10. Wiedemann HR. Complex malformatif familial avec hernie ombilicale et macroglossie. Un syndrome noveau? J Genet Hum 1964;13:223. 11. Irving I. The E.M.G. syndrome (exomphalos, macroglossia, gigantism). In: Rickham PP, Hacker WC, Prevot J (eds), Progress in Pediatrics, Vol I. Munich, Urban and Schwarzenberg, 1970, p I. 12. Fraumeni JF Jr, Miller RW.Adrenocortical neoplasms with hemihypertrophy, brain tumors and other disorders. J Pediatr 1967;70:129. 13. Harwood J, O'F1ynn E. Specimens from a case of right-sided hemihypertrophy associated with pubertas precos. Proc R Soc Med 1935;28:837. 14. Fraumeni JF Jr, Geiser CF, Manning MD. Wilms' tumor and congenital hemihypertrophy: Report of five new cases and review of literature. Pediatrics 1967;40:886. 15. Miller RW, Fraumeni JF Jr, Manning MD. Associations of Wilms' tumor with aniridia, hemihypertrophy and other congenital malformations. N Engl J Med 1964;270:922. 16. Kay R, Schumacher OP, Tank ES. Adrenocortical carcinoma in children. J Urol 1983;130:1130. 17. Tank ES, Kay R. Neoplasms associated with hemihypertrophy: Beckwith-Wiedemann syndrome and aniridia. J Urol 1980;124:266. 18. Roe TF, Kershnar AK, Weitzman 11, Madrigal LS. Beckwith's syndrome with extreme organ hyperplasia. Pediatrics 1973;52:372. 19. Cohen PR, Kurzrock R. Miscellaneous genodermatoses: BeckwithWiedemann syndrome, Birt-Hogg-Dube syndrome, familial atypical multiple mole melanoma syndrome, hereditary tylosis, incontinentia pigmenti, and supernumerary nipples. Dermatol Clin 1995;13:211. 20. Scrivner CR, et al (eds), Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, McGraw-Hill, 1995. 21. Jackson CE, Norum RA, Boyd SB, et aI. Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: A clinically and genetically distinct syndrome. Surgery 1990;108:1006. 22. Dinnen JS, Greenwood RH, Jones JH, et al. Parathyroid carcinoma in familial hyperparathyroidism. J Clin PathoI1977;30:966. 23. Kakinuma A, Morimoto I, Nakano Y, et al. Familial primary hyperparathyroidism complicated with Wilms' tumor. Intern Med 1994;33:123. 24. Shattuck TM, Valimaki S, Obara T, et aI. Somatic and gerrnline mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 2003;349: 1722. 25. Her C, Wu X, Griswold MD, Zhou F: Human MutS homologue MSH4 physically interacts with von Hippel-Lindau tumor suppressor-binding protein 1. Cancer Res 2003;63:865.

Non-Multiple Endocrine Neoplasia Endocrine Syndromes - - 779 26. Crossey PA, Richards FM, Foster K, et al. Identification of intragenic mutations in the von Rippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Rum Mol Genet 1994;3:1303. 27. Rough DM, Stephens DR, Johnson CD, Binkovitz LA. Pancreatic lesions in von Rippel-Lindau disease: Prevalence, clinical significance, and CT findings. AJR Am J RoentgenoI1994;162:1091. 28. Mount SL, Weaver DL, Taatjes OJ, et al. von Rippel-Lindau disease presenting as a pancreatic neuroendocrine tumour. Virchows Arch 1995; 426:523. 29. Gagel RF. Pheochromocytoma, multiple endocrine neoplasia type 2 and von Rippel-Lindau disease. N Engl J Med 1994;330:1090. 30. Arroja JM, Gudinchet F, Maeder P, Fournier D. Multiple familial pheochromocytomas: Sonographic demonstration of multiple adrenal, celiac and bladder localizations in a child. Schweiz Rundsch Med Prax 1995;84:1231. 31. Tisherrnan SE, Tisherrnan BG, Tisherrnan SA, et al. Three-decade investigation of familial pheochromocytoma: An allele of von RippelLindau disease? Arch Intern Med 1993;153:2550. 32. Glowniak JV, Shapiro B, Sisson JC, et al. Familial extra-adrenal pheochromocytoma: A new syndrome. Arch Intern Med 1985;145:257. 33. Camey JA, Go VLW,Gordon H, et al. Familial pheochromocytoma and islet cell tumor of the pancreas. Am J Med 1980;68:515. 34. Camey JA. The Camey complex (myxomas, spotty pigmentation, endocrine overactivity, and schwannomas). Derrnatol Clin 1995;13:19. 35. Camey JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985;64:270. 36. Mahilmaran A, Seshadri M, Nayar PG, et al. Familial myxoma: Camey's complex. Tex Heart Inst J 2003;30:80. 37. Washecka R, Dresner MI, Honda SA. Testicular tumors in Camey's complex. J UroI2002;167:1299. 38. Perniciaro C. Gardner's syndrome. Derrnatol Clin 1995;13:51. 39. Traill Z, Tuson J, Woodham C. Adrenal carcinoma in a patient with Gardner's syndrome: Imaging findings. AJR Am J Roentgenol 1995; 165:1460. 40. Mallory SB. Cowden syndrome (multiple hamartoma syndrome). Derrnatol Clin 1995;13:27. 41. Salem as, Steck WO. Cowden's disease (multiple hamartoma and neoplasia syndrome). JAm Acad DerrnatoI1983;8:686.

42. Starink THM. Cowden's disease: Analysis of fourteen new cases. J Am Acad DerrnatolI984;11: 1127. 43. Noonan JA. Noonan syndrome: An update and review for the primary pediatrician. Clin Pediatr 1994;33:548. 44. Jamieson CR, VanderBurgt I, Brady AF, et al. Mapping a gene for Noonan syndrome to the long arm of chromosome 12. Nat Genet 1994;8:357. 45. Flintoff WF, Bahauau M, Lyonnet S, et al. No evidence for linkage to the type 1 or type 2 neurofibromatosis loci in Noonan syndrome families. Am J Med Genet 1993;46:700. 46. Sharland M, Burch M, McKenna WM, Patton MA. A clinical study of Noonan syndrome. Arch Dis Child 1992;67:178. 47. Marghoob AA, Orlow SJ, Kopf AW. Syndromes associated with melanocytic nevi. JAm Acad Derrnatol 1993;29:373. 48. Roos KL, Muckway M. Neurofibromatosis. Derrnatol Clin 1995;13:105. 49. The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993;75:1305. 50. Gutmann DH, Geist RT, Rose K, et al. Loss of neurofibromatosis type I (NFl) gene expression in pheochromocytomas from patients without NFL Genes Chromosomes Cancer 1995;13:104. 51. Dayal Y, Tallberg KA, Nunnemacher G, et al. Duodenal carcinoids in patients with and without neurofibromatosis: A comparative study. Am J Surg Pathol 1986;19:348. 52. Roach ES, Degado MR. Tuberous sclerosis. Derrnatol Clin 1995;13:151. 53. Kim H, Kerr A, Morehouse R. The association between tuberous sclerosis and insulinoma. AJNR Am J Neuroradiol 1995;16:1543. 54. Davoren PM, Epstein MT. Insulinoma complicating tuberous sclerosis. J Neurol Neurosurg Psychiatry 1992;55:1209. 55. Schwarzkopf G, Pfisterer J. Metastasizing gastrinoma and tuberous sclerosis complex: Association of coincidence. Zentralbl Pathol 1994; 139:477. 56. Harris RM, Carter NP, Griffiths B, et al. Physical mapping within the tuberous sclerosis linkage group in region 9q31-q34. Genomics 1993;15:265. 57. Birt AR, Hogg GR, DuM WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch DerrnatoI1977;113:1674.

Neuroendocrine Tumors Laurent Brunaud, MD • Hans-Dietrich Roeher, MD • Dietmar Simon, MD

Neuroendocrine tumors (carcinoid tumors) are unusual, rare tumors that can be localized in all organs originating from the endoderm. They are derived from neoplastic proliferation of cells of the diffuse neuroendocrine system. These cells have been called enterochromaffin or Kulchitsky cells; they are ubiquitous throughout the gastrointestinal tract, urogenital tract, and bronchial epithelium and are considered to be the largest endocrine organ of the human body.'? The neuroendocrine system has been described as a diffuse network of nerve and endocrine cells with a common phenotype characterized by the simultaneous expression of general protein markers and hormonal products specific to each neuroendocrine cell." The incidence of neuroendocrine tumors is 1 per 100,000 per year. The most frequent sites are the small intestine (35%), the appendix (33%), the rectum (14%), and the bronchial system (9%). However, a marked increase in the percentage of lung-bronchial tumors and a decrease in the percentage of appendiceal neuroendocrine tumors have been reported.l In organs that rarely develop malignant tumors, neuroendocrine tumors become the most frequent tumors; thus, 34% of all small intestinal cancers and 77% of all appendiceal tumors are neuroendocrine tumors. In organs that develop tumors more frequently (e.g., the colon, stomach, lung, and breast), neuroendocrine tumors make up only 1% of the tumors. The overall prevalence of neuroendocrine tumors is estimated at 0.5%.6

History The first description of carcinoid tumors dates back to the 19th century, when Merling (1808), Langhans (1867), and Beger (1882) identified appendiceal carcinoids as a unique histologic entity. Lubarsh described multicentric small tumors in the small intestine originating from the intestinal glands (Lieberkuhn).? In 1907 Oberndorfer for the first time used the term carcinoid to define the tumors as benign and carcinoma-like." Between 1914 and 1928 Masson described 780

special staining techniques with silver impregnation (Grimelius), which showed the carcinoid tumor cells to be argentaffin.v'" Thus, these tumors were attributed to the enterochromaffin cells named after Kulchitsky and were postulated to be of endocrine origin." In 1938 Feyrter, a German pathologist, described special cells and their morphologic similarity to other neuroendocrine cells and defined the diffuse endocrine system distributed throughout the body.12 In 1953 serotonin was identified as the characteristic product of the carcinoid tumors. In 1954, Thorson, coincidentally with Cassidy, Bjorck, Isler, Hedinger, and Waldenstrom, defined the "carcinoid syndrome" with the typical symptoms of flushing, diarrhea, and valvular heart disease. Williams and Sandler classified carcinoid tumors according to their distribution in the foregut, midgut, and hindgut.'> In 1969 Pearse included carcinoid tumors in the amine precursor uptake and decarboxylation (APUD) system.lv" However, their presumed common origin from the neural crest holds true only for some of these cells. 16,17 In 1984, Falkmer characterized carcinoid tumors by immunohistochemistry, showing a specific pattern of neurohormonal peptides. It has become apparent, however, that the general term carcinoid fails to describe the diverse spectrum of neoplasms with regard to functional state, localization, growth pattem, degree of differentiation, expression of different neuroendocrine marker molecules, and prognosis. A new classification emerged in 1995 that includes not only the site of origin but also variations in the histologic characteristics of carcinoid tumors (Table 86_1).4,18 Using this system, carcinoid tumors are classified as well-differentiated neuroendocrine tumors and well-differentiated (low-grade) and poorly differentiated (high-grade) neuroendocrine carcinomas. The term carcinoid tumor should preferably be used for classical midgut carcinoids, whereas other types of carcinoids should be termed neuroendocrine tumor followed by their primary location, for example, neuroendocrine thymic, gastric, small bowel, or rectal tumor.

Neuroendocrine Tumors - - 781 Foregut

Midgut

Hindgut

Liver/pancreas

FIGURE 86-1. Carcinoid tumors of the primitive gut. (From

Simon D, Goretzki PE, BranscheidD, et al. Chirurgische Therapie von intestinalen Karzinoidtumoren. AktuelChir 1992;27:8.)

Pathogenesis and Pathophysiology Although the histogenesis of neuroendocrine tumors is incomplete and varies from organ to organ, it appears that neuroendocrine tumors and naive endocrine cells arise from the same progenitor cell. 3 ,19 Although controversial, it appears that neuroendocrine tumors and low-grade neuroendocrine carcinomas arise from orthotopic neuroendocrine cells of the epithelium of the respective organs, whereas high-grade neuroendocrine carcinomas derive from a putative stem cell rather than from neuroendocrine cells." Microenvironmental or functional differentiation or dedifferentiation may lead the enterochromaffin cells to produce and secrete neuroendocrine peptides. They also express many cell surface peptide receptors that enable them to respond to several growth factors. I The exact function of Kulchitsky cells is not known, although they are presumed to have endocrine and enzymatic functions. II The cells have a characteristically uniform pattern and neurosecretory granules. Neuroendocrine tumors are able to metabolize biogenic amines and thus are called APUDomas. 14 ,15 Phylogenically, neuroendocrine tumors are divided into those from the foregut, midgut, and hindgut. The foregut includes the bronchus, thymus, stomach, duodenum, and pancreas. The midgut includes the small bowel, appendix, and right hemicolon. The hindgut includes the left colon, rectum, and ovaries. 13 Each group of neuroendocrine tumors has a typical clinical presentation and prognosis. Foregut neuroendocrine tumors may stain for multiple hormones with preferential production and secretion of 5-hydroxytryptophan. Hindgut tumors may also stain for multiple hormones, but they usually do not secrete any hormone (Fig. 86-1). The exact cause of neuroendocrine tumors is not known. The vast majority of cases are sporadic, although familial cancer syndromes associated with an increased risk of

neuroendocrine tumors occur in multiple endocrine neoplasia type 1 (MEN 1), in MEN 2, and in von Recklinghausen's disease (duodenum)." Moreover, studies of sporadic neuroendocrine tumors showed that a loss of heterozygosity at the MEN 1 locus was present in 26% to 78% of these tumors. Mutations were identified at this locus using other techniques in 18% of cases. 22,23 Foregut tumors very often show involvement of the MEN 1 gene.>' Links between carcinogenesis (familial or sporadic tumors) and MEN 1 gene could be explained by growth factor-related angiogenesis (vascular endothelial growth factor, fibroblastic growth factor, and transforming growth factor), but this relation is difficult to confirm experimentally" Gastric neuroendocrine tumors are frequently found in patients with chronic atrophic gastritis (with or without pernicious anemia) and Zollinger-Ellison syndrome, leading to the assumption that hypergastrinemia is one pathogenic factor. Experimental studies and clinicopathologic results give strong evidence that omeprazole through achlorhydria leads to hypergastrinemia and enterochromaffin-like (ECL) cell hyperplasia. Thus, ECL cell hyperplasia may be the first step in the development of carcinoid tumors. Loss of function of one allele of the MEN 1 gene is probably required for progression to true neoplasia, and this gene may function as a tumor suppressor gene for fundic tumors in Zollinger-Ellison syndrome." However, the problem may be more complex than was initially appreciated because gastric neuroendocrine tumors can occur in MEN 1 patients without hypergastrinemia and the MEN 1 gene is not lost in some patients with gastric type II

lesions."

Gains of chromosomes 4, 5, and 19 and losses of chromosome 18 by comparative genomic hybridization have been associated with sporadic midgut carcinoids.Pv? Hindgut tumors in general show rather low proliferation capacity, and transforming growth factor-a or epidermal growth factor receptor autocrine mechanism may playa role in the tumor development." In contrast to a number of nonendocrine tumors, neither common oncogenes (ras, src) nor common tumor suppressor genes (P53) are generally important in the molecular pathogenesis of neuroendocrine tumors except for the more atypical forms."

782 - -

Endocrine Pancreas

Histopathology Several specific staining techniques have been developed for identifying neuroendocrine cells. The traditional ones are the argentaffin and argyrophil reactions. The argentaffin reaction as described by Masson characterizes endocrine cells that can take up and reduce silver ions." Argentaffinpositive staining is typically found in midgut carcinoid tumors and generally is assumed to be associated with the presence of serotonin. For example, argyrophilic reaction with the Grimelius technique is preferentially found in foregut and appendiceal neuroendocrine tumors. An argentaffin reaction is very specific for neuroendocrine cells, whereas an argyrophilic reaction is much more sensitive. Immunohistochemical techniques have greatly facilitated the characterization of neuroendocrine tissues by using monoclonal or polyclonal antibodies against neuron-specific enolase, chromograninA, and synaptophysin." These markers are important for the differential diagnosis and can also be elevated in the serum and thus used as tumor markers for follow-up. Diagnosis of well-differentiated neuroendocrine tumors is usually easy because of their characteristic uniform cell pattern with round nuclei and eosinophilic cytoplasm on hematoxylin and eosin staining.P Discrimination of atypical carcinoids and poorly differentiated or small cell neuroendocrine tumors may be difficult because they look like metastatic tumors from the lungs or other sites. The same applies for neuroendocrine carcinomas of the colon, which may resemble poorly differentiated colon cancers or lymphomas. Typical neuroendocrine tumors have a yellow-grayish color and can demonstrate various morphologic patterns, such as insular growth with solid nests; trabecular growth; glandular growth with alveolar, acinar, or pseudoglandular pattern; and a mixed or undifferentiated growth.F Although these different patterns can be seen in neuroendocrine tumors from all sites, foregut and hindgut tumors show preferentially a trabecular pattern arid midgut carcinoids show an insular pattern. Foregut neuroendocrine tumors almost always stain positively for thyroid transcription factor I (TTF-I), whereas gastrointestinal carcinoids do not. Staining for TTF-I can, therefore, help identify the site of origin when it is not known. The various growth patterns do not affect the prognosis, which is determined more by tumor location (Fig. 86-2).

Clinical Syndrome

+ +

Biochemical evaluation

Endoscopy

+

Biopsy

t

Removal?

/

Serotonin, 5-HTP, 5-HIAA

Ultrasonogram

+

CTscan

+ +

Liver metastases?

~Barium examination

+

Stenosis? Adhesions?

SMS scintigraphy

c

(MIBG scintigraphy)

Symptoms

FIGURE 86-2. A, Small, solid intramural carcinoid tumor of the duodenum. B, Carcinoid tumor of small intestine is partially obstructive. C, Diagnostic localization of carcinoid tumors. CT = computed tomography; 5-HIAA = 5-hydroxyindoleaceticacid; HTP = hydroxytryptophan; MmG = metaiodobenzylguanidine; SMS = somatostatin.

The endocrine activity of neuroendocrine tumors is one of their most characteristic features. They may secrete many different hormones, neuropeptides, and neurotransmitters. The best known is serotonin or its precursor, 5-hydroxytryptophan, which is predominantly secreted by gastric neuroendocrine tumors. Many other hormones (e.g., corticotropin, corticotropin-releasing factor, catecholarnines, calcitonin, somatostatin, substance P, pancreatic peptide, vasoactive intestinal peptide, and ghrelin) and other neurohormonal substances (e.g., bradykinin, tachykinin, neurokinin A,

neuropeptide K, and histamine) can be secreted from these tumors. Not all of these substances produce clinical symptoms (Tables 86-2 and 86-3). The classical carcinoid syndrome is assumed to be caused by serotonin and bradykinin. Carcinoid syndrome is defined by the presence of flushing, diarrhea, and endocardial or myocardial fibrosis with valvular heart disease."

Neuroendocrine Tumors - - 783

Carcinoid syndrome is found in 10% to 30% of the patients, depending on the location of the primary tumor. In carcinoid tumors of the gastrointestinal tract, the syndrome has been described in 10% to 20% of the patients. The presence of carcinoid syndrome should make one suspicious of metastases or large mesenteric lymph node involvement, presumably because of a lack of first-pass inactivation of the secreted hormones by the liver. In contrast, neuroendocrine tumors of the bronchus or the ovaries often arise with carcinoid syndrome in the absence of distant metastases (Table 86-4).33 Clinical observation shows various types of flushing that may indicate the location of the primary neuroendocrine tumor. A diffuse erythematous flushing affecting mainly the face, neck, and upper chest and lasting for 2 to 30 minutes is mostly associated with high urinary 5-hydroxyindoleacetic acid (5-HIAA) and gastrointestinal carcinoids. In contrast, long-lasting flushing (for hours or days) combined with profuse lacrimation and suffused conjunctiva often indicates a bronchial carcinoid" Serotonin probably plays a role in mesenteric fibrosis as well as in myocardial fibrosis, causing valvular heart disease. Ten percent to 15% of the patients have evidence of carcinoid heart disease; intra-abdominal fibrosis, including retroperitoneal fibrosis, occurs even more often and can cause bowel obstruction. Intestinal obstruction is one of the most common symptoms in gastrointestinal carcinoid tumors. It is caused by mesenteric fibrosis, intraluminal growth, intussusception,

or intestinal infarction resulting from vascular compression or adventitial fibrosis. Bleeding and chronic abdominal pain are less frequent. In our experience, most patients with gastrointestinal carcinoid tumors present with acute symptoms so that a complete biochemical evaluation and elective operation are rare. Typical symptoms of bronchial neuroendocrine tumors are hemoptysis, recurrent pulmonary infections, coughing, and wheezing. Bronchial neuroendocrine tumors are the most frequent primary pulmonary neoplasms of childhood." They most commonly arise with recurrent pneumonitis with coughing, wheezing, and hemoptysis. Many bronchial neuroendocrine tumors are asymptomatic and are discovered by routine x-ray films. They may cause bronchial constriction and arise with a picture of bronchial asthma. Bronchial neuroendocrine tumors are typically associated with paraneoplastic syndromes; they may secrete corticotropin to produce Cushing's syndrome or growth hormone to produce acromegaly. Thymic neuroendocrine tumors may also cause ectopic Cushing's syndrome. Both bronchial and thymic neuroendocrine tumors may be associated with MEN 1.36

Diagnosis A specific diagnosis based on clinical suspicion of a neuroendocrine tumor is rare and in our own experience has been made in only 20% of the patients. The most important examinations are the serum level of serotonin and the 24-hour urine collection for 5-HIAA. Because the amount of hormone secreted varies, multiple assessments may be necessary. When a gastric neuroendocrine tumor is suspected, serum 5-hydroxytryptophan should be measured instead of serotonin. In case of rare occasional flushing, pentagastrin can be infused to prevent flushing and confirm the diagnosis.'? Location of the neuroendocrine tumor determines whether endoscopic or radiologic examination is more useful. Endoscopic examination and biopsy are valuable in bronchial, gastric, and rectal neuroendocrine tumors. Gastric and rectal neuroendocrine tumors are often incidental findings when endoscopy is performed for other reasons. Because neuroendocrine tumors may grow in submucous areas, they may often be overlooked. Primary midgut carcinoids are initially generally too small to be diagnosed with conventional bowel contrast studies, and localization of these tumors remains a problem. When patients present with symptoms related to obstruction or the carcinoid syndrome, the tumors are larger and unfortunately have usually metastasized to the mesenteric nodes and liver. Computed tomography (CT) scanning is helpful in

784 - - Endocrine Pancreas

FIGURE 86-4. Somatostatin receptor scintigraphy of large ileal carcinoid tumor with extensive mesenteric infiltration and local lymph node metastases.

the hormonal hypersecretion can be controlled by somatostatin analogs (Fig. 86-4).41

Prognosis

FIGURE 86-3. A, Typical mesenteric fibrosis with isolated

structure. B, Typical multiple hepatic metastasis of varying size.

localizing the primary tumor in about 55% of cases.' The presence of a mesenteric mass with radiating densities is highly suggestive of mesenteric involvement of a midgut carcinoid. CT scanning of larger tumors often helps determine the size of the mesenteric tumor, its relation to the superior mesenteric artery, and possible extension retroperitoneally or above the pancreas. CT scanning is therefore recommended for appropriate planning prior to surgery. For patients with symptoms of intestinal obstruction, bowel contrast studies are recommended (Fig. 86-3).38 Somatostatin receptor scintigraphy has an accuracy of 80% and a positive predictive value of 100%. Because of its high sensitivity and ability to detect local and distant metastases, this examination is considered an essential imaging procedure.l-" However, this localization study displays images that are usually inadequate for precise anatomic details to be of help preoperatively." Positron emission tomography scanning is recommended for patients whose neuroendocrine tumor fails to be identified with somatostatin scanning. Preliminary studies comparing somatostatin receptor scintigraphy and positron emission tomography seem to show a higher sensitivity for the latter.v'? Somatostatin receptor scintigraphy can also predict whether

Primary tumor location and tumor size are the most relevant prognostic factors. Thus, appendiceal and rectal neuroendocrine tumors are mostly small tumors that almost never metastasize.w" In contrast, thymus neuroendocrine tumors arise with distant metastases in about 30%43,44 and gastric and small intestinal carcinoids in up to 100%.45,46 In gastric neuroendocrine tumors, pathogenesis also determines prognosis. The multiple carcinoid tumors found in the case of hypergastrinemia with ECL cell hyperplasia (type I or II) have a much better prognosis than solitary tumors unassociated with hypergastrinemia (type III). Tumor size also predicts the risk of metastatic spread in neuroendocrine tumors, whereas in other gastrointestinal tumors the depth of tumor invasion is a better prognostic factor.'? The appendiceal, colon, and rectal neuroendocrine tumors are mostly small and usually do not metastasize. Generally, tumors smaller than 1.5 or 2 em have a low risk of metastatic spread. However, size is less predictive of prognosis in small intestinal carcinoids. Even tumors smaller than the critical size of 1.5 ern may have nodal or distant metastases (Table 86-5). Identifying molecular alterations or other factors that categorize patients with aggressive tumors could be of great clinical value, allowing more aggressive treatment.P In general, all cytosolic and granular markers are found in welldifferentiated endocrine tumors. In poorly differentiated neuroendocrine carcinomas, however, only cytosolic markers and synaptophysin are generally widely expressed." The presence or type of somatic MEN 1 mutation has not been correlated with disease phenotype and to date has no role for neuroendocrine tumors in clinical prcgnosis/" Loss of

Neuroendocrine Tumors - -

neuropilin-2 expression in neuroendocrine cells has been shown to accompany tumor progression in neuroendocrine tumor.50 Moreover, MIB-l antibody reacts with the Ki-67 nuclear protein associated with cell proliferation and has been used to profile tumor aggressiveness. Although studies of Ki-67 have been helpful in assessing the malignant behavior of neuroendocrine tumors, multiparametric approaches examining the full range of cyclins, cyclin inhibitors, factors controlling apoptosis, oncogenes, and tumor suppressor genes are essential to resolve this issue." The overall survival in all groups of neuroendocrine tumors is about 50% to 60% at 5 years, 30% to 40% at 10 years, and 25% at 15 years. Five-year survival rate in patients with a distant metastases is about 20%. Thus, neuroendocrine tumors have a moderately good prognosis, and long-term survival is possible even in advanced stages.

Therapy The predicted prognosis of patients with neuroendocrine tumors influences therapy. Treatment modalities are numerous, including diverse surgical procedures, chemotherapy, arterial embolization, hormone antagonists (somatostatin), and cytokines (interferon-a). Surgery is the treatment of choice in early-stage tumors to remove the primary tumors and locoregionallymph nodes. Operations depend on tumor location, tumor size, and multicentricity. Tumor location is the most important factor and is strongly correlated with tumor size. Therefore, the surgical procedures are discussed according to the location of the tumors. Besides the presence of lymph node involvement, tumor histology determines the prognosis of bronchial neuroendocrine tumors. Atypical tumors have a worse prognosis. The tumor histology and tumor grading are obtained in only about 70% of tumors by bronchoscopy and bronchial lavage. Magnetic resonance imaging and CT scanning are used to identify these tumors as well as delineate tumor growth and identify lymph node metastases. Because locoregional tumor spread is encountered in one third of patients, radical resection is mandatory. Tumor-free margins are essential, and lymph node dissection should be performed. On the other hand, surgery should save as much of parenchyma as possible. Therefore, lobectomy with or without bronchoplasty

785

should be the procedure of choice and pneumonectomy the exception. Bronchoscopic removal with laser coagulation should be reserved for unfit and high-risk patients. 1,26 Thymic neuroendocrine tumors are extremely rare tumors and often arise with local invasion and paraneoplastic syndromes. Thus, the aims of surgery are to resect the tumor radically and to relieve paraneoplastic symptoms. Radical resection should be performed even in the presence of perithymic or vascular invasionfollowed by adjuvant radiation therapy. For patients with MEN 1 and primary hyperparathyroidism, prophylactic upper thymectomy should be done during neck exploration because supernumerary parathyroid glands are found in 15% to 20% of these patients and it also removes the site where thymus tumors may develop (especially in men).52,53 In gastric neuroendocrine tumors, surgery may be indicated, depending on their pathogenesis, For solitary or multiple gastric tumors in the presence of hypergastrinemia and ECL cell hyperplasia, limited surgical procedures may be justified. They include endoscopic removal of tumors or antrectomy to remove the source of gastrin. There is, however, a certain risk of tumor recurrence despite the return of serum gastrin to normal. For other gastric neuroendocrine tumors, radical resection with gastrectomy and lymphadenectomy should be performed. 54 Duodenal neuroendocrine tumors are extremely rare tumors that may contain and secrete calcitonin or somatostatin and are often found as polypoid tumors by endoscopy. Endoscopic removal is justified because the tumors are small and the depth of invasion can be assessed by endoluminal ultrasonography. Full-thickness wall excision or resection is necessary for tumors over 4 em in diameter. The management of these lesions is determined on a case-by-case basis and dictated by presence of symptoms. 19 Small bowel carcinoid tumors are the most common neuroendocrine tumors, with increasing frequency from the jejunum to the ileum. The most important prognostic parameter is the presence of lymph node metastases. There is also a good correlation of tumor size with locoregional tumor spread, with a critical size of 1.5 to 2 em. Tumors of 1 em in diameter or less, however, are capable of metastasis. Therefore, segmental resection with lymph node dissection is mandatory. Resection can relieve endocrine tumor symptoms even in the presence of distant metastases. The risk of short bowel syndrome, which is difficult to manage in combination with the carcinoid syndrome, should always be kept in mind by the surgeon. 19,38,45,55,56 Appendiceal neuroendocrine tumors are mostly incidental findings, usually smaller than 1.5 em in diameter. Generally, the tumors are located at the apex and seldom at the appendiceal base. As a rule, appendectomy is the standard procedure. If the tumor is located proximally or larger than 2 em, additional partial resection of the cecum with lymph node dissection may be necessary. For larger tumors or suspicious lymph nodes, a right hemicolectomy is indicated. 19,26,42 Neuroendocrine tumors of the colon show a decrease in frequency from the right to the left colon. Tumor size is strongly correlated with the incidence of lymph node involvement, with a critical diameter of about 1.5 to 2 em. Most of the tumors are larger, so lymphatic tumor spread is

786 - -

Endocrine Pancreas

to be expected. Surgical resection should include the lymphatic drainage similar to that for adenocarcinomas.Wt-" Rectal neuroendocrine tumors are generally very small and rarely metastasize. Good access by palpation and proctoscopy presumably leads to early diagnosis, so that in most cases endoscopic removal or fulguration is sufficient. For larger tumors between 1 and 2 em or those with deeper infiltration, a transanal excision should be performed, Transanal endosonography may be particularly useful in this intermediate group to assess tumor extension. A more radical approach (low anterior resection with total mesorectal excision or abdominoperineal resection) is restricted to larger tumors with a higher risk of metastasis. 19,58

Carcinoid Syndrome Treatment of the carcinoid syndrome is more complicated because it is often associated with hepatic metastases. Carcinoid syndrome occurs with 5% of all neuroendocrine tumors but occurs more often in patients with small bowel . ids.59Many diifferent approaches, such as liver reseccarcmoi tion, tumor debulking, radiofrequency ablation, chemoembolization, and liver transplantation, as well as treatment with somatostatin analogs and interferon-a make it difficult to choose the optimal therapy. Therapy should be guided by whether curative or palliative therapy is possible and whether the endocrine symptoms or the tumor burden is the problem. ~es~ite the development of potent drugs for controlling carcinoid syndrome, surgery is still the treatment of choice for possible cure. When liver metastases are resectable, hepatectomy should be performed and the primary intestinal tumor removed. 45 ,60 ,6 1 Even when hepatic metastases are diffuse, operative intervention is critical in one or multiple stages." Tumor debulking can control carcinoid syndrome and reduce urinary 5-HIAA levels. The occurrence and severity of the syndrome are clearly related to tumor bulk. However, the tumor mass must be reduced to 10% to 20% to control the symptoms when cytoreductive hepatic surgery is performed.v With the advent of somatostatin analogs, the role of surgical debulking may be restricted to low-risk patients with one dominant tumor mass that did not respond to somatostatin treatment. Liver transplantation for diffuse hepatic metastases may be considered in selected patients when extrahepatic metastases have been excluded. 26,63 Methods for in situ destruction of liver tumors (radiofrequency, cryotherapy, or laser ablation) are new alternative regional treatment options. The long-term survival benefit of these interventions is not yet known. 60,64 Neither systemic chemotherapy nor hepatic dearterialization has been effective in controlling tumor growth and symptoms. 1,65 Chemoembolization with superselective occlusion, however, co~trols the tumor burden and symptoms in up to 80% of the patients for an average duration of 11 months. 66,67 Somatostatin has become the most important drug in the medical treatment of neuroendocrine tumors. It alleviates carcinoid syndrome symptoms in about 80% of patients at a dosage of 200 to 600 ug/day, The duration of remission, however, is short with a median of 8 to 12 months. Although biochemical markers transiently decrease in about 70% of

Clinical Syndrome

No Symptoms

~

~

Biochemical evaluation

Incidental guiding at operation

Diagnostic localization

~

Oncologic resection / " (exceptions: duodenum, appendix, rectum)

~

Hepatic metastases .

+S,M;!

Hepatic resection

+SMS\

•

a-IFN + SMS?

~

Chemoembolization

Octreotide (SMS)

FIGURE 86-5. Therapy for carcinoid tumors, IFN = interferon' , SMS = somatostatin,

pati~nts, tumor size reduction resulting from the antiproliferatrve effect of somatostatin analogs occurs in fewer than 10% of patients. Stabilization of tumor growth, however, occurs in about 50% of patients with a median response of about 18 months. 68,69 Somatostatin should be administered before tumor manipulation, including all operative procedures and catheter embolization. Somatostatin reduces the risk of severe flushing resulting from massive release of hormones and kinins.?? Interferon-a inhibits tumor proliferation with short-term relief from the carcinoid syndrome, Interferon-a alone or in combination with somatostatin analogs and interferon in combination with fluorouracil may result ~n a biochemical response in up to 50% of patients, but evidence of tumor regression is reported in only 10% to 20% of patients. 1,71 Thus, resection of hepatic metastases c~ be performed with curative intention or for symptomatic rehef. Another attractive option is cytoreduction by multimodal therapy (Fig. 86-5). Hepatic radioembolization and somatostatin receptor-targeted radiotherapy are new approaches to localized radiotherapy and are under clinical evaluation."

Summary Carcinoid tu~ors are neuroendocrine tumors that frequently produce vanous hormones and kinins that may cause characteristic symptoms, including carcinoid syndrome. The symptoms, treatments, and prognosis depend mostly on the location and size of the tumor. Surgical resection can be palliative even when there is metastatic tumor. Somatostatin analogs can alleviate the symptoms of carcinoid syndrome,

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4. Capella C, Heitz PU, Hofler H, et ai. Revised classification of neuroendocrine tumors of the lung, pancreas and gut. Virchows Arch 1995;425:547. 5. Jensen RT. Natural history of digestive endocrine tumors. In: Mignon M, Colombel JF (eds), Recent Advances in the Pathophysiology and Management of Inflammatory Bowel Diseases and Digestive Endocrine Tumors. Paris, John Libbey Eurotext, 1999, p 192. 6. Moertel CG, Sauer WG, Dockerty MB, et ai. Life history of the carcinoid tumor of the small intestine. Cancer 1961;14:901. 7. Teitelbaum SL. The carcinoid. Am J Surg 1972; 123:546. 8. Obemdorfer S. Karzinoid Tumoren des Diinndarmes. Frankf Z Pathol 1907;1:425. 9. Masson P. Carcinoids (argentaffin-cell tumors) and nerve hyperplasia of the appendicular mucosa. Am J PathoI1928;4:181. 10. Masson P. La glande endocrine de I'intestin chez l'homme. Coli R Acad Sci (Paris) 1914;158:59. 11. Warren KW, Coyle EB. Carcinoid tumors of the gastrointestinal tract. Am J Surg 1951;82:372. 12. Feyrter F. Uber die periphen endokrinen (parakrinen) Driisen des Menschen. Verlag fur medizinische Wissenschaften. Wien-Diisseldorf, Wilhelm Maudrich, 1938. 13. Williams ED, Sandler M. The classification of carcinoid tumours. Lancet 1963;1:238. 14. Pearse AGE. The APUD concept and hormone production. Clin Endocrinol Metab 1980;9:211. 15. Pearse AGE. The APUD cell concept and its implication in pathology. Pathol Annu 1974;9:27. 16. Fontaine J, Le Dourain NM. Analysis of entoderm formation in the avian blastoderm by the use of quail-chick chimeras. J Embryol Exp MorphoI1977;41:209. 17. Bolande RP. The neurocristopathies: A unifying concept of disease arising in neural crest maldevelopment. Hum Pathol 1974;5:409. 18. Solcia E, Kloppel G, Sobin LH. Histological Typing of Neuroendocrine Tumors. Berlin, Springer, 2000. 19. Lauffer JM, Zhang T, Modlin 1M. Review article: Current status of gastrointestinal carcinoids. Aliment Pharmacol Ther 1999;13:271. 20. Helpap B, Kollermann J. Immunohistochemical analysis of the proliferative activity of neuroendocrine tumors from various organs. Virchows Arch 2001 ;438:86. 21. Wheeler MH, Curley IR, Williams ED. The association of neurofibromatosis, pheochromocytoma, and somatostatin-rich duodenal carcinoid tumor. Surgery 1986;100:1163. 22. Jensen RT. Carcinoid and pancreatic endocrine tumors: Recent advances in molecular pathogenesis, localization, and treatment. Curr Opin OncoI2000;12:368. 23. Gortz B, Roth J, Krahenmann AN, et al. Mutations and allelic deletions of the MEN 1 gene are associated with a subset of sporadic endocrine pancreatic and neuroendocrine tumors and not restricted to foregut neoplasms. Am J Pathol 1999;154:429. 24. Oberg K. Carcinoid tumors: Molecular genetics, tumor biology, and update of diagnosis and treatment. Curr Opin OncoI2002;14:38. 25. Calender A. New insights in genetics of digestive neuroendocrine tumors. In: Mignon M, Colombel JF (eds), Recent Advances in the Pathophysiology and Management of Inflammatory Bowel Diseases and Digestive Endocrine Tumors. Paris, John Libbey Eurotext, 1999, p 155. 26. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999;340:858. 27. Bordi C, Corleto VD, Azzoni C, et ai. The antral mucosa as a new site for endocrine tumors in multiple endocrine neoplasia type I and Zollinger-Ellison syndromes. J Clin Endocrinol Metab 2001;86:2236. 28. Tonnies H, Toliat MR, Ramel C, et ai. Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation. Gut 2001;48:536. 29. Lollgen RM, Hessman 0, Szabo E, et ai. Chromosome 18 deletions are common events in classical midgut carcinoid tumors. Int J Cancer 2001;92:812. 30. Kytola S, Hoog A, Nord B, et ai. Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids. Am J PathoI2001;158:1803. 31. Wilander E. Diagnostic pathology of gastrointestinal and pancreatic neuroendocrine tumors. Acta Oncol 1989;28:363. 32. Johnson LA, Lavin P, Moertel CG, et ai. Carcinoids: The association of histological growth pattern and survival. Cancer 1983;51:882. 33. MacGillivray DC, Snyder DA, Drucker W. Carcinoid tumors: The relationship between clinical presentation and the extent of the disease. Surgery 1991;110:68.

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34. Graham E, Smith DG. What is the cause of the carcinoid flush? Gut 1987;28:1413. 35. Wang LT, Wilkins EW, Bode HH. Bronchial carcinoid tumors in pediatric patients. Chest 1993;103:1426. 36. Teh BT. Thymic carcinoid tumors in multiple endocrine neoplasia type 1. Ann Surg 1998;228:99. 37. Frolich JC, Bloomgarden ZT, Oates JA, et ai. The carcinoid flush. N Engl J Med 1978;299:1055. 38. Ohrvall U, Eriksson B, Juhlin C, et al. Method for dissection of mesenteric metastases in midgut carcinoid tumors. World J Surg 2000;24:1402. 39. Kaltsas G, Korbonits M, Heintz E, et ai. Comparison of somatostatin analog and metaiodobenzylguanidine radionuclides in the diagnosis and localization of advanced neuroendocrine tumors. J Clin Endocrinol Metab 2001;86:895. 40. Hoegerle S, Altehoefer C, Ghanem N, et ai. Whole-body 18F dopa PET for detection of gastrointestinal carcinoid tumors. Radiology 2001;220:373. 41. Ahlman H, Wangberg B, Tisell E, et al. Clinical efficacy of octreotide scintigraphy in patients with midgut carcinoid tumours and evaluation of intraoperative scintillation detection. Br J Surg 1994;81: 1144. 42. Moertel CG, Weiland LH, Telander L. Carcinoid tumor of the appendix in the first two decades of life. J Pediatr Surg 1990;25: 1073. 43. Izbicki JR, Eypasch E, Seel R, et ai. Zur Frage der chirurgischen Behandlung malinger Tumoren der appendix. Zentralbl Chir 1989; 114:1217. 44. Economopolous GC, Lewis JW, Lee MW, et al. Carcinoid tumors of the thymus. Ann Thorac Surg 1990;50:58. 45. Akerstrom G, Makridis C, Johansson H. Abdominal surgery in patients with midgut carcinoid tumors. Acta OncoI199l;30:547. 46. Marshall JB, Bodnarchuk G. Carcinoid tumors of the gut. J Clin GastroenteroI1993;16:123. 47. Agranovich AL, Anderson GH, Manji M, et ai. Carcinoid tumor of the gastrointestinal tract: Prognosis factors and disease outcome. J Surg OncoI1991;47:45. 48. Rindi G, Capella C, Solcia E. Pathobiology and classification of gut endocrine tumors. In: Mignon M, Colombel JF (eds), Recent Advances in the Pathophysiology and Management of Inflammatory Bowel Diseases and Digestive Endocrine Tumors. Paris, John Libbey Eurotext, 1999, P 177. 49. Schussheim D, Skarulis M, Agarwal S, et al. Multiple endocrine neoplasia type 1: New clinical and basic findings. Trends Endocrinol Metab 2001;12:173. 50. Cohen T, Gluzman-Poltarak Z, Brodzky A, et al. Neuroendocrine cells along the digestive tract express neuropilin-2. Biochem Biophys Res Commun 2001;284:395. 51. Delellis RA. Proliferation markers in neuroendocrine tumors: Useful or useless? Verh Dtsch Ges PathoI1997;81:53. 52. Dotzenrath C, Goretzki P, Cupisti K, et ai. Malignant endocrine tumors in patients with MEN I disease. Surgery 2001;129:91. 53. Mullan M, Gauger P, Thompson N. Endocrine tumors of the pancreas: Review and recent advances. ANZ J Surg 2001;71 :475. 54. Schindl M, Kaserer K, Niederle B. Treatment of gastric neuroendocrine tumors. Arch Surg 2001;136:49. 55. Makridis C, Rastad J, Oberg K, et al. Progression of metastases and symptom improvement from laparotomy in midgut carcinoid tumors. World J Surg 1996;20:900. 56. Hellman P, Lundstrom T, Ohrvall U, et ai. Effect of surgery on the outcome of midgut carcinoid disease with lymph node and liver metastases. World J Surg 2002;26:991. 57. Federspiel BH, Burke AP, Sobin LH, et al. Rectal and colonic carcinoids. Cancer 1990;65:135. 58. Jetmore AB, Ray JE, Gathright JB, et ai. Rectal carcinoids: The most frequent carcinoid tumor. Dis Colon Rectum 1992;35:717. 59. Ballantyne GH, Savoca PE, Flannery JT, et ai. Incidence and mortality of carcinoids of the colon. Cancer 1992;69:2400. 60. Siperstein A, Berber E. Cryoablation, percutaneous alcohol injection, and radiofrequency ablation for treatment of neuroendocrine liver metastases. World J Surg 2001;25:693. 61. Jaeck D, Oussoultzoglou E, Bachelier P, et ai. Hepatic metastases of gastroenteropancreatic neuroendocrine tumors: Safe hepatic surgery. World J Surg 2001;25:689. 62. Nave H, Mossinger E, Feist H, et ai. Surgery as primary treatment in patients with liver metastases from carcinoid tumors: A retrospective, unicentric study over 13 years. Surgery 2001;129:170.

788 - - Endocrine Pancreas 63. Olausson M, Friman S, Cahlin C, et al. Indications and results of liver transplantation in patients with neuroendocrine tumors. World J Surg 2002;26:998. 64. De Vries H, Verschueren RJC, Willemse PH, et aI. Diagnostic, surgical and medical aspect of the midgut carcinoids. Cancer Treat Rev 2002;28:11. 65. Moertel CG, Johnson CM, McKusick MA, et aI. The management of patients with advanced carcinoid tumors and islet cell carcinomas. Ann Intern Med 1994;120:302. 66. Therasse E, Breitmayer F, Roche A, et al. Transcatheter chemoembolization of progressive carcinoid liver metastases. Radiology 1993;189:541. 67. Proye C. Natural history of liver metastasis of gastroenteropancreiltic neuroendocrine tumors: Place for chemoembolization. World J Surg 2001;25:685.

68. Arnold R, Trautmann ME, Creutzfeldt W, et al. Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumors. Gut 1996;38:430. 69. Skogseid B. Nonsurgical treatment of advanced malignant neuroendocrine pancreatic tumors and midgut carcinoids. World J Surg 2001; 25:700. 70. Mulvihill SJ. Perioperative use of octreotide in gastrointestinal surgery. Digestion 1993;54(Suppl 1):33. 71. Oberg K. Chemotherapy and biotherapy in neuroendocrine tumors. CUIT Opin Oncol 1993;5:110.

Endocrine Emergencies: Hypoglycemic and Hyperglycemic Crises Silvio E. Inzucchi, MD • Barbara K. Kinder, MD

Hypoglycemic and hyperglycemic crises are potentially life-threatening events encountered with sufficient frequency in surgical patients to warrant a comprehensive understanding of their causes and management. These aberrations of carbohydrate metabolism occur most commonly in diabetic patients, who are hospitalized and undergo surgery more frequently than the general population. I To provide a framework for the understanding of the pathophysiology of these metabolic disorders, we first briefly review the normal mechanisms of glucose homeostasis and then discuss these emergencies individually, their clinical presentations, pathogenesis, and recommended therapy. The chapter concludes with our approach to the management of diabetes in the surgical setting.

Overview of Glucose Metabolism Physiology of Systemic Glucose Homeostasis Whole-body glucose homeostasis represents a balance between glucose supply and glucose disposal (or utilization). When the supply of glucose exceeds its disposal, blood glucose concentration rises; when utilization exceeds supply, glucose levels fall. In normal individuals, this balance is intricately maintained so that blood glucose remains stable, typically between 60 and 140 mg/dL, even in the setting of such disparate stressors as the ingestion of a large, simple carbohydrate load or a prolonged fast.' In contradistinction, marked metabolic abnormalities occur when this balance is perturbed, such as in diabetes mellitus or insulinoma. The sources of blood glucose include gastrointestinal carbohydrate absorption and de novo hepatic production in the form of glycogenolysis and gluconeogenesis. The major source of glucose at any particular time depends on the phase of the

meal cycle. In the postprandial phase, hepatic glucose production is suppressed, with new glucose appearance primarily due to absorption of digested carbohydrates. Glucose absorption generally lasts for 2 to 5 hours after a meal, depending on the caloric content and composition of the meal. The tissues responsible for glucose utilization include those that require insulin and those that are insulin independent. The brain is the organ responsible for most of the insulin-independent glucose utilization in the fasting state, with erythrocytes and the renal medulla involved to a lesser extent. In the postprandial phase, insulin-requiring glucose disposal occurs in many body tissues, most prominently in the liver and muscle. After nutrient ingestion, insulin secretion is stimulated directly by a rise in both plasma glucose and amino acids and indirectly through the action of a variety of incretins, or intestinal factors that promote insulin secretion.' In liver and muscle, insulin stimulates storage of glucose into glycogen and amino acids into protein. In adipose tissue, insulin stimulates free fatty acid (FFA) incorporation into triglycerides (TGs). Insulin action is balanced by the effects of counter-regulatory hormones, most notably glucagon and catecholamines.v' Both hormones stimulate hepatic glycogenolysis and gluconeogenesis in the liver, whereas catecholarnines have additional effects on the pancreas to inhibit insulin release and on muscle to inhibit insulin action. In the postabsorptive or fasting phase, the liver becomes an organ of net glucose production; glycogenolysis contributes approximately 40% of the new glucose supply and gluconeogenesis contributes approximately 60%. As the fast progresses, the percentage of gluconeogenesis contribution rises. By day 3, gluconeogenesis accounts for virtually all glucose production.t Substrates for gluconeogenesis include amino acids from catabolized muscle protein, lactate, pyruvate, and glycerol. In general, the liver is the major gluconeogenic organ in the body. However, under certain

789

790 - - Endocrine Pancreas circumstances such as prolonged fasting (lasting longer than several weeks), the kidney can supply up to 40% of whole body glucose production." In the postabsorptive phase, circulating insulin levels are low. At this time, insulin-independent organs consume about half of the body's glucose production, whereas other tissues derive most of their energy needs from fat oxidation (ketone bodies).

Hormonal Regulation of Glucose Metabolism The major hormones responsible for glucose homeostasis are insulin and glucagon, both products of pancreatic islet cells. Insulin, originally isolated from pancreatic tissue by Banting and Best in 1921,7 is synthesized in the beta cells of the islets. The insulin gene is located on the short arm of chromosome 11. Because of the action of negative regulatory elements found in other tissues, insulin gene expression and insulin biosynthesis are limited to beta cells as well as to cells of the fetal yolk sac and liver," Glucose regulates all aspects of insulin metabolism. In addition to directing hormone exocytosis, glucose stimulates transcription of the insulin gene 9 •10 as well as certain post-transcriptional events. The primary RNA transcript of the insulin gene encodes a prepro sequence, alpha and beta chains, and an intervening C peptide. Cleavage of the signal sequence on entry of the nascent protein into the rough endoplasmic reticulum yields proinsulin. II Although the pancreatic beta cell uses both constitutive and regulated pathways to deliver its synthetic products to their proper destinations, under normal circumstances proinsulin is sorted almost exclusively to the regulated pathway.P Conversion of proinsulin to insulin and C peptide occurs in the immature secretory granule during intracellular transport. Proteolytic cleavage takes place in two steps: first at the beta chain-C peptide junction and second at the C peptide-alpha chain site. 13 This process of conversion is accelerated when ambient glucose is elevated. 14 Despite the efficiency of targeting proinsulin to the regulated pathway and of its intragranular conversion, intact proinsulin and conversion intermediates are detected in the blood stream." Increased proinsulin-insulin ratios are commonly found in patients with type 2 diabetes mellitus (T2DM; formerly, non-insulin-dependent diabetes mellitus) and in some with type 1 diabetes mellitus (TlDM; formerly, insulin-dependent diabetes mellitus). Although the exact mechanisms are unknown, evidence supports both abnormalities of proinsulin conversion and rapid granule turnover, preventing complete proteolysis." Increased proinsulininsulin ratios in patients with insulinoma may be due to hormone release via constitutive rather than regulated pathways in these transformed cells. 17 The primary stimulants of insulin secretion are glucose and other energy substrates, such as amino acids. Secondary stimuli include glucagon, acetylcholine, and various gastrointestinal hormones, such as gastric inhibitory polypeptide and glucagon-like peptide (GLP), that are capable of potentiating insulin secretion in the presence of a primary agent." Glucose stimulation of insulin secretion requires the entry of glucose into the beta cell and its metabolism. Glucose enters the beta cell via GLUT-2 transporters, and its subsequent

aerobic glycolysis generates several adenosine triphosphate (ATP)-dependent intracellular signals. Among these, closure of ATP-sensitive potassium channels results in cell membrane depolarization and the influx of calcium via voltagedependent calcium channels.'? An increase in cytosolic calcium, in tum, triggers exocytosis by a network of complex protein-protein and lipid-protein interactions similar to those involved in neurotransmitter secretion and common to all cellular membrane fusion events." Glucagon was identified in 1923 as the hyperglycemic component of canine pancreatic extracts.P The glucagon gene is located on the long arm of chromosome 2 21 and is expressed in pancreatic alpha cells, small intestinal L cells, and certain hypothalamic cells.P Tissue-specific enzymes permit cell-selective cleavage of preproglucagon into various peptides such as glicentin (enteroglucagon), oxyntomodulin, and GLP, but only alpha cells produce glucagon.P Glucagon is the primary guarantor of cerebral fuel delivery and is regulated by both glucose and insulin." In the human islet the different endocrine cell types are arranged in a nonrandom fashion, with the glucagon-producing alpha cells surrounding a beta-cell core." Glucose acts directly on alpha cells to suppress glucagon release. In addition, insulin secreted into the islet microcirculation from centrally located beta cells potently inhibits glucagon secretion." Glucagon secretion is also influenced by adrenergic, cholinergic, and peptidergic innervation of the islets. For example, adrenergic stimulation initiated by exercise immediately stimulates secretion of glucagon, preventing the development of exercise-related hypoglycemia. During feeding, cholinergic and peptidergic signals, amplified by the effects of various gastrointestinal hormones, regulate the release of glucagon as nutrient absorption begins.?? Despite circulating glucose levels in the low-normal range, insulin secretion continues at a basal rate during fasting. Within minutes of a carbohydrate meal, a prompt rise in pancreatic insulin secretion, with a concomitant decline in glucagon production, is observed. Postprandial (mixed-meal) glucose excursions are thus maintained within a relatively narrow window of +20 to 30 mg/dL. 28 By 180 minutes, insulin levels have returned to baseline. Subsequent caloric intake will result in similar fluctuations of these hormones, depending on the size and nutrient composition of a particular meal. In patients with established TlDM, insulin is no longer released to any significant degree. In T2DM, insulin secretion is variable. However, because most of these individuals demonstrate cellular insulin resistance, fasting insulin levels are typically elevated early in the course of disease." With carbohydrate challenge, insulin secretion is further augmented, although the rise is comparatively delayed and prolonged. As T2DM progresses, insulin secretory capacity declines, although rarely to the extent demonstrated in TlDM. In patients with postabsorptive hypoglycemia, as occurs in insulinoma, inappropriate hyperinsulinemia is the rule. A pathologically high degree of insulin secretion persists despite low ambient circulating glucose levels.'? In addition, defective secretion of counter-regulatory hormones has also been demonstrated in these patients." In those affected by postprandial or reactive hypoglycemia, insulin secretion may be inappropriately exuberant in response to meals, although in the fasting state it is appropriately attenuated"

Endocrine Emergencies: Hypoglycemic and Hyperglycemic Crises - -

Hyperglycemic Crises A mismatch between glucose supply and disposal leads to clinical syndromes. Such defects in glucose homeostasis occur because of alterations in nutrient absorption, storage, or release.This may be a result of dysfunction of the pancreas, gastrointestinal tract, liver, skeletal muscle, or endocrine glands, such as the pituitary and adrenals, that is responsible for the secretion of counter-regulatory hormones. In most surgical patients, hyperglycemic or hypoglycemic crises are primarily due to inadequate or excessive insulin secretion or administration, accompanied by failure of compensatory mechanisms. These medical emergencies and their treatment in adult patients are reviewed.

Diabetic Ketoacidosis CLINICAL PRESENTATION AND PATHOGENESIS

By definition, diabetic ketoacidosis (DKA) exists when the plasma glucose level is higher than 250 mg/dL, whole blood pH is 7.30 or less, serum bicarbonate is 18 mEq/L or less, anion gap is greater than 12 mEq/L, and serum or urine ketones are identified" Symptoms include polyuria, polydipsia, nausea, vomiting, abdominal pain, and alterations in mental status. Physical signs include volume depletion (hypotension, tachycardia, decreased skin turgor, dry mucous membranes), ketosis (fruity odor to breath), and metabolic acidosis (Kussmaul's respirations, ileus). This potentially life-threatening condition results from severe insulin deficiency or, rarely, from marked augmentation of counter-regulation in an insulin-resistant patient. It is a common presentation in individuals with TlDM. Other precipitating factors include omission of insulin administration and the development of an intercurrent illness, such as a superimposed viral or bacterial infection. DKA may also occur in TIDM patients being treated with continuous subcutaneous (SC) insulin infusion via an external insulin pump." In this situation, because there is no SC depot of intermediate- or long-acting insulin, plasma insulin levels decrease quickly if pump delivery is interrupted for any reason or if provision for increased delivery is not made in the case of an intercurrent illness. DKA is uncommon in individuals with T2DM, because these patients, although frequently markedly hyperglycemic, typically produce enough insulin to avoid this catabolic state. When DKA occurs in T2DM, an underlying significant physical stress, such as severe infection, fulminant pancreatitis, or myocardial infarction, is almost always involved. Three factors are involved in the pathogenesis of DKA: (1) failure of insulin release (or administration); (2) increase in the secretion of counter-regulatory hormones; and (3) superimposed dehydration. Determination of circulating C-peptide levels (as a measure of insulin release) has confirmed decreased insulin secretion in patients with DKA compared with those with hyperglycemic, hyperosmolar syndrome (HHS) (see following discussion)." Although an increase in the levels of counter-regulatory hormones is not absolutely required for the development of DKA, these do exacerbate the diabetic state by increasing glucose production and contributing to negative nitrogen balance."

791

The third factor, dehydration, although more prominent in HHS, also helps define the clinical picture of DKA. In DKA, marked alterations occur in carbohydrate, lipid, and protein metabolism, as shown in Figure 87-1. The absolute or relative decrease in insulin availability and an increase in counter-regulatory hormones result in a generalized catabolic state, with enhanced hepatic gluconeogenesis and glycogenolysis, augmented lipolysis, and negative nitrogen balance. The proposed biochemical changes responsible for the alterations of intermediary metabolism in DKA are shown in Figure 87-2.33Both glucagon and catecholarnines stimulate liver and muscle phosphorylases, initiating the process of glycogenolysis. In the liver, increased gluconeogenesis occurs with activation of a series of rate-limiting enzymes: pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-biphosphatase, and glucose-6phosphatase (G-6-Pase). Activation of G-6-Pase by glucagon facilitates conversion of glucose-6-phosphate (G-6-P) to glucose. As a result, metabolism of G-6-P by glycolysis and via the hexose monophosphate shunt is correspondingly reduced. In adipose tissue, a lack of insulin and increased circulating catecholamines combine to accelerate TG metabolism into glycerol and FFAs. The former is a substrate for gluconeogenesis, and the latter are oxidized to ketone bodies (~-hydroxybutyrate and acetoacetate), which, as unmeasured anions, result in the hallmark nonanion gap metabolic acidosis. Somewhat paradoxically, hypertriglyceridemia may be seen in DKA36 because of new TG synthesis from increased circulating substrates in the form of FFAs. In addition, increased production of the TG-rich very-low-density lipoproteins (VLDLs) by the liver and decreased VLDL clearance as a result of decreased activity of lipoprotein lipase are demonstrated. Negative nitrogen balance results from decreased protein synthesis and increased proteolysis. Metabolic acidosis results from the titration of protons of ketoacids by bicarbonate." Once therapy is initiated, a pure hyperchloremic metabolic acidosis may also develop, resulting from extracellular space expansion with sodium chloride (NaCI) and concurrent renal changes. In the hours to days leading up to the marked metabolic changes of DKA, significant water and electrolyte losses occur primarily because of osmotic diuresis. At presentation, total body water, sodium, and potassium are depleted, with deficits in some cases approaching 5 to 8 L, 400 to 700 mEq, and 250 to 700 mEq, respectively. This results in a contracted intravascular space, decreased renal perfusion, a fall in glomerular filtration rate, and reduced renal clearance of both glucose and ketones. Both hyperglycemia and acidosis are thus potentiated. In severe cases, hypotension and vascular collapse may ensue-" THERAPY

Once the diagnosis of DKA is confirmed, treatment is initiated as outlined in Figure 87-3. Because of the gravity of this condition, treatment is best provided in a setting that affords close and expeditious monitoring of the clinical status, such as a medical intensive care unit. A loading dose of 10 units of regular insulin is given intravenously (IV) followed by a continuous IV drip of 5 to 10 units/hr. In mild cases, frequent SC doses may be given, although more rapid

792 - -

Endocrine Pancreas Glycogen

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Fatty

F-6-P ~ .-/

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P ruvate Kinase Pyruvate ~ ITCA Cycle

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FIGURE 87-1. Proposed biochemical changes that occur during diabetic ketoacidosis. These alterations lead to increased gluconeogenesis and lipolysis and decreased glycolysis. Note that lipolysis occurs mainly in adipose tissue. Other events occur primarily in the liver (except some gluconeogenesis in the kidney). ATP =adenosine triphosphate; CoA =co-enzyme A; FFA =free fatty acids; F-6-P =fructose6-phosphate; G-(X)-P = glucose-(X)-phosphate; HK = hexokinase; HMP = hexose monophosphate; PC = pyruvate carboxylase; PFK =phosphofructokinase; PEP =phosphoenolpyruvate; PEPCK =PEP carboxykinase; PK =pyruvate kinase; TCA =tricarboxylic acid; TG = triglycerides. (From Kitabchi AB, Fisher JN, Murphy MH, et al. Diabetic ketoacidosis and the hyperglycemic, hyperosmolar nonketotic state. In: Kahn CR, Weir GC reds], Joslin's Diabetes Mellitus, 13th ed. Philadelphia, Lea & Febiger, 1994, p 738.)

and precise dosing is possible with the IV route. In the early stages of DKA, if there is profound dehydration, absorption from SC tissues may be unreliable. Rehydration with 0.9% IV NaCI is begun as soon as possible. When the clinical examination and laboratory indexes suggest repletion of the intravascular space, or if hypernatremia develops, a solution containing more free water, such as 0.45% NaCI, is used. Glucose is measured hourly; electrolytes, arterial blood gases, and serum ketones are measured every 2 to 4 hours until stabilized. Once the blood glucose level falls to less than 250 mg/dL, which typically occurs within the first 12 to 24 hours, the insulin dosage is lowered to I to 2 units/hr and is given simultaneously with IV dextrose solution in water (usual ratio, 5 g of dextrose to 1 unit of insulin) in an effort to "clamp" the blood sugar in the low-200-mg/dL range. This provides enough insulin to suppress lipolysis; acidosis and ketonuria clear over the ensuing 24 to 36 hours. Once this occurs, and the patient is tolerating oral feeding, the insulin regimen is changed to the SC route. The recrudescence of acidosis and ketonuria is frequent after IV insulin is discontinued. This results from relative insulinopenia during the transition between rapidly cleared IV insulin and the onset of action of the first SC injection. We therefore recommend that the insulin drip be continued for several hours after the initial SC dose, depending on its type

and amount. SC therapy is typically initiated with two daily doses of intermediate-acting insulin (e.g., neutral protamine Hagedorn [NPHD, with more frequent "coverage" with short-acting regular (R) insulin or with one of the rapidacting insulin analogs (e.g., lispro, aspart). Coverage only with short-acting insulins is not advised, since the use of insulins with longer durations of action stabilizes blood glucose levels to a greater degree. The total daily dose of insulin should approximate 0.5 unitslkg. Two thirds of this amount should be given as NPH, which is typically divided as two thirds before breakfast and one third before the evening meal or before sleep. The remainder should be administered as R (or lispro or aspart) on a variable scale based on the glucose reading, and injected three times a day before meals; in those patients who are not yet eating, shortacting insulins are instead administered every 6 hours). At this point, blood glucose is monitored 4 to 6 hours, depending on the patient's status and response to therapy. Once the glucose is reasonably well controlled «200 mg/dL), the patient may continue this regimen or be transferred to a more conventional and convenient "split-mixed" regimen to be used at home (i.e., NPH and R before breakfast and supper). More meticulous regimen, such as ones using the combination of rapid-acting prandial insulins and long-acting basal insulin analogs (e.g., glargine, detemir) (i.e., four injections per day)

Endocrine Emergencies: Hypoglycemic and Hyperglycemic Crises - -

793

FIGURE 87-2. Left. Substrate utilization in the fed state showing the role of insulin in the promotion of fuel storage. Right. Metabolic alterations in diabetic ketoacidosis (DKA). Insulin deficiency and elevation of counter-regulatory hormones activate ketogenic, gluconeogenic, glycogenolytic, and lipolytic pathways. (Left and Right. From Kitabchi AE, Fisher JN, Murphy MB, et al. Diabetic ketoacidosis and the hyperglycemic, hyperosmolar nonketotic state. In: Kahn CR, Weir GC reds], Joslin's Diabetes Mellitus, 13th ed. Philadelphia, Lea & Febiger, 1994, p 738.)

or continuous SC insulin infusion (insulin pump) may also be considered in highly motivated and compliant patients. The ultimate goal is to maintain blood glucose at as near a physiologic range as possible while avoiding hypoglycemia. In certain patients, such as the very young and elderly, those with significant cardiovascular or cerebrovascular disease, and those with hypoglycemia unawareness, more conservative goals are preferable. Patients with DKA typically present with hyponatremia because of dilution of the extracellular compartment from intracellular water resulting from the osmotic effects of hyperglycemia." This corrects with the administration of insulin and isotonic solution. Hyperkalemia is common on presentation despite the fact that most patients with DKA, as previously noted, have a total body potassium (K+) deficit." An initial osmotic diuresis promotes inappropriate urinary K+ losses. K+ excretion may eventually become impaired, however, in the setting of significant intravascular depletion. In addition, acidemia results in an intracellular shift of hydrogen ions, with a counterbalancing flux of K+ into the extracellular space to maintain electrical neutrality. As the acidosis is corrected, as plasma volume is expanded, and as insulin is administered, serum K+ routinely falls. We do not recommend providing Kt-containing solutions until the serum K+ is in the normal range and adequate urine output is secured. Bicarbonate should not be given except in cases of severe acidosis (pH < 6.9 to 7.0) and then only to partially correct the pH to greater than 7.0. 40 Finally,

hypophosphatemia is common after the first 24 to 48 hours of treatment, although initial hyperphosphatemia may be manifest." If the phosphate falls below normal, oral or IV phosphorus replacement is required. A search for an underlying illness that may have precipitated the DKA is important in all patients. This is best performed with a careful physical examination and select laboratory tests, such as routine chemistries, complete blood count, urinalysis, and electrocardiogram. If the patient is febrile, urine and blood cultures must be obtained, and strong consideration should be given to empiric antibiotic coverage pending results. Further testing should be directed by physical or laboratory findings. Abdominal pain, often severe and accompanied by ileus, is common. Good diagnostic skills, with measurement of hepatic and pancreatic enzymes, are essential to rule out an underlying abdominal catastrophe. An elevated amylase level is commonly noted in DKA and may add to the confusion (lipase is usually normal unless there is superimposed concomitant pancreatitisj.f

Hyperglycemic, Hyperosmolar Syndrome CLINICAL PRESENTATION AND PATHOGENESIS

HHS is defined as severe hyperglycemia (blood glucose> 600 mg/dL), increased serum osmolality (effective serum osmolality> 320 mOsm/kg H 20 ), and dehydration without significant acidosis (serum bicarbonate> 15 mEqlL, anion

794 - - Endocrine Pancreas gap < 12 mEqlL, arterial pH > 7.30) or ketosis." Typically, HHS occurs in elderly patients with a history of T2DM. There is usually a more protracted history of polyuria, polydipsia, and blurring of vision and a gradual decline in overall status, occurring over days to weeks. Central nervous system signs are more frequent in this syndrome than in DKA, especially changes in mentation, lethargy, and, occasionally, frank coma. Dehydration is more severe, with volume deficits in the 8- to IO-L range." As in DKA, the volume depletion itself accentuates the hyperglycemia because of alterations in renal clearance. Although epidemiologic studies are limited, data indicate that mortality is increased in HHS compared with DKA.33 Whether this is due to the more advanced age and worse health status of patients with HHS or the intrinsic risk of more profound volume depletion is unclear. Several proposals have been made to explain the physiologic differences between HHS and DKA. First, some studies have shown that higher levels of counter-regulatory hormones and FFAs are found in DKA, although contrasting opinions

I

•

certainly exist. Second, the higher levels of insulin seen in patients with HHS may be adequate to prevent lipolysis (and ketogenesis) although not gluconeogenesis." Finally the hyperosmolar state itself may prevent ketogenesis by inhibiting lipolysis. THERAPY A treatment strategy for HHS is delineated in Figure 87-3. As in DKA, patients with HHS are inherently unstable and require close monitoring, sometimes in an intensive care environment. Although these individuals have relatively inadequate levels of insulin, the chief deficit is that of volume. We recommend an initial administration of I to 2 L of 0.9% NaCl followed by the administration of 5 to 10 units of IV insulin. If insulin is given before volume expansion, the resultant intracellular glucose flux may further deplete the extracellular space, leading to further hypotension. An insulin drip may be used, similar to that in the treatment of DKA, although these patients, once volume is expanded, usually

Glucose> 600 Effective serum osmolality >320 mOsm/kg H2O pH> 7.30 HCOa> 15 Ketones < 1:2

1

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Insulin 5-10 U/h IV

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+

Once BG < 250, "clamp" at 200-250 w/insulin 1-2 U/h IV + DsW 100-200 mUh

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•

to SC insulin after: 1. acidosis resolved, 2. ketones cleared, and 3. tolerating PO ~

•

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Glucose> 250 pH:s; 7.30 HCOa:S;18 Ketones > 1:2

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•

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•

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•

Insulin 5-10 U IVB

1 1000-2000 mL I

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~

FIGURE 87-3. Algorithm for the management of hyperglycemic crises.HC0 3 =bicarbonate radical; DKA =diabeticketoacidosis; HHS = hyperglycemic, hyperosmolar syndrome; NaCI = sodium chloride; IYB = intravenous bolus; K+ = potassium; P = phosphorus; IV = intravenous; PO = by mouth; NaHC03 = sodium bicarbonate; SC = subcutaneous; BG = blood glucose; DsW = dextrose 5% in water; qd = everyday; bid = twice a day.

Endocrine Emergencies: Hypoglycemic and Hyperglycemic Crises - -

795

do well with the frequent administration of SC short-acting insulin. As in DKA, patients should be carefully examined for clues of precipitating factors, such as infection. The metabolic abnormalities are usually corrected within 24 to 48 hours, whereas the volume deficits may take longer to normalize in elderly patients, who often have underlying cardiovascular disease. Many of these individuals do best on a similar split-mixed regimen, although in selected patients more conservative approaches are possible, such as oral antihyperglycemic agents (sulfonylureas or other insulin secretagogues (i.e. meglitinides), biguanides, thiazolidinediones, or a-glucosidase inhibitors), one to two injections of intermediate-acting insulin alone, or oral agents and insulin. However, the development of HHS usually implies significant insulin deficiency, and, as a result, aggressive regimens and close follow-up are typically necessary.

Hypoglycemic Crises Hypoglycemia, defined as a blood glucose level less than 50 mg/dL, occurs in a wide variety of clinical settings." This results from a failure of the normal homeostatic mechanisms previously discussed to achieve a balance in glucose production and utilization. In normal subjects, as plasma glucose decreases below the physiologic range, the counter-regulatory hormones epinephrine and glucagon are released followed by growth hormone and, ultimately, cortisol. Signs and symptoms of hypoglycemia are categorized as adrenergic and neuroglycopenic in origin." The glycemic threshold for epinephrine release is higher than that for neuroglycopenic symptoms and is reproducible for a given individual, although there is considerable variability between subjects." The physical sequelae of epinephrine release in response to hypoglycemia include pallor, diaphoresis, tachycardia, nausea, and anxiety. Because glucose is the preferred energy source for the central nervous system, neuroglycopenic symptoms reflect cerebral fuel deprivation. Symptoms include personality and behavioral changes, headache, lethargy, seizures, and coma. The brain can also use ketone bodies as energy sources, but these are usually in scarce supply in the fed state and do not rise to significant levels until fasting has continued for many hours. In addition, insulin decreases ketones by suppressing lipolysis and promoting ketone utilization by peripheral tissues. Because no alternative neural energy substrates are available in hyperinsulinemic patients, the diabetic patient who has taken too much insulin and the patient with an insulin-secreting tumor are both at increased risk for hypoglycemic neurologic complications.f From a practical standpoint, hypoglycemic disorders are classified by the temporal setting: either postprandial or fasting. A differential diagnosis is displayed in Table 87-1. Because hypoglycemic symptoms are nonspecific, the first goal is to document the presence of an abnormally low blood glucose. Whipple's triad is defined as the presence of symptoms consistent with hypoglycemia, documentation of low glucose when symptoms occur, and resolution of symptoms with glucose repletion. Measurement of blood glucose should specify whether the sample is whole blood or plasma. In general, glucose should not be measured on serum because

of glucose consumption by erythrocytes. Samples for whole blood or plasma glucose determination are collected in tubes containing oxalate and fluoride, which inhibit glycolysis. Frequently, capillary finger prick tests are used. However, capillary glucose levels are 7% to 8% higher than in venous blood, except in severely hypotensive patients, in whom they may be lower, falsely suggesting hypoglycernia." Glucose meters and reagent strips may yield falsely low glucose values for technical reasons because they are intrinsically more reliable in the hyperglycemic range. In general, these convenient methods of glucose determination may be used to exclude hypoglycemia, and low glucose readings should be interpreted with caution."

Postprandial Hypoglycemia Postprandial hypoglycemia occurs 1 to 5 hours after food consumption and not during fasting. Normal blood glucose in patients with postprandial symptoms implies a nonhypoglycemic disorder. The postprandial hypoglycemias include alimentary hypoglycemia and reactive (idiopathic) hypoglycemia. ALIMENTARY HYPOGLYCEMIA

Alimentary hypoglycemia typically occurs in postgastrectomy patients, approximately 30 to 60 minutes after eating, and is manifested by both adrenergic and neuroglycopenic symptoms. Its cause may be related to the loss of the reservoir function of the stomach, with rapid absorption of glucose, excess release of insulin, with a mismatched hypoglycemic effect.t" Studies have raised the possibility of disordered secretion of insulin-stimulating gut peptides in this syndrome." The diagnosis can be made in the appropriate patient by measurement of blood glucose when symptoms appear or by a glucose tolerance test. Because the symptoms

796 - -

Endocrine Pancreas

may be severe, the test must be carefully supervised and terminated early if necessary. Alimentary hypoglycemia can be effectively treated with multiple small feedings and avoidance of concentrated sweets. REACTIVE HYPOGLYCEMIA

Although a popular diagnosis in the past for a variety of somatic complaints, from fatigue and depression to anxiety and palpitations, reactive (or idiopathic) hypoglycemia is, in fact, extremely uncommon.t" However, the use of the oral glucose tolerance test to diagnose this disorder is controversial. Marked hypoglycemia (glucose < 45 mg/dL) occurring 2 to 5 hours after ingestion of a large glucose load (75 g) that reliably reproduces symptoms may be helpful. However, there is a great deal of variability in the response to this stimulus in normal individuals. Indeed, when symptomatic patients are tested rigorously, their symptoms often do not correlate with decreases in blood glucose.F Thus, in many patients, no definitive therapy exists. Abnormalities in circulating levels of neuroactive compounds have been described in some patients with "postprandial syndromev'" although the significance of this remains unclear. When it is reliably diagnosed, true reactive hypoglycemia can be managed by avoiding concentrated sweets and by frequent, small feedings rich in complex carbohydrates and proteins.>' Reactive hypoglycemia may also occur in patients predisposed to T2DM, possibly related to delayed and prolonged insulin secretion from partially compromised beta cells. Sometimes seen in patients years before the diagnosis of diabetes, this syndrome may be an early indicator of islet dysfunction.

Fasting Hypoglycemia If evaluation confirms the presence of hypoglycemia during fasting, different and generally more worrisome clinical entities must be considered. It is first necessary to determine whether the process is exogenous or endogenous in origin. If endogenous, insulin-mediated and insulin-independent processes must be distinguished. All the causes of fasting hypoglycemia, when severe enough, may also be responsible for postprandial decreases in blood glucose.

Exogenous Causes Diabetes mellitus accounts for most cases of hypoglycemia seen in hospital emergency departments'" and is also the most common cause in the surgical patient. Because diabetic treatments such as insulin injections and oral insulin secretagogues such as sulfonylureas result in an unregulated increase in circulating insulin levels, patients so treated and their physicians must ensure adequate and regular nutritional intake to maintain glucose levels in a safe range. To complicate matters, many diabetic patients with recurrent hypoglycemia suffer from "hypoglycemia unawareness," resulting from abnormal adrenergic response to a falling blood glucose. 56 Insulin reactions related to diabetes therapy are frequently seen in the hospitalized patient, when a patient's insulin or oral agent dose is not adjusted to nutritional intake. A common scenario is that of a diabetic patient who experiences a rapidly improved glycemic profile once placed on

a more regimented hospital diet. If medication dose is not appropriately altered, hypoglycemia may ensue. In addition, certain drugs that are highly protein bound when added to a stable sulfonylurea regimen may promote increased free levels of the hypoglycemic agent, with resultant decreases in ambient glucose. Treatment-associated hypoglycemia is frequently encountered in diabetic patients with renal failure, because of poor nutritional intake and decreased insulin clearance. In nondiabetics with hypoglycemia, it is important to exclude the surreptitious use of insulin or an oral hypoglycemic agent. Exogenous insulin administration is best confirmed by the simultaneous measurement of insulin, glucose, and C-peptide levels as a measure of endogenous insulin secretion. In the hypoglycemic patient receiving exogenous insulin, the C-peptide level is discordantly IOW. 45 Abuse of sulfonylurea hypoglycemic agents can be detected by the presence of circulating or urinary sulfonylurea compounds. In addition to insulin and the sulfonylureas, a variety of drugs (see Table 87-1) are associated with the development of hypoglycemia, especially in metabolically compromised patients such as the very young and elderly, the malnourished, and those with hepatic or renal disease. 57 Among the most important of these is alcohol. Alcohol-induced hypoglycemia typically occurs in settings in which caloric intake is otherwise restricted, during which time hepatic glycogen stores may be depleted in 1 to 2 days. Maintenance of blood glucose levels becomes wholly dependent on gluconeogenesis, which is itself inhibited by alcohol, via alterations of the hepatic cytosolic ratio of the reduced form of nicotinamide-adenine dinucleotide to the whole form of nicotinamide-adenine dinucleotide. In addition, alcohol depresses hepatic uptake of lactate, alanine, and glycerol. Other exogenous causes of hypoglycemia should be excluded by a careful history and biochemical evaluation when indicated.

Endogenous Causes INSULIN MEDIATED

Fasting hypoglycemia in an otherwise healthy patient raises the possibility of an insulin-secreting islet cell tumor. This topic is discussed in detail elsewhere in this text. The biochemical diagnosis of insulinoma is made on the basis of fasting hypoglycemia (glucose < 45 mg/dL) accompanied by inappropriate hyperinsulinemia (insulin> 5 to 6IlU/mL). Exogenous administration of hypoglycemic agents must be excluded. Determination of plasma C-peptide levels confirms an endogenous source of insulin production." Nesidioblastosis, the diffuse proliferation of pancreatic islet cells, has been implicated as a rare cause of hyperinsulinemic hypoglycemia in adults." Optimal methods of diagnosis and treatment remain controversial. INSULIN INDEPENDENT

A variety of systemic illnesses are associated with hypoglycemia in the setting of appropriately suppressed circulating levels of insulin. Hypoglycemia may be encountered in sepsis, severe hepatic dysfunction, renal insufficiency, and severe and prolonged nutritional deficiency. 3DIt may also be

Endocrine Emergencies: Hypoglycemic and Hyperglycemic Crises - -

seen in a variety of endocrine disorders. Fasting hypoglycemia occurs in Addison's disease as a result of the absence of cortisol, which has a key role in stimulating hepatic glucose production. Hypopituitarism may lead to hypoglycemia because of underproduction of both corticotropin and growth hormone. Hypoglycemia may also occur in isolated growth hormone deficiency states (although almost exclusively in the pediatric population). Autoimmune hypoglycemia results from antibodies to either the insulin receptor or to insulin itself." Insulin receptor antibodies cause hypoglycemia in some patients (receptor activation) and insulin resistance in others (receptor blockade), possibly as a function of the titers of antibody produced. Insulin secretion is usually decreased, but circulating levels may be increased as a result of failure of receptormediated endocytosis, an important mechanism of insulin clearance.59 Antibodies to insulin may develop spontaneously, particularly in patients with early insulin-dependent diabetes mellitus or with other autoimmune diseases such as systemic lupus erythematosus and Graves' disease. In these circumstances, C-peptide levels are not suppressed as they are in patients with surreptitious insulin administration. Hypoglycemia is usually reactive, reflecting the delayed effect of insulin as it dissociates from the antibodies, but can occur in fasting states. Hypoglycemia occurs as a manifestation of some non-islet cell tumors. The clinical presentation mimics that of insulinoma. Tumors are usually large, indolent, and of mesenchymal origin. Research has determined that the mechanism of hypoglycemia in most of these neoplasms involves the secretion of insulin-like growth factor (IGF).60 IGF-II is structurally homologous to insulin. It promotes glucose utilization and also inhibits growth hormone secretion, thus decreasing hepatic glucose output (Fig. 87-4). Normal or modestly elevated circulating IGF-II levels in the presence

Uncontrolled Tumor Production of IGF-II

(

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\

~ , Decreased: • Hepatic GlucoseOutput • IGF-I Production • Synthesisof IGF Binding Proteins

Tumor-Induced Hypoglycemia

x

FIGURE 87-4. Mechanism of tumor-induced hypoglycemia. IGF = insulin-like growth factor.

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of low plasma IGF-I levels in a patient with insulinindependent hypoglycemia suggests this diagnosis." Hypoglycemia is also occasionally associated with other tumors without elevated IGF-II levels. The origin of the hypoglycemia is unclear in these cases but may be due, in part, to increased glucose utilization by the neoplasm.

Treatment In the patient presenting with coma or mental status changes consistent with hypoglycemia, immediate administration of IV glucose (50 mL of 50% dextrose solution or 25 g of dextrose) is indicated pending results of plasma glucose levels. (Intramuscular glucagon injection is often helpful in unresponsive diabetic patients when IV access cannot be secured, such as in the home setting.) Improvement in mentation usually occurs within several minutes, although occasionally a second bolus of dextrose is required. The patient is then maintained on an IV drip of 5% to 10% dextrose in water and, when able, provided carbohydrates orally. In patients with symptomatic hypoglycemia who are cooperative with oral feeding, rapidly absorbed concentrated sweets containing 15 to 20 g of carbohydrates may be administered. Those patients with reactive hypoglycemia are typically initially helped by such treatment, although rapidly absorbed simple sugars may set into motion another cycle of insulin release followed by recurrent hypoglycemia. In diabetic patients suffering from medication-induced hypoglycemia, future doses of insulin or oral agents must be appropriately adjusted. The cause of proven hypoglycemia is determined when the patient's acute condition is stabilized. In many patients with fasting hypoglycemia secondary to endogenous hyperinsulinism, treatment with diazoxide suppresses insulin secretion and normalizes blood glucose. This maneuver is temporizing until more definitive therapy, such as resection of the responsible insulinoma, is carried out. In certain tumors that elaborate IGF-II, resulting in severe hypoglycemia, continuous feeding by IV or by nasogastric tube may be necessary pending more definitive antitumor therapy.

Perioperative Management of the Diabetic Surgical Patient Patients with diabetes undergo surgery more frequently than the unaffected population. I The most common procedures typically involve lengthy operative time and hospital stays, such as cardiac and peripheral vascular surgery. In addition the neuroendocrine stress response to surgery and anesthesia result in the secretion of counter-regulatory hormones that lead to peripheral insulin resistance, hepatic glucose production, decreased insulin secretion, and lipolysis and proteolysis. Because of the inherent temporary alterations in nutritional intake perioperatively and postoperatively, judicious diabetes management is important. This becomes of particular concern during lengthy surgeries that involve general anesthesia because of the patient's unconscious state. In addition, these patients may be more prone to postoperative infections, especially if ambient glucose is high.

798 - - Endocrine Pancreas In patients with TlDM, withholding insulin leads to the development of ketosis, adding to the nutritional and electrolyte problems that often accompany surgical illness. In these individuals, it is important to provide a certain amount of insulin at all times, even during fasting. This is most easily done with the IV coadministration of 5% dextrose in water (l00 to 200 mLlhr) and R insulin (l to 2 unitslhr) begun the evening before surgery. Ambient blood levels are maintained between 100 and 150 mg/dL. Blood glucose is monitored every 1 to 2 hours before surgery and hourly during surgical anesthesia to optimize metabolic control. More commonly used methods, such as providing one half to two thirds of the usual intermediate insulin dose on the morning of surgery, may be adequate. However, this method results in a peak of insulin action, which will not necessarily coincide with a planned meal. In addition, insulin absorption from SC tissues may be altered during surgery because of peripheral vasoconstriction. Thus, smoother glycemic control is afforded with the IV technique. Postoperatively, IV insulin is continued until the patient is eating, at which time the preoperative regimen may be reinstituted. Blood glucose monitoring should continue four times daily to coincide with meals and night-time snack, so that a variable dose of R insulin can be administered as "coverage," thus allowing for tighter control during this important time. Postoperatively, the goal should be to maintain blood glucose in the 90 to 130 mg/dL range preprandially and no higher than 160 to 180 mg/dL postprandially. This minimizes the added risks of fluid and electrolyte shifts associated with hyperglycemia. In addition, euglycemia may enhance wound healing and immune function, allowing for shortened recovery time and decreased risk of nosocomial infection. 62 .63 A recent randomized trial in critically ill postoperative patients showed that meticulous blood glucose control (80 to 110 mg/dL) using IV insulin infusion significantly reduced length of intensive care unit stay and mortaliry.f In T2DM patients, a less aggressive approach may be successful. (Glucose targets should be the same, but, because they are not absolutely insulin deficient, many patients with T2DM are able to maintain euglycemia or near-euglycemia when they are fasting.) With those patients on oral agents, the medication is withheld on the day of surgery. If there is a considerable wait before the procedure, coverage with small amounts of R insulin will suffice, with a continuous IV drip of 5% dextrose in water (50 to 100 mLIhr). For those being treated with insulin, administering a fraction (one half to two thirds) of the usual morning NPH dose may be adequate, although the limitations of this custom, as previously discussed, should be considered. Continuous IV insulin may also be indicated for this group of patients, particularly those with critical illness with stress hyperglycemia.

Summary In most surgical patients, hyperglycemic or hypoglycemic crises are due primarily to inadequate or excessive insulin secretion or administration. Hyperglycemic crises may be due to diabetic ketoacidosis or an HHS. IV rehydration with

normal saline and IV insulin is the initial therapy for both. Hypoglycemic crises are classified as postprandial hypoglycemia (postgastrectomy or reactive hypoglycemia) and fasting hypoglycemia. Fasting hypoglycemia can be due to exogenous use of insulin or secretagogues or endogenous unregulated secretion of insulin by an insulinoma or by tumors that secrete IGF-II or consume glucose, or by lack of counter-regulatory hormones. Acute treatment is IV glucose; treatment depends on the specific cause. Patients with an insulinoma have increased C-peptide levels as well as inappropriately high insulin levels when hypoglycemic. Diabetic patients are at risk for hyperglycemic and hypoglycemic crises, especially during illnesses and peri operatively. Appropriate monitoring of glucose levels as well as management with IV saline, insulin, and glucose is the key to treatment.

REFERENCES 1. Songer TJ. The economic costs of NIDDM. Diabetes Metab Rev 1992;8:389. 2. Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab 2oo3;284:E671. 3. Marks V, Morgan L, Oben J, Elliot R. Gut hormones in glucose homeostasis. Proc Nutr Soc 1991;50:545. 4. Cryer PE. Glucose counterregulation: Prevention and correction of hypoglycemia in humans. Am J PhysioI1993;264:EI49. 5. Rothman DL, Magnusson I, Katz LD, et al. Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13 C NMR. Science 1991;254:573. 6. Castellino P, DeFronzo RA. Glucose metabolism and the kidney. Semin NephroI1990;10:458. 7. Banting FG, Best CH. The internal secretion of the pancreas. J Lab Clin Med 1922;7:251. 8. Steiner DF, Chan SJ, Welsh 1M, et al. Structure and evolution of the insulin gene. Annu Rev Genet 1985;19:463. 9. Welsh M. Glucose regulation of insulin gene expression. Diabetes Metab 1989;15:367. 10. Shalwitz A, Herbst T, Carnaghi L. Time course for effects of hypoglycemia on insulin gene transcription in vivo. Diabetes 1994; 43:929. II. Walter P, Lingappa VR. Mechanism of protein translocation across the endoplasmic reticulum membrane. Annu Rev Cell Bioi 1986;2:499. 12. Rhodes CJ, Halban PA. Newly synthesized proinsulin/insulin and stored insulin are released from pancreatic B cells predominantly by a regulated, rather than a constitutive, pathway. J Cell Bioi 1987; 105:145. 13. Orci L, Ravazzola M, Storch M-J, et al. Proteolytic maturation of insulin is a post-Golgi event which occurs in acidifying clathrin-coated vesicles. Cell 1987;49:865. 14. Nagamatsu S, Bolaffi JL, Grodsky GM. Direct effects of glucose on proinsulin synthesis and processing during desensitization. Endocrinology 1987; 120:1225. 15. Sobey WJ, Bear SJ, Carrington CA, et al. Sensitive and specific twosite immunoradiometric assays for human insulin, proinsulin, 65-66 split and 32-split proinsulin. Biochem J 1989;260:535. 16. Porte D, Kahn SE. Hyperproinsulinemia and amyloid in NIDDM: Clues to etiology of islet B-cell dysfunction? Diabetes 1989;38:1333. 17. Gold G, Gishizky ML, Chick WL, et al. Contrasting patterns of insulin biosynthesis, compartmental storage, and secretion: Rat tumor versus islet cells. Diabetes 1984;33:556. 18. Henquin JC. Cell biology of insulin secretion. In: Kahn CR, Weir GC (eds), Joslin's Diabetes Mellitus, 13th ed. Philadelphia, Lea & Febiger, 1994, p 56. 19. Barg S. Mechanisms of exocytosis in insulin-secreting B-cells and glucagon-secreting A-cells. Pharmacol Toxicol 2003;92:3. 20. Kimball CP, Murlin JR. Aqueous extracts of pancreas. J Bioi Chern 1923;58:337. 21. Tricoli N, Bell GI, Shows TB. The human glucagon gene is located on chromosome 2. Diabetes 1984;33:200.

Endocrine Emergencies: Hypoglycemic and Hyperglycemic Crises - 22. Kervan A, Blanche P, Tataille D. Distribution of oxyntomodulin and glucagon in the gastrointestinal tract and the plasma of the rat. Endocrinology 1987;121:704. 23. Orskov C, Holst 11, Poulsen SS, et al. Pancreatic and intestinal processing of proglucagon in man. Diabetologia 1987;30:874. 24. Unger RH, Orci L. Glucagon and the A-cell: Physiology and pathophysiology. N Engl J Med 1981;304:1518. 25. Orci L, Unger RH. Functional subdivisions of islets of Langerhans and possible role of D-cells. Lancet 1975;2: 1243. 26. Maruyama H, Hisatomi A, Orci L, et al. Insulin within islets is a physiologic glucagon release inhibitor. J Clin Invest 1984;74:2296. 27. Unger RH, Eisentraut AM. Enteroinsularaxis. Arch Intern Med 1969;123:261. 28. Nelson RC. Oral glucose tolerance test: Indications and limitations. Mayo Clin Proc 1988;63:263. 29. Gerich JE. Contributions of insulin-resistance and insulin-secretory defects to the pathogenesis of type 2 diabetes mellitus. Mayo C1in Proc 2003;78:447. 30. Marks V. Recognition and differential diagnosis of spontaneous hypoglycemia. Clin EndocrinoI1992;37:309. 31. Maran A, Taylor J, MacDonald lA, Amiel SA. Evidence for reversibility of defective counterregulation in a patient with insulinoma. Diabetes Med 1992;9:765. 32. Service FJ. Diagnostic approach to adults with hypoglycemic disorders. Endocrinol Metab Clin North Am 1999;28:519. 33. Kitabchi AE, Fisher IN, Murphy MB, et al. Diabetic ketoacidosis and the hyperglycemic, hyperosmolar nonketotic state. In: Kahn CR, Weir GC (eds), Joslin's Diabetes Mellitus, 13th ed. Philadelphia, Lea & Febiger, 1994, p 738. 34. Bending 11, Pickup JC, Keen H. Frequency of diabetic ketoacidosis and hypoglycemic coma during treatment with continuous subcutaneous insulin I infusion: Audit of medical care. Am J Med 1985;79:685. 35. Chupin M, Charbonnel B, Chupin F. C-peptide blood levels in ketoacidosis and in hyperosmolar non-ketotic diabetic coma. Acta Diabetol 1981;18:123. 36. Foster DW, McGarry JD. The metabolic derangements and treatment of diabetic ketoacidosis. N Eng1 J Med 1983;309:159. 37. Adrogue HJ, Wilson H, Boyd AB, et al. Plasma acid-base patterns in diabetic ketoacidosis. N Engl J Med 1982;307:1603. 38. Lebowitz HE. Diabetic ketoacidosis. Lancet 1995;345:767. 39. Ishikawa S, Sakuma N, Fujisawa G, et al. Opposite changes in serum sodium and potassium in patients in diabetic coma. Endocr J 1994;41:37. 40. Gamba G, Oseguera J, Castejon M, Gomez-Perez FJ. Bicarbonate therapy in severe diabetic ketoacidosis: A double-blind, randomized, placebo-controlled trial. Rev Invest Clin 1991;43:234. 41. Kebler R, McDonald FD, Cadnapaphornchar P. Dynamic changes in serum phosphorous levels in diabetic ketoacidosis. Am J Med 1985;79:571. 42. Vinivor F, Lehrner LM, Kam RC, Merritt AD. Hyperamylasemia in diabetic ketoacidosis: Sources and significance. Ann Intern Med 1979; 91:200. 43. Marshall SM, Alberti KGMM. Hyperosmolar nonketotic diabetic coma. Diabetes Annu 1988;4:235.

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44. Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am 1995;79:39. 45. Service FJ. Clinical review 42: Hypoglycemias. J Clin Endocrinol Metab 1993;76:269. 46. Amiel SA, Gale E. Physiological response to hypoglycemia: Counterregulation and cognitive function. Diabetes Care 1993;16 (Suppl 3):48. 47. Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 1991;260:E67. 48. Axelrod L, Levitsky LI. Hypoglycemia. In: Kahn CR, Weir GC (eds), Joslin's Diabetes Mellitus, 13th ed. Philadelphia, Lea & Febiger, 1994, p 976. 49. Fleming DR. Accuracy of blood glucose monitoring for patients: What it is and how to achieve it. Diabetes Educ 1994;20:495. 50. Becker HD. Disorders of gastrointestinal hormones after surgery. Acta Hepatol Gastroenterol 1979;26:516. 51. Milholic J, Orskov J, Holst 11,et al. Emptying of the gastric substitute, glucagon-like peptide-1 and reactive hypoglycemia after total gastrectomy. Dig Dis Sci 1991;36:1361. 52. Palardy J, Havrankova J, Lepage R. Blood glucose measurement during symptomatic episodes in patients with suspected postprandial hypoglycemia. N Engl J Med 1989;321:1421. 53. Lechin F, van der Dijs B, Lechin A, et al. Doxepin therapy for postprandial symptomatic hypoglycemic patients: Neurochemical, hormonal and metabolic disturbances. Clin Sci 1992;80:373. 54. Lev-Ran A, Anderson RW. The diagnosis of postprandial hypoglycemia. Diabetes 1981;30:996. 55. Fisher KF, Lees JA, Newman JH. Hypoglycemia in hospitalized patients: Causes and outcomes. N Engl J Med 1986;31:1245. 56. Cryer PE. Hypoglycemia unawareness in IDDM. Diabetes Care 1993;16(SuppI3):440. 57. Seltzer HS. Drug-induced hypoglycemia. Endocrinol Metab Clin NorthAm 1989;18:163. 58. Farley DR, van Heerden JA, Myers JL. Adult pancreatic nesidioblastosis. Arch Surg 1994;129:329. 59. Taylor SI, Barbetti F, Accili D, et al. Syndromes of autoimmunity and hypoglycemia: Autoantibodies directed against insulin and its receptor. Endocrinol Metab Clin North Am 1989;18:123. 60. Zapf J. Role of insulin-like growth factor II and IGF binding proteins in extrapancreatic tumor hypoglycemia. Horm Res 1994;42:20. 61. Teale JD, Marks V. Inappropriately elevated plasma insulin-like growth factor II in relation to suppressed insulin-growth factor I in the diagnosis of non-islet cell tumour hypoglycaemia. Clin Endocrinol (Oxf) 1990;3:87. 62. Selam JL, Clot J, Andary M, et al. Circulating lymphocyte subpopulations in juvenile insulin-dependent diabetes: Correction of abnormalities by adequate blood glucose control. Diabetologia 1979;16:35. 63. Marks JB. Perioperative management of diabetes. Am Family Physician 2003;67:93. 64. van den Berge G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359.

Chemotherapy for Unresectable Endocrine Neoplasms Anne C. Larkin, MD • Kathryn L. Edmiston, MD • Nilima A. Patwardhan, MD

Neoplasms arising from endocrine organs are rare and have unique clinical features. In contrast with most solid tumors, symptoms from endocrine neoplasms may arise as a result of the production of biologically active substances by the tumor or invasion of surrounding structures and their ability to metastasize. Tumors that are biologically active may become clinically apparent as a result of endocrine hyperfunction, whereas those that do not produce active hormones become apparent through local invasion and distant spread. More sophisticated diagnostic tests have improved the ability to recognize and characterize endocrine neoplasms. The development of radioimmunoassays for circulating peptides produced by endocrine neoplasms has revolutionized the recognition and diagnosis of hormone-secreting tumors. Improved radiologic methods such as ultrasonography, endoscopic ultrasonography, computed tomography (CT), magnetic resonance imaging, radionuclide scans, and selective arteriography with selective venous sampling for measurement of peptide concentration have improved diagnostic localization of endocrine neoplasms. Most endocrine neoplasms have an indolent clinical course. Survival after diagnosis is often measured in years and decades. Because the morbidity associated with endocrine tumors is often related to the metabolic and endocrine abnormalities caused by hormonal hypersecretion, the suppression of tumor-related peptide secretion can produce relatively long-lasting symptomatic and biochemical remission, even in the absence of treatment directed at halting tumor growth. Because most endocrine neoplasms are slowly progressive, surgery has been the mainstay of treatment, even in cases of metastatic disease. 1.2 Hepatic resection for metastatic neuroendocrine tumors is safe, provides effective palliation, and prolongs survival. 3 Cytotoxic therapy is reserved for patients with unresectable local or metastatic disease.t"

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The efficacy of therapy for endocrine neoplasms is judged not only by the effect of treatment on tumor size but also by its effect on circulating levels of biologically active substances produced by the tumor. The results of clinical trials of chemotherapy for endocrine neoplasms are confounded by the rarity of these tumors and the variable criteria for assessing response. A decrease in the production of hormone mayor may not be accompanied by a decrease in symptoms, shrinkage of the tumor, or prolongation of survival.

Islet Cell Tumors Endocrine tumors of the pancreas are rare and arise from the normal elements of the pancreatic islets. Insulinoma is the most common islet cell tumor followed by gastrinoma. As shown in Table 88-1, its primary symptom is hypoglycemia. Histologic criteria of malignancy, such as cytologic atypia, angioinvasion, and perineural invasion, are often absent, even in metastatic islet cell tumors'? The only universally agreed-on proof of malignancy is infiltration of adjacent organs and spread to distant sites.' Only 10% to 15% of insulinomas are malignant." In contrast, 60% of islet cell tumors producing gastrin 10 or vasoactive intestinal polypeptide (VIP)ll are malignant. The characterization of islet cell tumors by plasma or hormone production provides important prognostic information. Endocrine tumors of the pancreas may produce local symptoms such as pain and jaundice as a result of involvement of the pancreas and compression of the common bile duct or symptoms caused by involvement of the liver by metastases. They may also exert profound systemic symptoms as a result of secretion of biologically active hormones. The systemic symptoms usually dominate the clinical

Chemotherapy for Unreseetable Endocrine Neoplasms - -

picture and may be life threatening, even in patients with a low tumor burden. Thus, a dual therapeutic strategy to eradicate the tumor and alleviate symptoms from the systemic effects of hormone secretion is required to optimally manage these patients. The incidence of insulinoma is generally considered to be I per 1,000,000 to 1,250,000 people, but it may be up to 4 patients per 1 million individuals per year. 12 Approximately 75% of insulin omas are solitary and benign, 10% to 15% are malignant, and the remaining 10% to 15% are manifestations of multifocal disease of the pancreas, including islet cell hyperplasia, microadenomatosis, or nesidioblastosis.? Insulinomas are characterized by their ability to secrete insulin and frequently produce hypoglycemia. The duration of symptoms in patients with islet cell tumors may be as short as 2 weeks or as long as 20 years." Symptoms are common in patients with either benign or malignant tumors, 14 The results of surgical resection for insulinoma are good. Operative failures occur because of the inability to locate the insulinoma or the presence of unresectable metastatic disease, which occurs in 2% to 5% of patients." Malignant insulinomas occur in an older age group, and delay in diagnosis is a major problem. The liver is the most frequent site of metastasis. Penetration of tumor through the capsule and invasion of adjacent lymph nodes and blood vessels are indicative of malignancy.v-" Zollinger-Ellison syndrome (ZES) was originally described as a combination of hypersecretion of gastric acid and intractable and severe peptic ulceration as a result of a pancreatic islet cell tumor." ZES accounts for two thirds of pancreatic tumors found in patients with multiple endocrine neoplasia (MEN) type 1.16 Gastrinomas are rarely found among the general population. Many of the patients first identified with gastrinoma had metastatic disease to the lymph nodes." In spite of metastasis, patients may have a long survival. Before the routine use of histamine receptor antagonists, death was due to complications of peptic ulcer disease. Currently, death is due to tumor growth." The earliest signs and symptoms of ZES are indistinguishable from those of uncomplicated peptic ulcer disease. Abdominal pain is reported by most patients, and 18% initially experience diarrhea. The major goal of therapy is to

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identify and resect the primary tumor. Cytoreductive surgery may be helpful in those with bulky nodal metastases in the absence of hepatic involvement." Treatment with proton pump inhibitors has become the mainstay of therapy in patients with unresectable disease.'? Glucagonomas are tumors that cause a distinct syndrome composed of diabetes, dermatosis, diarrhea, and dementia.?? It is estimated that approximately 70% of patients with this syndrome have malignant tumors. Fifty percent of patients with malignant glucagonomas have hepatic metastases at diagnosis. The cardinal feature is a rash that is a necrolytic migratory erythema, which occurs in about 90% of cases. By the time of diagnosis, glucagonomas are usually larger than 3 em in diameter. Because of the high malignancy rate, surgery is curative in less than 5% of patients with glucagonoma. Palliative debulking can reduce hormone levels and potentially improve survival." Radical excision of the tumor with hepatic transplantation for improving survival, disease-free interval, and control of endocrine-related syndromes has been reported." VIP-secreting tumor (VIPoma) results from the excess secretion of vasoactive intestinal peptide. These tumors cause a watery diarrhea, hypokalemia, and achlorhydria syndrome. About 50% of the tumors are malignant, and 50% will have metastasized at the time of diagnosis. The remaining 50% are benign and potentially curable. Therefore, when the diagnosis is established but the tumor is not localized, "blind" laparotomy is justifiable. Intraoperative localization may be aided by the use of intraoperative ultrasonography. Surgery may also be helpful in debulking metastatic disease.P Nonfunctioning islet cell tumors are not associated with a recognized hormonal syndrome. About 50% of all endocrine tumors of the pancreas are nonfunctioning." As a result of the advent of CT scans, the diagnosis of nonfunctioning tumors has increased dramatically.V' Most tumors are malignant.P and curative resection is possible in about 25% to 40%.8 Liver transplantation has been successfully done for metastatic nonfunctioning islet cell tumors.P Surgery to remove all tumor should adequately treat both local and systemic symptoms and offers the only chance of cure for malignant endocrine neoplasms. Even with localized disease, complete surgical excision is not always possible. Complete surgical resection rates range from 24% to 65%. Criteria of inoperability include invasion of contiguous structures (e.g., the superior mesenteric vein and portal vessels), extension into the porta hepatis, and portal hypertension or widespread involvement of the retroperitoneum. Hepatic and other distant metastases or widespread lymphatic involvement may render the tumor unresectable, although surgical debulking of the primary and metastases can provide palliation. 3,8.9,12 Up to half of patients who undergo noncurative resection demonstrate symptomatic improvement. For patients with unresectable disease, chemotherapy is indicated when there is significant morbidity because of tumor bulk encroaching on normal structures or symptoms resulting from hormone hypersecretion. Therapy is not usually recommended for the asymptomatic patient with advanced islet cell tumors unless the tumor manifests an aggressive biologic behavior.P Patients who are considered for chemotherapy must have adequate liver and kidney function and a good performance status at the time of treatment.

802 - - Endocrine Pancreas Studies of cytotoxic chemotherapy usually include heterogeneous groups of patients because of the rarity of these tumors and their indolent clinical course. Specific antihormonal therapy for the subtypes of islet cell tumors is discussed separately in other chapters. Streptozocin (STZ) is the most effective single chemotherapeutic agent for treating patients with advanced islet cell tumors. The activity of STZ was first reported in 1968 by Murray-Lyon and colleagues, who described a favorable response in one patient with an advanced islet cell tumor.v STZ is a naturally occurring nitrosourea that causes relatively selective destruction of the pancreatic beta cells. The most common side effect is vomiting, although nephrotoxicity is frequently seen and may be dose limiting. Although STZ was initially used as a single agent, it has more recently been combined with doxorubicin (Adriamycin) or 5-fluorouracil (5-PU). Combination therapy with 5-PU and STZ is the most effective regimen for patients with advanced symptomatic islet cell cancer and has become the standard of care. The overall response rate and survival with this combination are significantly better than with STZ alone: A doubling of the response rate (63% vs. 36%) was seen in a prospective, randomized trial comparing combination therapy with STZ alone. Complete remissions occurred in 33% of the patients receiving combination therapy but in only 12% of those receiving STZ alone. The median duration of response was 17 months for all responders and 24 months for patients who achieved a complete remisslon.'? The most common side effects are gastrointestinal, but kidney, liver, and bone marrow function need to be closely monitored. More recently, the combination of STZ and 5-FU was compared with STZ plus doxorubicin or chlorozotocin alone. In this prospective trial, the addition of doxorubicin was superior to 5-FU, with increased rates of tumor regression (69% vs. 45%) and median survival (2.2 vs. 1.4 years). Chlorozotocin had similar results as the STZ/5-FU combination but with fewer side effects." Dacarbazine (DTIC, dimethyl triazeno imidazole carboxamide) is an antitumor agent that inhibits DNA synthesis. It has produced dramatic biochemical and objective tumor responses in patients with islet cell tumors when used as a single agent.t-'? In a recent study of 50 patients, DTIC was administered at a dose of 850 mg/m- every 4 weeks. It produced a response rate of 34% and a median survival of 19.3 months. The best results were noted in previously untreated patients with advanced pancreatic islet cell tumors.'? A number of agents have been identified for the treatment of symptoms resulting from hormonal hypersecretion in patients with functioning islet cell neoplasms. Somatostatin occurs naturally throughout the gastrointestinal tract and in the D cells of the pancreatic islets. Somatostatin has been found to reduce the concentrations of marker hormones effectively in patients with insulinoma, glucagonoma, gastrinoma, and VIPoma, with a consequent improvement in symptoms related to hypersecretion." Octreotide (SMS 201995) is a synthetic somatostatin analog with a longer half-life than somatostatin. This has considerable advantages over natural somatostatin, which must be administered by continuous intravenous infusion. Octreotide inhibits peptide secretion by islet cell tumors, resulting in marked improvement of

symptoms caused by hypersecretion. It appears to be helpful in patients with VIPoma syndrome, glucagonoma syndrome, ZES, and hyperfunctioning insulinomas.v-" In the last several years, long-acting depot forms of octreotide have become available. Lanreotide is a slow-release somatostatin analog, with activity for 10 to 14 days. Recent studies have confirmed that the therapeutic efficacy and tolerability are similar to octreotide, but it is administered in the amount of 30 mg every 2 weeks as opposed to three times a day.34.35 Interferon a may be useful in the treatment of islet cell tumors. In a phase II trial in seven patients with advanced islet cell tumors, one patient had a partial response that lasted 8 months and four had stable disease for a median of 13 months." However, the treatment was poorly tolerated, requiring frequent dose reductions. Another report indicated good symptomatic control of disease and tumor regression when combined with 5_PU.37 The potential beneficial effects of interferon need closer study, and combination regimens with other cytotoxic agents should be evaluated. Various other agents have been used for symptomatic relief of patients with unresectable and metastatic insulinomas unresponsive to conventional chemotherapeutic measures. Diazoxide, calcium-channel blockers, propranolol, and phenytoin all have been used with some success. Diazoxide is a nondiuretic benzothiadiazine that suppresses insulin release from the pancreas, resulting in increased blood sugar levels. Calcium-channel blockers and ~-adrenergic receptor blockers are also theoretically capable of blocking insulin secretion. Phenytoin inhibits in vitro release of insulin from beta cells but has a less significant effect in vivo.

Carcinoid Tumors Carcinoid tumors arise from Kulchitsky's or enterochromaffin cells and have been described in almost every organ in the body. Carcinoid tumors occur most commonly in the intestine. Carcinoids of the pancreas are rare and make up less than 5% of all carcinoid tumors.t-" In contrast with midgut carcinoids, they often secrete the serotonin analog hydroxytryptophan. Episodic flushing and diarrhea are the most common symptoms of the carcinoid syndrome and are usually associated with metastases to the liver from a small bowel carcinoid. Metastatic disease may require no treatment for months or even years if the patient is asymptomatic or the symptoms are mild." Numerous therapeutic options are available for the symptomatic patient, and it is important to consider the severity of symptoms and select the appropriate therapy for the clinical situation. Surgical resection is often curative for early-stage disease, and it can prolong survival and provide significant improvement in symptoms, even in patients with metastatic disease." Potentially curative surgery should be considered in all patients who can be rendered disease free with resection, and palliative surgery should be offered to selected patients because it improves symptoms and may delay or reduce the need for chemotherapy.'? Selected patients not suitable for hepatic resection for metastatic disease may benefit from hepatic artery embolization." However, this may be associated with significant side effects such as fever, nausea, and pain.

Chemotherapy for Unresectable Endocrine Neoplasms - -

Chemotherapy can be considered for patients with progressive, symptomatic, unresectable disease. STZ-based regimens are helpful in the treatment of patients with carcinoid tumors of the pancreas.o? Etoposide and cisplatin have been given to 27 patients with carcinoid syndrome; unfortunately, only two patients showed partial tumor regression.'? In patients with aggressive variants of carcinoid tumor, the same combination was administered and a 67% response rate was noted. Patients with typical carcinoids did not respond in this study.f? Octreotide is effective for treating symptoms in patients with metastatic carcinoid and may result in disease stabilization or even objective tumor regression." Cyproheptadine (Periactin) is a serotonin and histamine antagonist and is indicated for diarrhea caused by carcinoid syndrome. Although it does not decrease circulating hormone levels, it blocks the effects of these hormones in the bowel. Most patients have significant relief of diarrhea. Interferon has been used in patients with metastatic carcinoid with the malignant carcinoid syndrome. Twenty percent of patients had a measurable regression of tumor, 40% had a decrease in hormone excretion, 65% had relief of flushing, and 33% were relieved of diarrhea. Unfortunately, these results were transient.43 The addition of interferon to somatostatin analogs has been helpful in patients resistant to octreotide alone."

Adrenocortical Carcinoma Adrenocortical carcinoma is a rare malignant disease with a dismal prognosis and an estimated incidence of 0.5 cases per 1 million individuals per year," Patients with nonfunctioning tumors have manifestations attributable to a large abdominal mass. Forty percent to 70% of adrenocortical carcinomas are secretory.tv" and these patients usually present with clinical features of hormone excess. The clinical features depend on the predominant excess steroid production: glucocorticoid-secreting tumors cause Cushing's syndrome; androgen-secreting tumors lead to virilization; mineralocorticoid-secreting tumors cause hypertension and hypokalemia; and estrogen-secreting tumors result in gynecomastia and testicular atrophy in men and menstrual irregularities and precocious puberty in girls. 45.46 Diagnosis is confirmed by elevated levels of urinary steroids. Eighty percent of patients demonstrate a suprarenal mass on CT scan. 45.46 Pooled data from several institutions confirm that more than 60% of adrenal tumors are stage IV with local invasion, positive lymph nodes, or distant metastasis at initial diagnosis." Complete surgical excision, which may include a nephrectomy, is the only therapy that offers an opportunity of cure, but recurrence rates are up to 73% and 5-year survival may reach only 37%.48 Symptoms are largely proportional to tumor bulk; therefore, resection of hepatic metastases and excision of peritoneal and omental implants may be indicated for symptom control. Mitotane (o,p'-DDD) is an insecticide that causes necrosis of the adrenal cortex and has been used in the therapy of adrenocortical carcinomas. Response to therapy can be measured by objective decreases in tumor size or by changes in the levels of circulating hormones. Biochemical response rates are high but do not necessarily correlate with objective

803

decreases in tumor size." Treatment toxicity includes gastrointestinal and neuromuscular symptoms. Experience with other chemotherapeutic agents is limited. Antitumor responses have been reported in patients treated with etoposide and cisplatin. One of 11 patients showed a complete response and 2 of 11 showed partial responses with 1- and 2-year survival rates of 18% and 9%, respectively.'? A subsequent phase II trial was unable to improve on these results, with only a 13% response rare." The combination of doxorubicin, vincristine, and etoposide with daily mitotane yielded a response rate of 22%, but the authors noted that it is uncertain whether this is superior to mitotane alone.>'

Malignant Pheochromocytomas Pheochromocytomas are rare tumors of chromaffin tissue that secrete catecholamines, either paroxysmally or continuously, producing hypertension. Diagnosis is made by measuring urinary concentrations of metanephrine, vanillylmandelic acid, and free unconjugated catecholamines. When there is increased excretion of urinary catecholarnines, CT scanning or iodine-131-metaiodobenzylguanidine (MIBG) scan is used to identify the location of the tumor. Approximately 10% of pheochromocytomas are malignant. They are usually slow growing and may not cause hypertension or symptoms. The tumors may spread locally or may metastasize to the lungs, bones, and soft tissues. Recurrent and metastatic pheochromocytomas should be resected whenever possible. Palliation is achieved by excision of as much catecholamine-secreting tissue as possible. Radioiodinated (1 231, 1311) MIBG, which is concentrated by these tumors, has also been used for treatment. Brief responses to therapeutic doses of 1311_MIBG have been described. In one report, none of the nine patients showed complete tumor regression and five patients showed symptomatic improvement. In addition, three complete hormonal responses were observed. 1311_MIBG is believed to be a useful therapeutic modality that provides temporary palliation but is rarely curative.V Combination chemotherapy using cyclophosphamide, vincristine, and dacarbazine in 14 patients produced complete or partial responses in 8 patients (57%), with a mean duration of response of 21 months.P There has been a case report of a patient with familial malignant pheochromocytoma who had an objective response lasting for 2 years with cisplatin and 5_FU.54 Patients who are treated with chemotherapy may have a hypertensive crisis and should be pretreated with a- and ~-adrenergic blockers, vigorous hydration, and metyrosine, which inhibit catecholamine secretion. Classic symptoms of catecholamine excess from unresectable disease can be treated with a-adrenergic blockade with phenoxybenzamine or, if necessary, n-methylparatyrosine, Arrhythmias can be controlled by ~ blockers such as propranolol.

Thyroid Cancer Malignant thyroid neoplasms have a wide spectrum of biologic behavior ranging from indolent growth of

804 - - Endocrine Pancreas well-differentiated neoplasms to the aggressive behavior of anaplastic cancers, which can cause death in only a few months. Management of papillary and follicular thyroid carcinomas consists of surgery and radioactive iodine (RAI). Medullary carcinomas of the thyroid arise from the parafollicular C cells, which secrete calcitonin. Surgery is the definitive treatment. Total thyroidectomy with a thorough central neck dissection as well as a modified lateral neck lymph node dissection is recommended. RAI has little value as an adjuvant to surgery in the management of medullary thyroid cancer. External-beam radiation therapy may be administered for remaining tumor that cannot be excised. Anaplastic cancer of the thyroid is a rapidly fatal tumor. Survival is not appreciably altered by treatment with either radiation therapy or chemotherapy alone, and the tumor often grows, even during treatment. In most patients symptoms are caused by local tumor invasion. The median survival after diagnosis is estimated to be 2 to 6 months, and in only exceptional cases does survival exceed 12 months.P Most chemotherapy trials involve heterogeneous groups of patients with differentiated, medullary, and anaplastic carcinomas. Experience with chemotherapy for differentiated thyroid cancer is limited because most recurrences are treated with surgery or RAJ. The addition of lithium to RAI in the treatment of well-differentiated thyroid has shown some promise. 56 Combined chemotherapeutic regimens appear to have a higher response rate (27%) than monotherapy (17%).57 However, a phase II trial indicated that the combination of doxorubicin, cisplatin, and vindesine was not superior to doxorubicin alone in patients with advanced differentiated thyroid cancer." Patients whose tumors do not concentrate 131 1 may benefit from retinoic acid, which is thought to redifferentiate tumor cells. A small study indicated some positive responses as evidenced by an increase in serum thyroglobulin levels.59 The results of chemotherapy for the treatment of metastatic medullary thyroid carcinoma are disappointing. Twentythree patients who had metastatic thyroid cancer were treated with various chemotherapeutic agents. The drugs most often used were doxorubicin alone, doxorubicin plus cisplatin, semustine (MeCCNU), and etoposide (VP-16). No patient had a complete remission, and few had even partial or minor responses." Although octreotide alone has not been shown to be efficacious in the management of advanced thyroid cancer," lanreotide has been combined with interferon a2b in one small study. Clinical benefit was obtained in six of seven patients, with decreases in flushing and fatigue and increased performance status.F Anaplastic tumors of the thyroid are highly resistant to any form of therapy and are rarely cured. Surgery, chemotherapy, and radiation therapy used separately have not been effective. The best survival rates have been reported after combined surgery, external-beam radiation, and chemotherapy. A clinical trial treated 20 patients with anaplastic cancer with chemotherapy and radiation. Two types of chemotherapy were used, depending on patients' ages. For those younger than 65 years, a combination of doxorubicin (60 mg/m-) and cisplatin (90 mg/m-) was given, and for older patients mitoxantrone (14 mg/m-) was used. Radiation therapy was administered to the neck and superior mediastinum. Three patients survived for 20 months, and complete local tumor

response was observed in 5 patients. No response was seen in distant metastasis, which was the cause of death in 14 patients." Protocols using paclitaxel and combinations of doxorubicin and bleomycin have similarly dismal responses.63.64 All authors agree that gross tumor resection should be performed whenever possible.55.65 However, surgery should not delay commencement of the combinedmodality treatment with chemotherapy and radiation. There is no consensus regarding the selection of chemotherapeutic agents for the treatment of anaplastic thyroid cancer.

Summary Chemotherapy for unresectable endocrine neoplasms is usually palliative rather than curative. Palliative surgical resection is indicated, especially for functioning tumors. Octreotide or similar agents can be effective in controlling symptoms in a variety of endocrine tumors. New agents or combinations of agents need to be developed to treat patients with these malignant endocrine neoplasms.

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Index Page numbers followed by the letter f refer to figures; those followed by the letter t refer to tables. A Abscess, in acute (suppurative) thyroiditis, 34,35 Accessory duct of Santorini, 669 Acetaminophen, for decompensation in thyroid storm, 218 Acidosis, metabolic, in diabetic ketoacidosis, 791 Acquired immunodeficiency syndrome (AIDS) acute suppurative thyroiditis in, 34 Addison's disease in, 635 Actin, cytoskeletal, 296 Addison's disease, 634-639 adrenal autotransplantation for, 695 bilateral adrenal hemorrhage and, 637-639 causes of, 637t CT scan of, 638, 638f bilateral adrenal metastases and, 639 drugs causing, 639, 639t exogenous steroid usage and, 635--636 hormone replacement therapy for, 695 in acquired immunodeficiency syndrome, 635 in autoimmune adrenalitis, 634 in polyglandular autoimmune syndromes, 634-635 in surgery, 635 in tuberculosis, 635 primary insufficiency in, 634-635 secondary insufficiency in, 635--636 stress-induced, 636 surgical, 635, 637 causes of, 634, 635t Adenoma adrenal. See Adrenal gland(s), adenoma of. Hiirthle cell, 123, 124f, 228. See also Hiirthle cell neoplasms. chromosomal aberrations in, 348, 348f mediastinal, arteriography of, 434, 434f parathyroid. See Parathyroid gland(s), adenoma of. pituitary corticotropin-secreting, Cushing's syndrome from, 612 in Carney's complex, 776 in multiple endocrine neoplasia 1, 675, 675f thyroid follicular, 116, 116f pathology of, 223-224 Adenomatosis, endocrine, 757

Adenosine monophosphate (AMP), cyclic desensitization of, to thyroid-stimulating hormone,273-274,273f in pancreatic islet B cells, 703f, 707-708 in parathyroid hormone secretion, 374 in phosphorylation, 273 in thyroid regulation, 257t, 258, 258f Adenosine triphosphate (ATP), from glucose, 707 Adenylase cyclase, response of, to thyroid-stimulating hormone, 268, 268f Adenylase cyclase-protein kinase A system, in signal transduction, 266-269, 267f Adhesion plaque, integrin-mediated, 297,297f Adjuvant therapy for adrenocortical carcinoma, 609-610, 610f for papillary thyroid carcinoma, 107-108 for recurrent thyroid carcinoma, 183 Adrenal artery(ies), development of, 559 Adrenal carcinoma Cushing's syndrome from, 618 fine-needle aspiration of, 590 imaging of, 581-582, 582f, 590, 591f pathology of, 586, 587f screening for, 589-590 tumor size in, 589-590, 590f Adrenal cortex aldosterone in, 571-572 physiologic effects of, 573 androgens in, physiologic effects of, 573 carcinoma of. See Adrenocortical carcinoma. corticosteroids in biosynthesis of, 571, 572f physiologic effects of, 573 cortisol in, 572-573 physiologic effects of, 573 embryology of, 558, 558f fetal (primitive), 558, 558f microscopic anatomy of, 564, 565f morphology of, 571, 572f nerve supply to, 564 physiologyof,571-573 sex steroid secretion in, 573 zonation of, 564-565, 565f, 571, 572f Adrenal gland(s), 557-569 accessory tissue in, 560 adenoma of, 587f aldosterone-producing, hyperaldosteronism from, 597-598 ACTH infusion and, 599 CT scan of, 598, 599f

Adrenal gland(s) (Continued) surgery for, hypertension after, 600-60 I, 60 It venous sampling in, 599, 600t Cushing's syndrome from, 618 frequency of, 586 imaging of, 582, 586 anatomic relations of, 560-562, 562f, 562t anatomy of, 560-566 macroscopic aspect in, 560, 561£ microscopic, 564-566, 565f surgical,641-642 arterial supply to, 562-563, 563f arteriography of, 577 autotransplantation of animal experiments in, 695-697, 696f for Addison's disease, 695 bilateral hemorrhage of, Addison's disease from, 637-639 causes of, 637t CT scan of, 638, 638f capsule of, 561 carcinoma of. See Adrenal carcinoma; Adrenocortical carcinoma. cortex of. See Adrenal cortex. CT scan of, 562f, 566, 576, 577f cyst in, 587f embryology of, 558-560, 558f-559f adrenal artery development in, 559 stereogenesis and, 559-560 fetal, 558, 558f, 560 Gerota's fascia of, 561 hereditary syndromes involving, 774t historical background on, 557-558 hyperplasia of, Cushing's syndrome from, 618 imaging of, 562f, 566, 576-577, 577f for adrenal adenoma, 582 for adrenocortical carcinoma, 581-582, 582f, 583, 583f for hyperadrenocorticism, 577-579, 578f for incidentaloma, 581-582, 582f, 583f for metastatic disease, 582-583 for pheochromocytoma, 580-581, 580£-581£ for primary hyperaldosteronism, 579-580, 579f incidentaloma of, 586-592. See also Adrenaloma. left, 561, 561£, 562t lymphatic drainage of, 563 mass in, clinically inapparent, 586. See also Adrenaloma.

807

808 - - Index Adrenal gland(s) (Continued) medulla of. See Adrenal medulla. metastases to, Addison's disease and, 639 MR imaging of, 562f, 566, 576 nerve supply to, 563-564 pheochromocytoma of. See Pheochromocytoma. physiology of, 571-575 right, 560-561, 561f, 562t scintigraphy of, 566, 576-577 surgery on, 566-569, 641-646. See also Adrenalectomy. anterior approach to, 567t, 568-569, 642-646,642f-643f flank approach to, 646 incision lines for, anatomic stratification in, 567t-568t lateral transthoracic approach to, 644-645, 645f posterior approach to, 566-568, 567t, 645-646,645f preparation for, 642 retroperitoneal laparoscopic approach to, 569 transabdominal approach to, 644-645, 644f-645f laparoscopic, 569 ultrasonography of, 566, 577 venography of, 577 venous drainage of, 563 zona fasciculata of, 564, 565f zona glomerulosa of, 564, 565f zona reticularis of, 564, 565f Zuckerkandl fascia of, 561-562 Adrenal insufficiency. See Addison's disease. Adrenal medulla catecholamines in physiologic effects of, 574-575 release of, 574 chromaffin cells of, 565-566, 573, 574f embryology of, 558, 558f microscopic anatomy of, 565-566 nerve supply to, 563-564 physiology of, 573-575 transmitter mechanisms in, 573-574, 574f Adrenal vein, dissection of, in laparoscopic adrenalectomy, 650-651, 651f Adrenalectomy anterior approach to, 567t, 568-569, 642-646, 642f-643f anticoagulation prophylaxis after, 616-617 bilateral, for Cushing's disease, 616-617 complications of, 617 steroid replacement therapy after, 6l7t compensatory hypertrophy of remaining gland after, 565 flank approach to, 646 incision lines for, anatomic stratification in, 567t-568t indications for, 641 laparoscopic, 569, 647-660 as gold standard, 659 bilateral, 653, 659 indications for, 655t care after, 654 choice of approach to, 658 complications of, 654-657, 656t contraindication(s) to malignancy as, 658-659 tumor size as, 659 cortical-sparing, 659-660 for adrenaloma, 648, 659 for Cushing's disease, 648 complications of, 656

Adrenalectomy (Continued) for Cushing's syndrome, 648 complications of, 656-657 for hyperaldosteronism, 600, 648 for pheochromocytoma, complications of, 656 indications for, 647-648, 655t left-side adrenal vein dissection in, 650-651, 65 If dissection in, 649-650, 650f extraction in, 651 patient positioning for, 649, 650f retroperitoneal, 569 transabdominal, 569, 649-651, 649f-651f operating room layout for, 649, 649f outcome of, 654-657, 655t for malignancy, 657 outpatient, 659 partial, 653-654 preparation for, 648 recent advances in, 659-660 results of, vs. open adrenalectomy, 658 retroperitoneal, 652-653 decubitus approach to, 653 prone jackknife approach to, 653 right-side dissection in, 651-652, 652f retroperitoneal, 569 transabdominal, 569, 651-652, 651f-652f trocar sites for, 651, 651f technique of, 649-654 laparoscopic ultrasonography in, 657 lateral transthoracic approach to, 644-645,645f left,568 needlescopic, 654 Nelson's syndrome after, 617 posterior approach to, 566-568, 567t, 645-646,645f preparation for, 642 results of, vs. laparoscopic adrenalectomy, 658 right, 568-569 transabdominal approach to, 644-645, 644f-645f Adrenaline, 557. See also Epinephrine. Adrenalitis, autoimmune, 634 Adrenaloma, 586-592 benign vs. malignant, 586, 587f evaluation of, 588-590 screening for adrenal carcinoma in, 589-590, 590f-591f screening for Cushing's syndrome in, 588-589 screening for pheochromocytoma in, 589 screening for primary aldosteronism in, 589 frequency of, 586 genetic studies of, 590 imaging of, 581-582, 582f flow chart in, 583f in adrenocortical carcinoma, 606-607 laparoscopic adrenalectomy for, 648, 659 management of, 591-592 surgical approach in, 592 pathology of, 586, 587f, 588 ~-Adrenergic receptor blockers, for thyroid storm, 218 Adrenocortical carcinoma, 604-610 adjuvant therapy for, 609-610, 610f adrenaloma in, 606-607

Adrenocortical carcinoma (Continued) Anderson's syndrome in, 606, 607f biochemical features of, 604 capsule of, 608 characteristics of, 604, 605t chemotherapy for, 803 clinical features of, 604 clinical presentation of, 605-607, 606f-607f CT scan of, 607, 607f hypersecretion in, 606 imaging of, 581-582, 582f, 583, 583f preoperative, 607, 607f, 608 in childhood, 610 in multiple endocrine neoplasia I, 686 incidence of, 604 macroscopic venous invasion in, 608 malignant, criteria for, 604-605, 605t mitotane for, 609-610 preoperative, 608 survival associated with, 6IOf morphology of, 608 MR imaging of, 607 postoperative care in, 609 preoperative treatment of, 608 prognosis of, 609 recurrence of, 609 scintigraphy of, 607 staging of, 607-608, 608t surgery for, 608-609 metastatic disease and, 609 results of, 609, 609f survival rates for, 609, 609f, 6 !Of tumor size and weight in, 605 Adrenocorticotropic hormone, infusion of, in differentiation of aldosterone-producing adenoma vs. hyperaldosteronism, 599 Aerodigestive tract, thyroid carcinoma invasion of, 318-332. See also Thyroid carcinoma, aerodigestive invasion by. Age, effect of on outcome of thyroid carcinoma, 250 on radiation-associated thyroid carcinoma, 241, 241f, 242t AGES scoring system for papillary thyroid carcinoma, 102, 110, 111, lIlt, 226 for recurrent thyroid carcinoma, 181 for thyroid carcinoma, 251 AIDS. See Acquired immunodeficiency syndrome (AIDS). Airway obstruction of, intrathoracic goiter in, 309 thyroid carcinoma invasion of, 318-332. See also Thyroid carcinoma, aerodigestive invasion by. Alcohol abuse hypoglycemia from, 717, 796 in sporadic gastrinoma, 747 Aldosterone in adrenal cortex, 571-572 physiologic effects of, 573 plasma concentration of, in hyperaldosteronism, 596-597. See also Hyperaldosteronism. subclinical, screening for, 589 Aldosterone-plasma renin ratio, 589 Aldosteronoma, 587f imaging of, 580 Allotransplantation of parathyroid tissue, 694-695 of thyroid tissue, 692 efficacy of, 693 rejection of, 693 prevention of, 692-693

Index - - 809 All-trans-retinoic acid, 335, 335f Alpha cells, pancreatic, 666. See also Pancreatic islets, A cells of. AMES scoring system for papillary thyroid carcinoma, 102, 104, lIO, Ill, lilt for recurrent thyroid carcinoma, 181 for thyroid carcinoma, 251 Amine precursor uptake and decarboxylation (APUD) chromaffin cells in, 560 in multiple endocrine neoplasia 2B, 758 Amine precursor uptake and decarboxylation (APUD) tumor, 764 Amino acid concentrations, in glucagonoma, 768, 769f Aminoglutethimide, for Cushing's disease, 616 Amiodarone hypothyroidism from, 45 thyroid disorders associated with, 25 AMP. See Adenosine monophosphate (AMP). Ampulla of Vater, 669 Amylin, production of, by pancreatic islet B cells, 703 Amyloid polypeptide, production of, by pancreatic islet B cells, 703 Anaplastic thyroid carcinoma. See Thyroid carcinoma, anaplastic. Anderson's syndrome, in adrenocortical carcinoma, 606, 607f Androgens, adrenal, physiologic effects of, 573 Anemia after parathyroidectomy, 515 in secondary hyperparathyroidism, 506 normochromic, normocytic, in chronic renal failure, 506 Anesthesia for parathyroidectomy, 442 local, for parathyroidectomy, 459 Angina, levothyroxine and, 71 Angiogenesis, 300 Angiography of gastrinoma, 750 of insulinoma, 720, 721f Ankle reflex, delayed, in hypothyroidism, 47-48,47t Anticancer therapy. See also specific therapy, e.g., Chemotherapy. targeting tumor growth, invasion, and angiogenesis, 30 I Anti-CEA monoclonal antibodies, medullary thyroid carcinoma imaging with, 148 Anticoagulation in bilateral adrenal hemorrhage, 637--638 prophylactic, after adrenalectomy, for Cushing's syndrome, 616-617 Antithyroid agents. See also specific drug. for Graves' disease, 59--60, 60t for Plummer's disease, 65 for thyroid storm, 217-218 prophylactic, 63-64 APe gene, 235, 292 Appendix, carcinoid tumors of, 780 treatment of, 785 APUD. See Amine precursor uptake and decarboxylation (APUD) entries. Aromatic fatty acids, in thyroid tumor growth inhibition and redifferentiation, 336 Arrestin proteins, in desensitization, 273 Arteriography of adrenal glands, 577 preoperative, for recurrent (persistent) hyperparathyroidism, 434

Artery(ies), rupture of, from invasive thyroid carcinoma surgery, 330 Askanazy cell(s), in Hashimoto's thyroiditis, 39 Askanazy cell tumors, 123. See also Hiirthle cell neoplasms. Aspiration biopsy, fine-needle. See Fine-needle aspiration biopsy. ATP (adenosine triphosphate), from glucose, 707 Autotransplantation of adrenal cells animal experiments in, 695-697, 696f for Addison's disease, 695 of parathyroid tissue, 486-487, 514, 694-695,694f cryopreservation with, 487, 523, 532-534 pocket storage in, 695 of thyroid tissue, 691-692 cryopreservation in, 691 for Graves' disease, 692 for multinodular goiter, 692 for postoperative hypothyroidism, 691-692,692f long-term follow-up of, 691

B Bacterial infection, in acute suppurative thyroiditis, 34 Bayley's symptom complex, in thyroid storm, 216 B-celllymphoma, of thyroid, 174, 232, 233f. See also Thyroid lymphoma. Beckwith-Wiedemann syndrome, 773-774 Benign familial hypocalciuric hypercalcemia. See Hypercalcemia, benign familial hypocalciuric. Benzimidazoles, for gastrinoma, 751 Beta cells, pancreatic, 666. See also Pancreatic islets, B cells of. ~ Blockers before pheochromocytoma surgery, 626 for thyroid storm, 218 Bexarotene, central hypothyroidism from, 47 Bioassays, of parathyroid hormone, 379 Biopsy during parathyroid surgery, 443 fine-needle aspiration. See Fine-needle aspiration biopsy. lymph node, in gastrinoma, 751, 752f Birt-Hogg-Dube syndrome, 778 Bisphosphonate agents for hypercalcemia, 540 in parathyroid carcinoma, 552 for hypercalcemic crisis, 546 Bleeding. See Hemorrhage. Blood collection, timing and processing of, for intraoperative PTH assays, 474-475, 475f Blood pressure, high. See Hypertension. Body, distribution of calcium in, 424, 425f Bone densitometry studies, of hyperparathyroidism, 386, 398-399 Bone disease after parathyroidectomy, 515 in asymptomatic hyperparathyroidism, 419 in chronic renal failure, 505 in normocalcemic hyperparathyroidism, 422 in secondary hyperparathyroidism, 505-506 Bone loss, in primary hyperparathyroidism, 387,399 Bone marrow transplantation, allogeneic, thyroid transplantation across major histocompatibility complex barriers using, 693

Bone metastases, surgical management of, 154, 154f-155f Bone morphogenic protein, anaplastic thyroid carcinoma and, 164 Bone resorption, inhibition of for hypercalcemia, 540 in parathyroid carcinoma, 552 for hypercalcemic crisis, 546 Bone tumors, in primary hyperparathyroidism, 385 Bovine seminal ribonuclease, anaplastic thyroid carcinoma and, 164 Brachioradialis muscle, transplantation of cryopreserved thyroid tissue into, 691, 692f BRAF mutations, in anaplastic thyroid carcinoma, 164-165 Brain, metastases to, surgical management of,I 54 Breathing, difficulty in, after thyroid surgery, 211 Bronchus, carcinoid tumors of, 783 Burch and Wartofsky's criteria, for diagnosis of thyroid storm, 217t

c C (parafollicular) cells, in medullary thyroid carcinoma, 129, 13Of, 229 C peptide, 715, 790 in insulinoma measurement of, 718 plasma concentration of, 719 CA4P, anaplastic thyroid carcinoma and, 164 Cadherins, in cell-cell interactions, 297-298, 298f Caffeine, carcinogenic effect of, 246 Calcification, extraskeletal, in secondary hyperparathyroidism, 506 Calciphylaxis, in secondary hyperparathyroidism, 506 Calcitonin in calcium homeostasis, 420 peripheral action of, 7 salmon for hypercalcemia, 540 in parathyroid carcinoma, 552 for hypercalcemic crisis, 546-547 secretion of, 7 C cells in, 129 in medullary thyroid carcinoma, 138, 138f Calcitrol. See also 1,25-Dihydroxyvitamin D. for hypoparathyroidism, 528 in secondary hyperparathyroidism secretion of, 504 synthesis of, 503 preoperative, for parathyroidectomy, 511 Calcium cytoplasmic, in pancreatic islet B cells, 709 elemental, for hypoparathyroidism, 528 homeostasis of, 424-425 in pancreatic islet B cells, 707, 708 in parathyroid hormone secretion, 372-374, 373f-374f ionized, 425 metabolism of, after parathyroidectomy, 515 serum concentration of. See also Hypercalcemia; Hypocalcemia. body distribution of, 424, 425f in primary hyperparathyroidism, 387, 397,397f psychiatric symptoms associated with, 406 parathyroid hormone serum levels and, 372,373f ultrafiltrable, 425

810 - - Index Calcium channel blockers, before pheochromocytoma surgery, 626 Calcium gluconate, for hypoparathyroidism, 528 Calcium infusion test for gastrinoma, 748 for insulinoma, 719, 719f Calcium sensor protein in multiple endocrine neoplasia I-associated hyperparathyroidism, 377 on parathyroid cells, 375-376 Calcium-calmodulin-dependent protein kinase, in thyroid growth regulation, 267f, 271 Carbohydrate metabolism, in primary hyperparathyroidism, 408-409, 408t Carcinoembryonic antigen, in anaplastic thyroid carcinoma, 161 Carcinogenesis. See also Oncogenesis. in thyroid tumors, 344, 345f molecular, 245 Carcinoid syndrome, 786 classic, 782-783, 783t definition of, 782 Carcinoid tumors, 780-786 appendiceal, 780 treatment of, 785 bronchial, 783 causes of, 781 chemotherapy for, 802-803 colonic, treatment of, 785-786 diagnosis of, 783-784, 784f duodenal, 782f treatment of, 785 gastric, 781 treatment of, 785 histopathology of, 782, 782f history of, 780, 78lt hormone secretion by, 782, 783t in multiple endocrine neoplasia I, 686, 781 in multiple endocrine neoplasia 2, 781 in Zollinger-Ellison syndrome, 781 incidence of, 780 Kulchitsky cells in, 780 neurotransmitter secretion by, 782, 783t nonfunctioning, 770-771 pathogenesis of, 781, 78lf pathophysiology of, 781 prognosis of, 784-785, 785t rectal,780 treatment of, 786 serotonin secretion by, 783 sites of, 780, 781 small bowel, 780 treatment of, 785 somatostatin receptor scintigraphy of, 784, 784f surgery for, 739, 740f symptoms of, 782-783, 783t thymic, 783 treatment of, 785 treatment of, 785-786, 786f Carcinoma. See specific type; under specific organ. Cardiovascular disease, in primary hyperparathyroidism, 405-406 Carney's syndrome, 776 paraganglioma in, 629 pheochromocytoma in, 631 Carotid artery, rupture of, from invasive thyroid carcinoma surgery, 330 CASR gene, in benign familial hypocalciuric hypercalcemia, 386, 496 Catecholamines in insulin secretion, 706

Catecholamines (Continued) in pheochromocytoma, 621 physiologic effects of, 574-575 release of determination of, 574 into systemic circulation, 564 synthesis of, in adrenal medulla, 573, 574f ~-Catenin

activation of, in anaplastic thyroid carcinoma, 159 alterations of, in thyroid carcinoma, 298 Catheterization, venous, for medullary thyroid carcinoma, 136 Cattell's maneuver, in adrenocortical carcinoma surgery, 608 CD4+ T cells, in Hashimoto's thyroiditis, 38-39 CD8+ T cells, in Hashimoto's thyroiditis, 39 CDHI gene, in malignancies, 297-298 Cell biology of pancreatic islet B cells, 703f, 707-708 of pancreatic islet non-B cells, 708 Cell-cell contacts, in cytoskeleton, 296-297 Cerebrospinal fluid concentrations, of calcium, in primary hyperparathyroidism, 406-407 Cervicotomy, traditional conversion of endoscopic parathyroidectomy to, 470, 47lt conversion of minimally invasive parathyroidectomy to, 465, 465t Chemoembolization, hepatic artery, for insulinoma, 728 Chemotherapy. See also specific chemotherapeutic agent. for adrenocortical carcinoma, 803 for carcinoid tumors, 802-803 for insulinoma, 728 for islet cell tumors, 728, 800-802, 801t for malignant pheochromocytoma, 803 for thyroid carcinoma, 803-804 anaplastic, 163 medullary, 135-136 for thyroid lymphoma, 176 Chest radiographs, of intrathoracic goiter, 310f, 311, 312f, 315f Children. See also Neonates. adrenocortical carcinoma in, 610 endemic goiter in, 20 pheochromocytoma in, 631 thyroid carcinoma in, 93-99 acquired, 248-249, 249f clinical presentation of, 96, 96t cytogenic studies of, 94-95 etiology of, 93-95 fine-needle aspiration of, 96 follicular, 95, 95f historical aspects of, 93 incidence of, 93-95, 94f irradiation and, 94 long-term survival in, 99 medullary, 94 nodule and, 96 papillary, 95 pathology of, 95, 95f, 233 pulmonary metastases in, 252 radiation-associated, 240-242, 241f radioiodine therapy for, 98-99, 98f-99f complications of, 98t recurrence of, 98, 98t surgery for, 96-97 complications of, 97-98, 97t, 98t treatment of, 96-99 Chlorpromazine, for decompensation in thyroid storm, 218

Cholecystokinin immunoreactivity, in pancreatic islet nerves, 706 Chondrocalcinosis definition of, 409 in primary hyperparathyroidism, 409 Chromaffin bodies, 560 Chromaffin cells in APUD system, 560 of adrenal medulla, 565-566, 573, 574f Chromogranin A, in parathyroid tissue, 378 Chromosomal aberrations in anaplastic thyroid carcinoma, 350, 350t, 351f,352t in Hiirthle cell adenomas, 348, 348f in Hiirthle cell neoplasms, 348-349, 348t, 3491 in medullary thyroid carcinoma, 351 in papillary thyroid carcinoma, 346-347, 347t Chvostek's sign, in hypocalcemia, 528 Cimetidine, for gastrinoma, 750 Cisplatin for adrenocortical carcinoma, 803 for anaplastic thyroid carcinoma, 162,804 for carcinoid tumors, 803 9-cis-retinoic acid, 335, 335f 13-cis-retinoic acid, 335 Clear cells, pancreatic, 666. See also Pancreatic islets, F cells of. Clodronate, for hypercalcemia, in parathyroid carcinoma, 552 Col-3, inhibition of thyroid cancer cell invasion by, 340 Colon, carcinoid tumors of, treatment of, 785-786 Columnar cell carcinoma, of thyroid, 171-172, 171f. See also Thyroid carcinoma. Coma, myxedema. See Myxedema coma. Comparative genomic hybridization digital image acquisition and analysis in, 345-346,346f DNA extraction in, 344 limitations and difficulties of, 351, 353 metaphase spreads in, 344, 345f of anaplastic thyroid carcinoma, 349-351, 350t, 35lf-352f, 352t of follicular thyroid carcinoma, 347 of Hiirthle cell neoplasms, 347-349, 348f, 348t,349t of medullary thyroid carcinoma, 351 of papillary thyroid carcinoma, 346-347, 347t technique of, 344-345, 345f Compartmental syndromes, in recurrent goiter, 306 Computed tomography (CT) of adrenal glands, 562f, 566, 576, 577f of adrenocortical carcinoma, 607, 607f of aldosterone-producing adenoma, 598,599f of bilateral adrenal hemorrhage, in Addison's disease, 638, 638f of Cushing's syndrome, 614, 615f of gastrinoma, 732-733, 733f, 734t, 749 of goiter, 28, 29f of hyperadrenocorticism, 577-578, 578f of insulin oma, 720, 72lf, 730-731, 73lt of intrathoracic goiter, 31Of, 311-312, 315f of liver, in MEN 2A, 137 of medullary thyroid carcinoma, 136 of parathyroid adenoma, 482f of pheochromocytoma, 580, 580f, 623, 623f,625f of primary hyperaldosteronism, 579, 579f preoperative, for recurrent (persistent) hyperparathyroidism, 431

Index - - 811 Confusion, mental, in primary hyperparathyroidism, 406 Contrast media, hypothyroidism caused by, 25 Coronary artery disease, in primary hyperparathyroidism, 405 Coronary bypass surgery, intravenous triiodothyronine in, 50-51 Corticosteroids. See also Glucocorticoids. Addison's disease from, 635-636 biosynthesis of, in adrenal cortex, 571, 572f physiologic effects of, 573 Corticotropin corticotropin-releasing hormone and, in Cushing's syndrome, 613, 613f secretion of, diurnal variation in, 634 Corticotropin stimulation test, in Addison's disease, 636 Corticotropin-producing tumor, 769-770 Corticotropin-releasing factor, secretion of, diurnal variation in, 634 Corticotropin-releasing hormone, plasma corticotropin response to, in Cushing's syndrome, 613, 613f Cortisol, 634 adrenal, 572-573 physiologic effects of, 573 serum levels of, measurement of, 636 Cortisone acetate, replacement therapy with, after bilateral adrenalectomy, 617t Cowden's syndrome, 235, 777 Creatinine, serum levels of, in primary hyperparathyroidism, 396 Cretinism, endemic, iodine deficiency in, 16, 20 Cross-talk in malignant progression, 300-301 in signal transduction systems, 274 Cryopreservation of parathyroid tissue current technique in, 530-531 function of, 531-532, 532t, 533f, 533t historical aspects in, 530 in autotransplantation, 487, 523, 530-534 indications for, 532-534 reoperation and, 523, 533 research on, 534, 534t technical issues in, 530-531 thawing technique in, 531 variations of, 531, 532t of thyroid tissue, in autotransplantation, 691 CT. See Computed tomography (CT). Culture medium, for cryopreservation of tissue, 530-531 Cushing's disease, 612 bilateral adrenalectomy for, 61tHi 17, 617t steroid replacement therapy after, 617t irradiation for, 615 laparoscopic adrenalectomy for, 648 complications of, 656 medical therapy for, 616 selective transsphenoidal microsurgery for, 615 therapeutic approaches to, 617, 617f treatment of, 614-617, 617t Cushing's syndrome, 612-619 adrenal mass in, 588 clinical features of, 612-613, 613f-614f, 613t corticotropin-dependent, 612 corticotropin-independent, 612 treatment of, 618 CT scan of, 614, 615f cutaneous striae in, 612, 613f definition of, 588

Cushing's syndrome (Continued) dexamethasone suppression test for, 588-589, 613 diagnosis of, 613, 614f ectopic, 612 diagnosis of, 613 treatment of, 617-618 epidemiology of, 612 evaluation of, algorithm in, 614, 616f facial appearances in, 614f imaging of, 577-579, 578f, 613-614, 615f in Carney's complex, 776 laparoscopic adrenalectomy for, 648 complications of, 65tHi57 metabolic manifestations of, 613t MR imaging of, 614, 615f pathogenesis of, 612 pituitary-dependent, 612. See also Cushing's disease. therapeutic approaches to, 617, 617f treatment of, 614-617, 617t scintigraphy of, 614, 615f subclinical, screening for, 588-589 treatment of, 614-618 results of, 618, 619t venous sampling in, 577 Cyanoglucosides, 19 Cyclic adenosine monophosphate. See Adenosine monophosphate (AMP), cyclic. Cyproheptadine, for carcinoid tumors, 803 Cyst(s) adrenal, 587f thyroid, fine-needle aspiration of, 89 Cytokeratin, 296 expression of, in anaplastic thyroid carcinoma, 165 Cytokines. See also specific cytokine. associated with regulation, 356 hypothyroidism from, 45, 46 Cytoreductive surgery, for unresectable gastrinoma, 753 Cytoskeleton actin microfilaments of, 296 cadherins and catenins of, 297-298, 298f cell-cell contacts in, 296-297 integrins of, 297, 297f intermediate filaments of, 296 microtubu1es of, 295 structure of, 295-301 Cytotoxic agents, for thyroid carcinoma, antitumor activity of, 338

D Dacarbazine, for islet-cell tumors, 802 De Quervain's thyroiditis clinical presentation of, 36 diagnosis of, 36, 37f differential diagnosis of, 36 etiology and pathogenesis of, 35-36 histologic features of, 36, 36f treatment of, 36-37 Death after surgery for hyperparathyroidism, 415--416,416t premature, after parathyroidectomy, 406 Dehiscence, anastomotic, from invasive thyroid carcinoma surgery, 329 Dehydroepiandrosterone in placental estrogen production, 559-560 synthesis of, 571 Deiodinase, 5 Deiodination, 5 Delirium, in primary hyperparathyroidism, 406

Delta cells, pancreatic, 666. See also Pancreatic islets, D cells of. Deoxyribonucleic acid. See DNA entries. Depression, in primary hyperparathyroidism, 406,407t Depsipeptide, increased NIS gene expression with,358 Dermopathy, in Graves' disease, 57, 59f Desensitization, in signal transduction, 273-274,273f DEXA scans, for bone disease, in normocalcemic hyperparathyroidism, 422 Dexamethasone suppression test, for Cushing's syndrome,588-589,613,648 Diabetes mellitus glucagonoma and, 768-769 hypoglycemia in, 796 islet cell transplantation for, 697-698, 698f pancreatic transplantation for, 697 primary hyperparathyroidism in, 408--409, 408t type I diabetic ketoacidosis in, 791 surgery in, 797-798 type 2 diabetic ketoacidosis in, 791 endocrine pancreas and, 709, 709f hyperglycemic, hyperosmolar syndrome in, 794 surgery in, 798 Diabetic ketoacidosis biochemical changes in, 791, 792f clinical presentation of, 791 definition of, 791 hyperkalemia in, 793 hypertriglyceridemia in, 791 hyponatremia in, 793 insulin for, 791-792, 793f metabolic acidosis in, 791 pathogenesis of, 791 treatment of, 791-793, 793f vs. hyperglycemic, hyperosmolar syndrome, 794 Diarrhea, in VIPoma patients, 767 Diathermy, in thyroidectomy, restricted use of, 189 Diazepam-binding inhibitor, production of, in pancreatic islet D cells, 705 Diazoxide, for hypoglycemia in insulinoma, 727 Diet, influences of, on thyroid carcinoma, 245,245t DiGeorge syndrome, 3 Digestive tract, thyroid carcinoma invasion of, 318-332. See also Thyroid carcinoma, aerodigestive invasion by. Digital image, acquisition and analysis of, in comparative genomic hybridization, 345-346,346f 1,25-Dihydroxyvitamin D. See also Calcitrol. in calcium homeostasis, 425 in malignancy-associated hypercalcemia, 538-539 postoperative, for hypocalcemia, 388 Diiodotyrosine, synthesis of, 4f, 5 Diuretics, loop, for hypercalcemic crisis, 546 DMSO solution, in crypopreservation of tissue, 531 DNA, for hybridization extraction of, 344 labeling of, 344 DNA assessments, in parathyroid carcinoma, 552

812 - - Index DNA cytometry, of anaplastic thyroid carcinoma, 160 Doxazosin, before pheochromocytoma surgery, 626 Doxorubicin, for anaplastic thyroid carcinoma, 162,804 DPC4 tumor suppressor gene, 765 Drug(s). See also specific drug or drug group. causing Addison's disease, 639, 639t Duodenotomy, in Zollinger-Ellison syndrome, 733, 738 Duodenum carcinoid tumors of, 782f treatment of, 785 somatostatinoma of, 765f tumors of, in multiple endocrine neoplasia I, 681-682 Dysphagia, in intrathoracic goiter, 310 Dyspnea, after thyroid surgery, 211

E Edema in thyroid surgery, 208 periorbital, in hypothyroidism, 47, 47t postoperative, in neck dissection, 203 Electroencephalopathy, preoperative, in primary hyperparathyroidism, 407 Embryogenesis, of thyroid gland, 3, 4f EMG syndrome, 774 En bloc resection for aerodigestive invasive thyroid carcinoma, 327 thyroid carcinoma, aerodigestive invasion by, surgery for, 327 Endocrine deficiency states, 692t hormone replacement therapy for, 691 Endocrine glands. See also specific gland. adenomatosis of, 757 autoimmune disorders of, in Hashimoto's thyroiditis, 46 neoplasms of, chemotherapy for, 800-804 Endoscopy for advanced thyroid cancer, in upper airway, 319,319f in parathyroidectomy, 467-471. See also Parathyroidectomy, endoscopic. Endothelium-independent vasodilation, impaired, in primary hyperparathyroidism, 406 Enoxaparin prophylaxis, after adrenalectomy, for Cushing's syndrome, 616 Environment, effect of on goiter, 25 on Hashimoto's thyroiditis, 39 Environmental radiation, exposure to, thyroid carcinoma from, 243-245, 244f Epidermal growth factor(s), 256 in invasive thyroid carcinoma, 299-300, 300f in thyroid growth regulation, 77, 271-272, 272f Epidermal growth factor receptor, 259 and neu/HER2/erb-B2 and c-met gene, 284 overexpression of, in thyroid carcinoma, 339 Epidermal growth factor-transforming growth factor-a, in thyroid growth regulation, 258-259 Epinephrine, 557 degradation of, 574, 574f ERB2 family, of tyrosine kinase receptors, in thyroid carcinoma, 339 c-erb-Z oncogene, 290t, 291 epidermal growth factor receptor and, 284 overexpression of, in thyroid neoplasms, 284t

Esmolol during pheochromocytoma surgery, 626 for thyroid storm, 218 Esophagus displacement of, in intrathoracic goiter, 310 thyroid carcinoma invasion of papillary, 144-145 surgery for, 329 Etidronate, for hypercalcemia, in parathyroid carcinoma, 552 Etoposide for adrenocortical carcinoma, 803 for carcinoid tumors, 803 Euthyroidism, clinical, 19 Exercise hyperglycemia and, 710 hypoglycemia after, 717

F Facial nerve, marginal branch of, in neck dissection, 200 Familial adenomatous polyposis, 776-777 thyroid carcinoma associated with, 235-236, 235f Familial hyperinsulinemia, 774 Familial hyperparathyroidism. See Hyperparathyroidism, familial. Familial hypocalciuric hypercalcemia. See Hypercalcemia, benign familial hypocalciuric. Familial non-MEN medullary thyroid carcinoma, 129-130, 130t, 13It. See also Thyroid carcinoma, medullary. preventive surgery for, 134-135 Familial pheochromocytoma, 776. See also Pheochromocytoma. Family history, goiter recurrence associated with, 305-306 Fasting, hypoglycemia after, 717, 795t, 796, 797 Fasting test, for insulinoma, 718, 718f interpretation of, 718-719 Fatigue, in primary hyperparathyroidism, 407 Fatty acids, aromatic, in thyroid tumor growth inhibition and redifferentiation, 336 Fever, in thyroid storm, 218 Fibroblast growth factor(s), 256 in parathyroid cell growth regulation, 377 in thyroid growth regulation, 259, 259f Fibroblast growth factor receptor, 259 Fibronectin receptor, 297 Fibro-osseous tumors, of jaw in hereditary hyperparathyroidism, 774-775 in non-MEN familial hyperparathyroidism, 494 in primary hyperparathyroidism, 385 Fibrosis postoperative, around recurrent goiter, 306 pulmonary, risk of, radioiodine therapy and, 157 Fine-needle aspiration biopsy of acute suppurative thyroiditis, 35 of adrenal carcinoma, 590 of anaplastic thyroid carcinoma, 160 of follicular thyroid carcinoma, 118, 118f of Htirthle cell neoplasms, 125 of papillary thyroid carcinoma, 104 of parathyroid hormone in tissue samples, 475 of parathyroid tumor, 434 of plasmacytoma, 168 of spontaneous nontoxic goiter, 29 of thyroid carcinoma, in children, 96 of thyroid cysts, 89

Fine-needle aspiration biopsy (Continued) of thyroid lesions, interpretation of, 236 of thyroid lymphoma, 175 of thyroid nodules, 87-89, 295 cytologic features in, 88f-89f showing Htirthle cells, 124f Flavonoids, 19 Fluorhydrocortisone, replacement therapy with, after bilateral adrenalectomy, 617t Fluorodeoxyglucose positron emission tomography of adrenal carcinoma, 590, 591f of advanced thyroid cancer, 320 of medullary thyroid carcinoma, 137 of metastatic thyroid carcinoma, 148-149 5-Fluorouracil for anaplastic thyroid carcinoma, 162 for medullary thyroid carcinoma, 135 5-Fluorouracillstreptozocin, for islet cell tumors, 802 Focal adhesion kinase, 297 Follicular thyroid carcinoma. See Thyroid carcinoma, follicular. Food intake of, endocrine pancreas after, 711 iodine in, 18-19 c-fos protooncogene, 285, 291-292 Fracture, risk of, in hyperparathyroidism, 421-422

G G proteins. See Guanine nucleotide-regulatory proteins. Gagner procedure, for parathyroidectomy, 462, 463f Ganglioneuroblastoma, 560 Ganglioneuroma, from sympathetic ganglion cells,560 Ganglioneuromatosis, of lips and tongue, 759f Gardner's syndrome, 776-777 thyroid carcinoma associated with, 235-236, 235f Gastrectomy, for gastrinoma, 753 Gastric acid hypersecretion, 745, 746f analysis of, 747 pharmacologic control of, 747 Gastric inhibitory polypeptide, in insulin secretion, 707 Gastrin physiology of, 745, 747-748 serum concentration of, after secretin injection, 748, 748f Gastrinoma, 745-754, 801 angiography of, 750 calcium infusion test for, 748 chemotherapy for, 801 CT scan of, 732-733, 733f, 734t, 749 diagnosis of, 746, 748 familial, 745 surgery for. 751 gastrectomy for, 753 gastric acid hypersecretion in, 745, 747 gastrin secretion in, 745 liver metastases in, 753 localization studies for, 732-733, 732f-734f, 734t preoperative, 748-750, 749t, 750f recommendations in, 733 malignant, 746 medical management of, 750-751 vs. surgery, 750. See also Gastrinoma, surgery for. metastatic, treatment of, 753-754 morphology of, 746

Index - - 813 Gastrinoma (Continued) MR imaging of, 749 pancreatic, 753 pathology of, 746 peptic ulcer in, 745, 747 portal venous sampling of, 750 provocative tests for, 748, 748f SASI test for, 750, 750t secretin injection test for, 748, 748f selective arterial, 750, 750t somatostatin receptor scintigraphy of, 733, 733f, 734t, 749 sporadic, 745 etiology of, 747 surgery for, 738-739, 751 procedure of choice in, 752-753 staging of, 754 standardized meal test for, 748 surgery for, 738-739, 751 assessment of cure after, 753 follow-up after, 753 in multiple endocrine neoplasia I, 741-742, 742f intraoperative maneuvers in, 751-752, 752f ultrasonography of, 732, 732f, 734t, 749 endoscopic, 749-750 intraoperative, 733, 734f unresectable, cytoreductive surgery for, 753 Gastrinoma triangle, 670f, 732 Gastrin-releasing polypeptide, 706 Gastritis, Helicobacter pylori, 748 Gastrointestinal tract hamartomatous polyps of, 777 hereditary syndromes involving, 774t Geldanamycin, for thyroid carcinoma, antitumor activity of, 338 Gemcitabine, for thyroid carcinoma, antitumor activity of, 338 Gene(s). See also specific gene. for parathyroid hormone, 373, 374 in thyroid carcinoma, 233-236 Gene therapy for anaplastic thyroid carcinoma, 165 for differentiated thyroid carcinoma, 336-338,338-339 Genetic factors in Hashimoto's thyroiditis, 39 in sporadic nontoxic goiter, 24-25 Genetic testing, for hereditary medullary thyroid carcinoma, 134 Genomic hybridization, comparative. See Comparative genomic hybridization. Gerota's fascia, of adrenal glands, 561 Ghrelinoma, 770 Giant cells, in anaplastic thyroid carcinoma, 160, 160f, 23lf Glucagon production of, by pancreatic islet A cells, 704 secretion of, somatostatin inhibition in, 705 Glucagon test, for insulinoma, 719 Glucagonoma, 768-769, 769f skin rash in, 738 surgery for, 739, 769, 80 I Glucocorticoid response elements, 558 Glucocorticoids. See also Corticosteroids. for hypercalcemic crisis, 547 physiologic effects of, 573 synthesis of, in adrenal glands, 634 Gluconeogenesis, in diabetic ketoacidosis, 791,792f

Glucose. See also Hyperglycemia; Hypoglycemia. blood levels of in diabetic ketoacidosis, 792 in insulinoma, 717, 718f preoperative management of, 724--725 GLUT-2 transport of, 707 homeostasis of, physiology of, 789-790 impaired tolerance to in chronic renal failure, 506 in primary hyperparathyroidism, 408-409, 408t metabolism of hormonal regulation of, 790 overview of, 789-790 Glucose tolerance test, for insulinoma, 719 Glucose-dependent insulinotropic polypeptide, in insulin secretion, 707 GLUT-2, glucose transport by, 707 Glycolysis, in diabetic ketoacidosis, 791, 792f Goiter(s). See also Thyroid nodule(s). diffuse, in Graves' disease, 57, 58f endemic, 16-22 classification of, 20, 20f clinical presentation of, 20-21, 20f-2lf cyanoglucosides and, 19 diagnosis of, 20-21 goitrogens and, 19 in children, 20 iodine deficiency in, 18-19, 18t, 19t, 26 large mechanical problems associated with, 20, 21f malignancies and, 20-21 malnutrition and, 19 morphologic changes in, 19-20 nodular, 20 pathophysiology of, 19 prevalence of, 16-18, 17t, 18f prevention of, 16 prophylaxis for, 21-22 radiation therapy for, 22 surgery for, 22 thyroxine therapy for, 22 total goiter rate in, 17-18, 18t in Graves' disease, 57, 59f intrathoracic, 308-316, 310, 311f airway obstruction in, 309 case studies of, 309, 312, 313, 315 chest radiograph of, 31Of,311, 312f, 315f clinical presentation of, 309-311, 309t, 31Of-31lf complications of, 311 CT scan of, 310f, 311-312, 315f definition of, 308 esophageal displacement in, 310 hyperthyroidism in, 310-311 incidence of carcinoma in, 311, 311t laryngeal nerve entrapment or distortion in, 309 laryngoscopy of, 313 MR imaging of, 315f preoperative imaging and assessment of, 311-313,312f prevalence of, 308 removal of, 194 scintigraphy of, 312-313, 312f surgery for, 313-316 cervical approach to, 313-314 complications after, 316 indications for, 313t mediastinal approach to, 314--315 sternotomy in, 314, 314t thoracotomy in, 315-316 thyroid function tests in, 313

Goiter(s) (Continued) vocal cord paralysis in, 309-310 multinodular dominant nodule within, 86f thyrocyte regulation in, 73 thyroid tissue autotransplantation for, 692 thyroid-stimulating hormone suppressive therapy for, 73-74, 74t toxic, 64-66. See also Plummer's disease. nodular formation of, 26, 26f prevalence of, 68 thyroid-stimulating hormone suppressive therapy for, 73 toxic. See Graves' disease; Hyperthyroidism. recurrent, 304--308 after initial surgery, 306 case studies of, 306, 308 cause(s) of, 304--306 extent of initial surgical procedure as, 304-305 other factors as, 305-306 postoperative thyroxine supplementation as, 305 clinical presentation of, 306, 306t compartmental syndromes in, 306 hyperthyroidism in, 306 preoperative assessment of, 306-307 prevalence of, 304 surgical approach to, 307-308 complications after, 308, 308t indications for, 306t sporadic nontoxic, 24--31 causes of, 24-25 clinical evaluation of, 27-28 diagnosis of, 28-29, 29f environmentally induced, 25 genetic factors in, 24-25 growth of, 25-26 history of, 27-28 intervention vs. observation for, 26-27 management of patients with, 27 natural history of, 26 pathogenesis of, 25-26, 26f physical examination of, 28 radioiodine ablation therapy for, 29, 30t thyroidectomy for, 29-30, 30t indications for, 26-27 treatment options for, 30t substernal. See Goiter(s), intrathoracic. types of, 25t Goitrogens, 19, 26 natural, 19 Graves' disease, 55-56, SSt antithyroid drugs for, 59-60, 60t clinical manifestations of, 57, 58f-59f diagnosis of, 57-58, 59t epidemiology of, 55, SSt, 57 historical aspects of, 54, 55f pathogenesis of, 56f, 57 radioiodine therapy for, 60-61, 60t surgery for, 60t, 61-64, 6lf, 63f indications for, 6lt thyroid tissue autotransplantation for, 692 treatment of, 58-64 adverse effects of, 60t GRFoma (growth hormone-releasing factor tumor), 769, 770t Growth factor(s). See also specific growth factor. stimulatory and inhibitory, in thyroid cell proliferation, 256, 257t

814 - - Index Growth factor-tyrosine kinase, in thyroid growth regulation, 271-272, 272f Growth hormone-releasing factor tumor (GRFoma), 769, 770t gsp oncogene in oncogenesis, 291 in thyroid neoplasms, 265, 282, 282f, 283t Guanine nucleotide-regulatory proteins, 266-267,267f in insulinomas, 715 in parathyroid hormone secretion, 375 mutations in, 281-282, 282f, 283t Guanosine diphosphate, 266 Guanosine triphosphate, 266 Guanylyl nucleotide regulatory proteins, 266-267 GVASl gene, in pseudohypoparathyroidism, 528

H Hamartoma(s) multiple, 235, 777 parathyroid, 370 Hashimoto's thyroiditis clinical course of, 40, 40f clinical presentation of, 39-40 cytologic features of, 88f diagnosis of, 40 differential diagnosis of, 40 etiology and pathogenesis of, 38-39 histologic features of, 39, 39f hypothyroidism from, 44-46 prevalence of, 38 treatment of, 40 Heart disease, ischemic, thyroxine and, 71 Helicobacter pylori gastritis, 748 Hemithyroidectomy. See also Thyroidectomy. for papillary thyroid carcinoma, 102-108 advantages and disadvantages of, 103-104, 100t considerations in, 102-103, 103t lymph node dissection with, 106-107, 107f-108f postoperative adjuvant therapy with, 107-108 rationale and indications for, 104-106, 105f-l06f survival rates in, 105t, 106 Hemorrhage bilateral adrenal Addison's disease related to, 637-639 causes of, 637t CT scan of, 638, 638f in thyroid nodule growth, 26 in thyroid surgery, 208 control of, 189 Hemorrhagic stress, increased plasma glucose during, 710 Henry procedure, for parathyroidectomy, 463,463f Heparin, in bilateral adrenal hemorrhage, 637-638 Heparin prophylaxis, after adrenalectomy, for Cushing's syndrome, 616 Hepatic artery chemoembolization, for insulinoma, 728 Hepatocyte growth factor(s), 256 in thyroid growth regulation, 260 Hepatocyte growth factor receptor, 260 Hepatocyte growth factor/scatter factor, and invasion in thyroid carcinoma, 300 HER (c-erb-Z) oncogene, 290t, 291 epidermal growth factor receptor and, 284 overexpression of, in thyroid neoplasms, 284t

Hereditary central hypothyroidism, 47 Hereditary hyperparathyroidism-jaw tumor syndrome, 774-775 Hereditary hyperthyroidism, 775 Histone acetyltransferase, 358 Histone deacetylase, 358 Histone deacetylase inhibitor as anticancer agent, 358 in thyroid tumor growth inhibition and redifferentiation, 336, 337f Hoarseness, postoperative, in thyroid surgery, 211 Honnone(s). See also specific hormone. glucose metabolism regulation by, 790 secretion of, by carcinoid tumors, 782, 783t Hospital lethality, in surgery for aerodigestive invasive thyroid carcinoma, 329,329t HRPT2 gene in parathyroid carcinoma, 449 mutation of, 775 Hiirthle cell(s), 123 in adenoma, 123, 124f, 228 in Hashimoto's thyroiditis, 39, 39f in thyroid nodule, 123, 124f Hiirthle cell neoplasms, 123-127 capsular invasion in, 125f classification of, 123 clinical characteristics of, 123-124 comparative genomic hybridization in, 347-349, 348f, 348t, 349t demographics of, 124 diagnosis of, 124-125 fine-needle aspiration of, 125 frozen section of, 125 histology of, 123-124, 124f histopathology of, 124, 125f historical background on, 123 management of, 125-127 origin of, 123 pathology of, 228-229 postoperative follow-up for, 127 prediction of malignancy in, tumor size as, 125, 125f presentation of, 124 prognosis of, 127 radioiodine therapy for, 127 risk factors for, 124 surgery for, 126-127, 126f vascular invasion in, 125f Hiirtble cell nodule, 229 Hydrocarbons, carcinogenic effect of, 246 Hydrocortisone, replacement therapy with after bilateral adrenalectomy, for Cushing's disease, 617t for decompensation in thyroid storm, 218 for myxedema coma, 221 preoperative, for hypothyroidism, 50 Hyperadrenocorticism. See Cushing's syndrome. Hyperaldosteronism, 595-602 aldosterone-producing adenoma and, 597-598 ACTH infusion and, 599 CT scan of, 598, 599f surgery for, hypertension after, 600-60 I, 60 It venous sampling in, 599, 600t biochemical studies of, 597-598 clinical characteristics of, 596 diagnosis of, 597 hyperparathyroidism in, 596 idiopathic, 597-598 laparoscopic adrenalectomy for, 600, 648

Hyperaldosteronism (Continued) localization studies of, 598-599, 598f-599f, 600t pathologic features of, 595, 596f primary imaging of, 579-580, 579f subtypes of, 595 prolactinoma in, 596 screening for, 596-597 surgical treatment of, 599-600 persistent hypertension after, 600-60 I, 60 It results of, 600-60 I Hypercalcemia benign familial hypocalciuric CASR gene in, 386, 496 parathyroid hormone levels in, 386, 450 vs. non-MEN familial hyperparathyroidism, 496 vs. primary hyperparathyroidism, 386 calcium serum levels in, 394, 544 causes of, 534-544 differential diagnosis of, 385t, 544t health survey screening for, 393-394 follow-up of, 394-395, 395f in multiple endocrine neoplasia I, 496 in parathyroid hyperplasia, 482 in renal transplant recipients, 504 malignancy-associated, 384, 450, 536-540 biochemical characteristics of, 385t clinical syndrome of, 536 differential diagnosis of, 539-540 1,25-dihydroxyvitamin Din, 538-539 osteolytic, 539 parathyroid hormone secretion in, 539 parathyroid hormone-related protein in, 536-538, 537f-538f, 538t pathogenesis of, 536-539 prostaglandins in, 539 syndromes of, 543-544 treatment of, 540 tumor types in, 536, 537t persistent, after renal transplantation, 510--511 prevalence of, 394, 394f progression of rapid, 397-398 risk of, 395 relapsing, after renal transplantation, 511 screening for, 393-394, 394f subacute severe, after renal transplantation, 510 survival in, 394-395, 395f transient, after renal transplantation, 510 Hypercalcemic crisis, 543-547 clinical features of, 544 diagnosis of, 544-545 etiology of, 543-544 in pregnancy, 545 incidence of, 543 treatment of, 545-547, 546t, 547f Hypercalcitoninemia, in medullary thyroid carcinoma, 135 Hypercalciuria, in normocalcemic hyperparathyroidism, 425-426 Hypergastrinemia differential diagnosis of, 748t effects of, 745, 746f evaluation of, 747-748 progression of, after gastrinoma surgery, 753 Hyperglycemia exercise and, 710 hemorrhagic stress and, 710 in VlPoma patients, 767

Index - Hyperglycemia (Continued) insulinoma resection and, 725 sepsis and, 710--711 Hyperglycemic, hyperosmolar syndrome clinical presentation of, 793-794 definition of, 793 pathogenesis of, 793-794 treatment of, 794-795 algorithm for, 794f Hyperglycemic crisis, 791-795. See also Hyperglycemia; specific disorder, e.g., Diabetic ketoacidosis. Hyperinsulinemia, 408 familial, 774 Hyperinsulinism, ectopic (Anderson's syndrome), 606, 607f Hyperkalemia, in diabetic ketoacidosis, 793 Hyperlipidemia in chronic renal failure, 507 in secondary hyperparathyroidism, 507 Hyperparathyroidism asymptomatic, 419-422 existence of, 419-420 historical perspective in, 419 osteitis fibrosa cystica in, 419 PAS scores in, 420-421, 421f-422f quality of life (QOL) score in, 420 renal calculi in, 419 standardized health assessment tool (SF-36) used in, 420 surgery for, NIH-sponsored guidelines for, 419,421,421f treatment of, 421-422 utilization of outcome patient-based instruments in, 420-421, 421f-422f familial in multiple endocrine neoplasia I, 489-491 in multiple endocrine neoplasia 2, 491 neonatal, 498 non-MEN,493-498 in hyperaldosteronism, 596 mediastinotomy for, 446 multiple endocrine neoplasia l-associated, calcium sensor protein in, 377 neonatal, 483 non-MEN familial, 494t age in, 493-494 clinical features of, 493-494, 495t differential diagnosis of, 495-497 diseases associated with, 494 fibro-osseous tumors in, 494, 774-775 mechanism of inheritance of, 494 parathyroid cancer and, 497-498, 497t persistent (recurrent) disease in, 495, 495f surgery for, 495 thyroid disease with, 494 normocalcemic, 386,424-428 bone disease in, 427 calcium loading study of, 427-428, 428f diagnostic studies of, 427-428, 428f ionized calcium in, 425 renal calculi in, 425-427, 426f ultrafiltrable calcium in, 425 parathyroid hormone secretion in, regulation of,376-377 persistent. See Hyperparathyroidism, recurrent (persistent). primary biochemical characteristics of, 385t bone densitometry studies in, 386, 398-399 bone mass loss in, 387, 399 calcium concentrations in, 387, 397, 397f

Hyperparathyroidism (Continued) carbohydrate metabolism in, 408-409, 408t cardiovascular disease in, 405-406 chondrocalcinosis in, 409 classification of, 402, 403t clinical findings in, 403t clinical manifestations of, 384-385, 385t confusion and delirious states in, 406 conservative management of, follow-up in, 395-398, 396t, 397f creatinine levels in, 396 depression in, 406, 407t diabetes mellitus in, 408-409, 408t diagnosis of, 384-386, 450 epidemiology of, 393-394, 394f etiology of, 449 fatigue in, 407 histopathologic varieties of, 456-457, 457f hypercalcemia in, 393-394, 394f, 543 survival and, 394-395, 395f hypertension in, 399, 402-405, 404t hyperuricemia in, 409 in postmenopausal women, 393, 399 laboratory findings in, 385-386, 403t lipoprotein metabolism in, 409 metabolic complications of, 402-410 severity of, 402, 403t mild,450 multiple endocrine neoplasia I in, 673, 674t, 675--681 diagnosis of, 675-676, 676t localization studies of, 676 management of, 676--677 surgical approach to, 677 muscle weakness in, 407 natural history of, 393-400 neuromuscular disease in, 407-408 nonsurgical approach to, Consensus Development Conference guidelines in, 387, 387t osteitis fibrosa cystica in, 386, 398 parathyroid hormone concentration in, 385-386 parathyroidectomy for. See also Parathyroidectomy. benefits of, 450 bilateral approach to, 449-454 endoscopic,467-471 indications for, 386-387, 387t, 449 revised, 387 intraoperative PTH assay in, 472-479. See also Parathyroid hormone assay. minimally invasive, 462-466 rationale for, 388, 388f-390f, 390 strategy in, 450-452, 45lt, 452f unilateral approach to, 456-460 PAS scores in, 420-421, 421f-422f physical examination of, 385 population screening for, 393-394 progression of, 395, 397, 398-399 pseudogout in, 409 psychiatric disorders in, 406-407, 407t radiologic studies of, 386 renal calculi in, 396, 397 renal failure in, 399 renal function in, 396 standardized health assessment tool (SF-36) used in, 420 surgery for, 413-416 causes of death from, 415-416, 416t complications of, 413

815

Hyperparathyroidism (Continued) cure following, 413 historical background on, 456 long-term mortality after, 413-414, 414t,415t natural history after, 413-417 postoperative mortality after, 413, 414t risk factors associated with, 414-415, 415f,415t symptoms and associated conditions in, 384,385t Visual Analog Scale (VAS) questionnaire for, 385 vs. benign familial hypocalciuric hypercalcemia, 386 vs. malignancy-associated hypercalcemia, 384, 385t recurrent (persistent), 430-436 after parathyroidectomy, 514 after surgery, 518-519 arteriography of, 434 CT scan of, 431 fine-needle aspiration of, 434 in multiple endocrine neoplasia I, 677-679,678t,680f-68If surgical approach to, 679-681, 679f-680f results of, 681, 68lt in non-MEN familial disease, 495, 495f localization studies for, 430-435, 43lt intraoperative, 435, 522-523 preoperative invasive, 433-435, 434f preoperative noninvasive, 430-433, 43lf-433f, 434t, 521, 522f sensitivity of, 435t medical therapy for, 52 I MR imaging of, 431 , 43 If parathyroid hormone assay in, 434-435 radio-guided parathyroid surgery in, 435 reoperation for, 518-525. See also Parathyroid gland(s), reoperation on. technetium 99m sestamibi scintigraphy of, 432-433,432f-433f thallium 20I-technetium 99m pertechnetate scintigraphy of, 431-432 ultrasonography of, 430-431, 431f intraoperative, 435 secondary after renal transplantation, 504 clinical manifestations of, 507 anemia in, 506 before renal transplantation, 502-504 bone disease in, 505-506 bone resistance to parathyroid hormone in, 503-504 calciphylaxis in, 506 calcitrol secretion in, 504 calcitrol synthesis in, diminished, 503 clinical manifestations of, 505-507 extraskeletal calcification in, 506 hyperlipidemia in, 507 hypertension in, 506-507 hypocalcemia in, 502-503 impaired phagocytosis in, 507 insulin resistance in, 506 metabolic complications of, 502-507 parathyroid autonomy in, 504 parathyroid hormone in nonsuppressible secretion of, 504 parathyroid gland involution and, 504 set-point changes and, 504 pathogenesis of, 502-504 phosphate retention in, 503 pruritus in, 506

816 - - Index Hyperparathyroidism (Continued) renal,502 surgery for, 510-515 after renal transplantation, 510-511, SIlt anemia after, SIS before renal transplantation, 510, SIlt bone disease after, SIS calcium metabolism after, SIS care before, 511 clinical course of, 514-515 complications of, 514 critical criteria in, 512 indications for, 510-512 localization studies in, 511-512 selection of procedure in, 512-514, 513t uremic osteodystrophy in, 505-506 Hyperphosphatemia, in chronic renal failure, 503 Hyperplasia adrenal, Cushing's syndrome from, 618 parathyroid. See Parathyroid hyperplasia. thyroid. See Thyroid hyperplasia. Hypertension after adrenalectomy, 600-601, 60 It in pheochromocytoma, 621, 622 in primary hyperparathyroidism, 399, 402-405, 404t pathogenesis of, 403-404 in secondary hyperparathyroidism, 506-507 Hyperthyroidism hereditary, 775 in Graves' disease, 55, SSt. See also Graves' disease. pathogenesis of, 56f, 57 in intrathoracic goiter, 310-311 in Plummer's disease, SSt, 65 in recurrent goiter, 306 Jodbasedow. Zf Hypertriglyceridemia, in diabetic ketoacidosis, 791 Hyperuricemia, in primary hyperparathyroidism, 409 Hypoacidemia, in glucagonoma, 768 Hypocalcemia after parathyroidectomy for hyperplasia and hyperparathyroidism, 486t for secondary hyperparathyroidism, 514 biochemical characteristics of, 528t 1,25-dihydroxyvitamin D for, postoperative use of, 388 in secondary hyperparathyroidism, 502-503 postoperative, 444 in bilateral thyroidectomy, 213 transient, after parathyroidectomy, 514 Hypocalciuria, in benign familial hypocalciuric hypercalcemia, 496 Hypochondria, in VIPoma patients, 767 Hypoglycemia alcohol-induced, 717, 796 alimentary, 795-796 autoimmune, 797 definition of, 795 differential diagnosis of, 716-717, 717t, 795t endocrine pancreas and, 710 endogenous causes of, 796-797 exogenous causes of, 796 fasting, 717, 795t, 796, 797 in insulinoma, 716-717 diazoxide for, 727 long-term therapy for, 727-728 prevention of, 724-725

Hypoglycemia (Continued) somatostatin analogs for, 727 in myxedema coma, 220 insulin-independent, 796-797 insulin-mediated, 796 postprandial, 795-796, 795t reactive, 796 treatment of, 797 tumor-induced, 797, 797f Hypoglycemic crisis, 795-797. See also Hypoglycemia. Hyponatremia in diabetic ketoacidosis, 793 in myxedema coma, 220 Hypoparathyroidism after thyroid surgery, 212-213 for recurrent goiter, 308 after thyroidectomy, for Graves' disease, 62 permanent after childhood thyroidectomy, 97, 97t after parathyroidectomy, 514 postsurgical, 413, 527-528, 528t treatment of, 528 Hypophosphatemia, 408 Hypothermia, in myxedema coma, 220 Hypothyroidism, 44-51 after thyroid surgery, 213 amiodarone and, 45 autoimmune endocrine disorders and, 46 causes of, 44-47 central,47 cervical irradiation causing, 46 clinical features of, 44-47 congenital, 47 cytokines and, 46 drug-induced, 25 Hashimoto's thyroiditis causing, 44-46 in myxedema coma, 219 increased thyroid hormone destruction and,47 iodide-induced,47 iodination for, 51 iodine deficiency and, 46-47,51 iodine excess and, 45 iodine therapy causing, 46 laboratory evaluation of, 48 lithium and, 45-46 neonatal screening for, 51 postoperative prevention of, 51 thyroid tissue autotransplantation for, 691-692,692f pregnancy and, 45 prevalence of, 44 prevention of, 51 signs and symptoms of, 47-48, 47f, 47t smoking and, 45 subclinical, 44 levothyroxine treatment and, 70, 71 subtotal thyroidectomy causing, 46 surgery for approach to, 49-50 care in, 50, SOt complications of, 50, SOt thyroid hormone resistance and, 47 thyroid lymphoma and, 46 thyroxine therapy for, 48-49 adverse effects of, 49 maintenance dose of, 49 total thyroidectomy causing, 46 triiodothyronine therapy for, 48-49 coronary bypass surgery and, 50-51 Hypoventilation, in myxedema coma, 220

I IGF2 gene, 774 Imamura method, for insulinoma localization, 732 Immunohistochemical staining, of recurrent thyroid carcinoma, 185 Immunometric assays, of parathyroid hormone, 379 Incidentaloma, adrenal, 586-592. See also Adrenaloma. Incretins, in insulin secretion, 707 Infection bacterial, in acute suppurative thyroiditis, 34 in thyroid surgery, 208 wound in neck dissection, 203 in thyroid surgery, 208 Innervation. See also specific nerve. of adrenal glands, 563-564 of pancreas, 669-670 of pancreatic islets, 706 Innominate artery, rupture of, from invasive thyroid carcinoma surgery, 330 Insular carcinoma, of thyroid, 170-171, 171f, 230. See also Thyroid carcinoma. Insulin deficiency of, diabetic ketoacidosis from, 791 exogenous administration of, hypoglycemia from, 796 for diabetic ketoacidosis, 791-793, 793f for hyperglycemic, hyperosmolar syndrome, 794-795,794f perioperative administration of, for diabetic patient, 798 plasma levels of, in insulinoma, 717, 718, 718f production of, by pancreatic islet B cells, 702 resistance to, in secondary hyperparathyroidism, 506 secretion of. See also Insulinoma. after food intake, 711 catecholamines in, 706 cell biologic processes in, 703f, 707-708 cholecystokinin in, 706 from pancreatic islet B cells, 703f, 716f gastrin-releasing polypeptide in, 706 impaired, in chronic renal failure, 506 incretins in, 707 neuropeptide Yin, 706 pulsatility of, 708-709 somatostatin inhibition in, 705 vasoactive intestinal polypeptide in, 706 Insulin gene, RNA transcript of, 790 Insulin-glucose ratio, in insulinoma, 717 Insulin-like growth factor(s), 256 in thyroid growth regulation, 259 Insulin-like growth factor I, in thyroid growth regulation, 271 Insulin-like growth factor receptor, 259 Insulinoma, 715-728 angiography of, 720, 72lf arterial stimulation of, 720-722, 722f C peptide measurement in, 718 calcium infusion test for, 719, 719f chemotherapy for, 728 clinical aspects of, 716-717 CTscanof, 720, 72lf, 730-731, 73lt diagnosis of, 717-719, 718f delays in, 716 differential diagnosis of, 717t fasting test for, 718, 718f interpretation of, 718-719

Index - -

Insulinoma (Continued) glucagon test for, 719 glucose levels in, 717, 718f glucose tolerance test for, 719 hepatic artery chemoembolization for, 728 historical background on, 715 hypoglycemia in, 716-717 diazoxide for, 727 long-term therapy for, 727-728 prevention of, 724-725 somatostatin analogs for, 727 in multiple endocrine neoplasia 1,715, 719,720f surgery for, 742-743 insulin levels in, 717, 718f insulin-glucose ratio in, 717 isotope-labeled somatostatin analysis of, 722, 723f, 723t laparotomy for, 732 localization studies for, 719-723, 721f-725f, 723t, 730-732, 731f, 73 It benefits of, 724 recommendation in, 732 management of intraoperative, 725 postoperative, 725 preoperative, 724-725 MR imaging of, 720, 731, 73 it palpation of, intraoperative, 723 pathology of, 719, 720f pathophysiology of, 715, 716f percutaneous transhepatic portal venous sampling of, 720, 721f, 731-732, 73 It proinsulin measurement in, 718 provocative tests for, 719, 719f serum glucose in, preoperative management of,724-725 signs and symptoms of, 716, 716t somatostatin receptors in, 722, 723t surgery for, 725-727, 726f-727f, 737-738, 738f,742-743 care after, 725 care during, 725 complications of, 727 failure of, 80 I laparoscopic, 727 ultrasonography of, 720 endoscopic, 722-723, 724f, 730, 731t intraoperative, 723, 724f-725f venous sampling of, 720-722, 722f Insulinotropic polypeptide, glucose-dependent, in insulin secretion, 707 Integrins, 296 malignancy and, 297, 297f Interferon-a for islet cell tumors, 802 for medullary thyroid carcinoma, 136 hypothyroidism from, 45, 46 Interleukin(s), hypothyroidism from, 45, 46 Interleukin-Z, gene therapy using, for differentiated thyroid carcinoma, 339 Interleukin-12, gene therapy using, for differentiated thyroid carcinoma, 339 Intubation, of patient, with aerodigestive invasive thyroid carcinoma, 322 Iodide excess of, 25 metabolism of, 3-4 uptake of, 3-4, 4f Iodide therapy, for thyroid storm, 217-218 Iodide transport deficiency, congenital, mutations causing, 355, 357 Iodination for goiter prophylaxis, 21

Iodination (Continued) for hypothyroidism prophylaxis, 51 thyrotoxicosis from, 21 Iodine deficiency of endemic cretinism from, 16,20 endemic goiter from, 16,26 etiology of, 18-19, 18t, 19t hypothyroidism from, 46-47 populations at risk for, 17, 17t, 18f prevention of, implementation of salt iodinization programs for, 21 severe, 19 spectrum of disorders in, 17t dietary, 18 thyroid carcinoma and, 249 excess of, hypothyroidism from, 45 for goiter prophylaxis, 16 recommended daily intake of, 18t Iodine therapy, radioactive. See Radioiodine therapy; Scintigraphy, iodine 131. Islet amyloid polypeptide, production of, by pancreatic islet B cells, 703 Islet cells. See Pancreatic islets. Islet cell tumors. See also Pancreatic tumors, endocrine. chemotherapy for, 728, 800-802, 80lt enucleation of, 684f in multiple endocrine neoplasia I, 684 sporadic, surgery for, 739, 741 Isotope scanning. See Scintigraphy. Isthmectomy, 189 for follicular thyroid carcinoma, 119 for Hurthle cell neoplasms, 126 Isthmus, division of, for intrathoracic goiters, 194

J Jaw, fibro-osseous tumors of in hereditary hyperparathyroidism, 774-775 in non-MEN familial hyperparathyroidism, 494 in primary hyperparathyroidism, 385 Jodbasedow hyperthyroidism, 25 Jugular lymph nodes, metastases to, 197 Jugular vein, internal bleeding of, in thyroid surgery, 208 in neck dissection, 200-201, 201f intraoperative PTH assay sampling via, 475-476, 476f c-jun protooncogene, 285, 291

K Keratopathy, band, in primary hyperparathyroidism, 385 Ketoacidosis, diabetic. See Diabetic ketoacidosis. Ketoconazole, for Cushing's disease, 616 Kidney(s). See also Renal entries. response of, to parathyroid hormone, 425 stones in. See Renal calculi. Kocher maneuver in adrenocortical carcinoma surgery, 608 in insulinoma surgery, 725, 726f Kocher transverse collar incision, in modified neck dissection, 200 Kulchitsky cells, in carcinoid tumors, 780 Kupffer cells, in parathyroid hormone clearance by, 378 L Langerhans tumors, 123. See also Hurthle cell neoplasms. Lanreotide, for islet cell tumors, 802

817

Laparoscopy adrenalectomy with, 569, 647-660. See also Adrenalectomy, laparoscopic. diagnostic, of medullary thyroid carcinoma, 137, 137f insulinoma resection via, 727 Laparotomy for insulinoma, 732 for sporadic gastrinoma, 751 Laryngeal nerve damage to, thyroidectomy causing, 97, 97t entrapment or distortion of, intrathoracic goiter and, 309 inferior, 13 recurrent, 12-13, 12f in neck dissection, 200 in thyroid surgery, 62, 189-190, 191f damage to, 208f-209f, 209-210 dissection of, 192-193, 193f identification of, 210 protection of, 327 papillary thyroid carcinoma invasion of, 144 paralysis of, postoperative, 316 parathyroid glands and, 481, 482f superior in thyroid surgery damage to, 211-212, 211f-212f identification of, 212 in thyroidectomy, 190-192, 191f thyroid artery, 12, 12f Laryngoscopy, of intrathoracic goiter, 313 Laryngotracheal resection, for aerodigestive invasive thyroid carcinoma, 324 types of, 324-327, 325f, 325t, 326f, 328f Lethargy, in primary hyperparathyroidism, 406 Leukemia, risk of, radioiodine therapy and, 156 Levothyroxine. See also Thyroid-stimulating hormone suppressive therapy; Thyroxine (T4 ) . angina and, 71 for benign goiters, 75-76 for diffuse goiter, 74-75, 75t for multinodular goiter, 73-74 for myxedema coma, 221 for thyroid carcinoma, 78-79, 79f myocardial infarction and, 71 pharmacology of, 69 physiology of, 70 Lifestyle, effect of, on thyroid carcinoma, 245-246 Lipid metabolism, thyroxine and, 70-71 Lipoadenoma, parathyroid, 370 Lipoprotein high-density/low-density, levothyroxine effects on, 70 metabolism of, in primary hyperparathyroidism, 409 Lips, ganglioneuromatosis of, 759f Lithium causing hypothyroidism, 45-46 causing thyroid disorders, 25 Liver metastases in endocrine pancreatic tumors, 764 in VIPoma, 768 in Zollinger-Ellison syndrome, 754 Lobectomy, thyroid, 189. See also Thyroidectomy. for anaplastic thyroid carcinoma, 162 for follicular thyroid carcinoma, 119 for Hurthle cell neoplasms, 126 for multinodular goiter, goiter recurrence after, 305

818 - -

Index

Lobectomy, thyroid (Continued) for nodular disease, 90-91 for papillary thyroid carcinoma, 103, l04t. 110 for Plummer's disease, 66 Lugol's solution, for thyroid storm, 218 Lungs fibrosis of, risk of, radioiodine therapy and, 157 metastases to childhood thyroid carcinoma and, 96, 98, 98f,252 surgical management of, 154 Lymph nodes biopsy of. in gastrinoma, 751, 752f dissection of hemithyroidectomy with, for papillary thyroid carcinoma, 106-107, 107f-108f in childhood thyroid carcinoma, 97 in thyroid carcinoma, 196-197 metastases to bilateral intrathyroid tumors and, 133, l33t childhood thyroid carcinoma and, 96 endocrine pancreatic tumors and, 764 insulinoma and, 726f prognostic significance of, 198 thyroid carcinoma and, 197 neck dissection for, 198-200 complications of, 203 technique of, 200-203, 201£-202f therapeutic strategy in, 203f, 204 regional recurrence of, 204 unilateral intrathyroid tumors and, 132t, 133 regional, surgical removal of, in medullary thyroid carcinoma, 133-134, 133f thyroidal, drainage of, 196 Lymphadenopathy, in childhood thyroid carcinoma, 96 Lymphatic duct lesions, in thyroid surgery, 208-209,209f Lymphoma, thyroid. See Thyroid lymphoma.

M MACIS scoring system, for thyroid carcinoma, 251 papillary, 104 Magnetic resonance imaging (MRI) of adrenal glands, 562f. 566, 576 of adrenocortical carcinoma, 607 of advanced thyroid cancer, in upper airway, 319,319f of Cushing's syndrome, 6l4, 615f of gastrinoma, 749 of insulinoma, 720, 731, 73lt of intrathoracic goiter, 315f of parathyroid gland adenoma, 431-432, 431£ of pheochromocytoma, 581, 623, 623f-625f of pituitary adenoma, 675f preoperative, for recurrent (persistent) hyperparathyroidism, 431, 431£ Major histocompatibility complex (MHC) barriers, thyroid transplantation across, allogeneic bone marrow transplantation in, 693 Malabsorption, thyroid-stimulating hormone suppressive therapy in, 69, 70t Malignancy. See also specific malignancy. associated with Gardner's syndrome, 235-236,235~ 776-777 hypercalcemia in, 536-540

Malignancy (Continued) clinical syndrome of, 536 differential diagnosis of, 539-540 1,25-dihydroxyvitamin D and, 538-539 osteolysis and, 539 parathyroid hormone secretion and, 539 parathyroid hormone-related protein and, 536-538, 537f-538f, 538t pathogenesis of, 536-539 prostaglandins and, 539 treatment of, 540 tumor types in, 536, 537t in endemic goiter, 20-21 in Hiirthle cell neoplasms, tumor size as prediction of, l25, 125f integrins and, 297, 297f of adrenocortical tumors, criteria for, 604-605,605t potential for, thyroid nodules and, 85, 86 progression of, molecular crosstalk in, 300-301 second, risk of, radioiodine therapy and, 157 Malnutrition, in endemic goiter, 19 Manumycinlpaclitaxel, for anaplastic thyroid carcinoma, 163 Marafi6n's maneuver, in evaluation of goiter, 310 "Marfanoid" habitus, in multiple endocrine neoplasia 2B, 759, 760f Meal test, standardized, for gastrinoma, 748 Mediastinal tracheal resection, for aerodigestive invasive thyroid carcinoma, 327, 329 Mediastinotomy, 446 Mediastinum adenoma of arteriography of, 434, 434f reoperation for, 525, 525f exploration of, in parathyroid surgery, 522 goiter extension into. See Goiter(s), intrathoracic. goiters or thyroid tumors in, removal of, 194 lymph nodes of, metastases to, 197 Medullary thyroid carcinoma. See Thyroid carcinoma, medullary. MEN. See Multiple endocrine neoplasia (MEN) entries. MEN 1 gene, 673 mutations of, 673-674 menin gene, 399, 715 Menin protein, 673 Mental condition, of patient with aerodigestive invasive thyroid carcinoma, 32l Meperidine, for decompensation in thyroid storm, 218 Messenger RNA for parathyroid hormone, 373-374 insulin, 702 MET oncogene, 290t, 291 epidermal growth factor receptor and, 284 Metabolic acidosis, in diabetic ketoacidosis, 791 Metabolism calcium, after parathyroidectomy, 515 carbohydrate, in primary hyperparathyroidism, 408-409, 408t glucose hormonal regulation of, 790 overview of, 789-790 iodide, 3-4 lipid, 70-71 lipoprotein, in primary hyperparathyroidism, 409

Metabolism (Continued) parathyroid hormone, 378 thyroxine, 5 triiodothyronine, 5 Metalloproteinase(s) antitumor effect of, 299 in malignancy, 298-299, 299t enzymes implicated in, 299-300, 300f overexpression of, in thyroid carcinoma, 339 Metalloproteinase inhibitors, for differentiated thyroid carcinoma, 339-340 Metaphase spreads, preparation of, in comparative genomic hybridization analyses, 344, 345f Metastasis. See also under specific cancer. adrenal bilateral, 639 imaging of, 582-583 distant diagnostic procedures for, 152-153, 153f location of, 152, 153t prognosis of, 157 radioiodine therapy for. 154, 156-157, 156f surgery for, 154, 154f-155f thyroxine suppressive therapy for, 157 liver. See Liver metastases. lymph node. See Lymph nodes, metastases to. pulmonary. See Lungs, metastases to. thyroid, 176-177, 176f Methimazole for Graves' disease, 59 adverse effects of, 60, 60t for thyroid storm, 217 Metyrapone, for Cushing's disease, 616 Microcarcinoma, thyroid, 225 Microtubules, cytoskeletal, 295 Mifepristone, for Cushing's disease, 616 Minimally invasive parathyroid surgery, 462-466 advantages and disadvantages of, 464-465, 465f complications of, 464 indications for, 464 results of, 465-466, 465t, 466t techniques of, 462-463, 463f Mitogen-active protein, 271 Mitogen-active protein kinase, 271, 272, 272f Mitogenic pathways, in thyroid growth regulation, 256-257, 258f Mitotane for adrenocortical carcinoma, 609-610, 803 preoperative, 608 survival associated with, 610f for Cushing's disease, 616 Mitoxantrone, for anaplastic thyroid carcinoma, 804 Molecular carcinogenesis, 245 Monoclonal antibody therapy. for differentiated thyroid carcinoma, 339, 339f Monoiodotyrosine, synthesis of, 4f, 5 MRI. See Magnetic resonance imaging (MRI). MTS-l gene, 292 MTS-2 gene, 292 Mucoepidermoid carcinoma, of thyroid, 172. See also Thyroid carcinoma. Mucosa-associated lymphoid tissue (MALT) lymphoma, of thyroid, 174-175,232. See also Thyroid lymphoma. Multimodality therapy, for anaplastic thyroid carcinoma, 162-163 Multiple endocrine neoplasia I (MEN 1), 673-686 abnormal parathyroid glands in, 483

Index - Multiple endocrine neoplasia I (MEN I) (Continued) adenoma in, 675, 675f carcinoid tumors in, 686, 781 clinical presentation of, 673, 674t endocrine pancreatic tumors in, 765-766 backgroundin,681-682,68If-682f biochemical screening for, 682-683, 683t imaging of, 683, 683f incidence of, 770t localization studies of, 733-735, 734f surgery for, 683-684, 684t epidemiology of, 673 familial hyperparathyroidism in, 489-491 clinical aspects of, 489 follow-up and screening for, 490-491 treatment of, 490 gastrinoma in, surgery for, 741-742, 742f genetic counseling in, 674 genetic screening for, 674 indications for, 675t hypercalcemia in, 496 hypoglycemic syndrome in, 684 insulinoma in, 715, 719, nOf surgery for, 742-743 islet cell tumors in, 684 molecular biology of, 673-674 parathyroid cell proliferation in, 377 parathyroidectomy for, 452 pituitary tumors in, 674-675, 675f-676f prevalence of, 673 primary hyperparathyroidism in, 673, 674t, 675-677 diagnosis of, 675-676, 676t localization studies of, 676 management of, 676-677 surgery for, 677 recurrent (persistent) hyperparathyroidism in, 677-679, 678t, 680f-681f surgery for, 679-681, 679f-680f results of, 681, 681t vs. non-MEN familial hyperparathyroidism, 496-497 Zollinger-Ellison syndrome in, 734-735 surgery for, 684-686, 685f, 741-742, 742f Multiple endocrine neoplasia 2 (MEN 2) carcinoid tumors in, 781 familial hyperparathyroidism in, 491 gene carriers for, preventive surgery for, 134-135 in pheochromocytoma, 630-631 ret gene in, 491 vs. non-MEN familial hyperparathyroidism, 497 Multiple endocrine neoplasia 2A (MEN 2A), 757 familial hyperparathyroidism in, 491 medullary thyroid carcinoma in, 129-130, l30f-13lf, 130t, 13 It, 230 parathyroidectomy for, 452 ret mutations in, 134, 234 vs. non-MEN familial hyperparathyroidism, 497 Multiple endocrine neoplasia 2B (MEN 2B), 757-763 amine precursor uptake and decarboxylation in, 758 characteristics of, 757 clinical characteristics of, 758-762 diagnosis of, 762 familial hyperparathyroidism in, 491 historical considerations in, 757 "rnarfanoid" habitus in, 759, 760f

Multiple endocrine neoplasia 2B (MEN 28) (Continued) medullary thyroid carcinoma in, 129-130, 130f-131f, 130t, 13 It, 230, 760-761, 760f-76If preventive surgery for, 134-135 neuroma in, 759, 759f pathogenesis of, 758, 758f-759f pathology of, 758-762 pheochromocytoma in, 761-762 ret mutations in, 134,234,758, 758f-759f screening for, 762 vs. non-MEN familial hyperparathyroidism, 497 Multiple-gland disease, cryopreserved parathyroid transplantation for, 533 Muscle weakness, in primary hyperparathyroidism, 407 c-myc protooncogene, 285 Myelolipoma, 587f Myocardial infarction, levothyroxine and, 71 Myxedema, iodide-induced, 25 Myxedema coma, 219-221 cardiovascular complications in, 220 clinical manifestations of, 219-220 decreased mental function in, 220 diagnosis of, 220 hypoglycemia in, 220 hyponatremia in, 220 hypothermia in, 220 hypothyroidism in, 219 hypoventilation in, 220 metabolic complications of, 221 precipitants of, 217t elimination of, 221 pulmonary complications in, 220 supportive care for, 221 thyroid hormone replacement therapy for, 221 treatment of, 220-221 Myxoma, cardiac, in Carney's complex, 776

N National Institutes of Health (NlH)-sponsored guidelines, for parathyroidectomy, 419, 421,421f Neck exploration of, in parathyroid surgery, 521-522 irradiation of, hypothyroidism due to, 46 surgical anatomy of, 196-197 Neck dissection for thyroid carcinoma, 196-197 lymph node metastases in, 199-200 complications of, 203 surgical technique of, 200-203, 201f-202f therapeutic strategy in, 203f, 204 in parathyroidectomy, 442-443 incision in, 442 closure of, 444 radical, for Hiirthle cell neoplasms, 126, 126f Needlescopic adrenalectomy, 654. See also Adrenalectomy, laparoscopic. Nelson's syndrome, after adrenalectomy, 617 Neonates. See also Children. familial hyperparathyroidism in, 498 hyperparathyroidism in, 483 hypothyroidism screening in, 51 Neoplasms. See specific neoplasm. Nephrolithiasis. See Renal calculi. Nerve(s). See specific nerve, e.g., Laryngeal nerve.

819

neu (c-erb-2) oncogene epidermal growth factor receptor and, 284 overexpression of, in thyroid neoplasms, 284t Neural crest, 9, 558 Neural tube, 558 Neuroblastoma, of primitive sympathogonia, 560 Neuroendocrine tumors, 780-786. See also Carcinoid tumors. Neurofibromatosis paraganglioma in, 629 pheochromocytoma in, 631 Neurofibromatosis I, 777-778 Neurofibromatosis II, 777 Neuroglycopenia, 710 Neuroma, in multiple endocrine neoplasia 2B, 759, 759f Neuromuscular disease, in primary hyperparathyroidism, 407-408 Neuropeptide(s), endocrine, 704t Neuropeptide Y, as pancreatic neurotransmitter, 704, 706 Neurotensinoma, 770 Neurotransmitters in pancreatic islets, 706 secretion of, by carcinoid tumors, 782, 783t NIS gene and thyroid carcinoma, 357-358 cloning of, 359 expression of enhancement of, 358-359, 358f-359f regulation of, 356 function of, regulation of, 356 molecular characterization of, 355-356, 357f NIS gene therapy, for undifferentiated thyroid carcinoma, 336-337 Nodule(s) Hiirthle cell, 229 thyroid. See Thyroid nodule(s). Non-islet cell tumors, hypoglycemia in, 797, 797f Non-multiple endocrine neoplasia syndromes, 773-778. See also specific type, e.g., Beckwith-Wiedemann syndrome. Nonsteroidal anti-inflammatory drugs, for subacute thyroiditis, 36 Nonthyroid illness, 48 Noonan's syndrome, 777 Norepinephrine, degradation of, 574, 574f Nuclear explosions, radiation fallout from, thyroid carcinoma and, 243-245, 244f Nuclear oncogenes, 291-292

o Octreotide for islet cell tumors, 802 for VIPoma, 767, 768f Oil iodination for goiter prophylaxis, 21 for hypothyroidism prophylaxis, 51 Omeprazole for gastric acid hypersecretion, 747 for gastrinoma, 751 Oncocytic adenoma, parathyroid, 370 Oncocytoma, 123. See also Hiirthle cell neoplasms. Oncogene(s). See also specific gene, e.g., gsp oncogene. activating G proteins in, 291 as growth hormone receptors, 283-285, 284t, 285t dominant, 288 in thyroid carcinoma, 77

820 - - Index Oncogene(s) (Continued) in thyroid neoplasms, 280-286, 281f nuclear, 285, 291-292 of thyroid-stimulating hormone, 280-283, 282f,283t ras family of, 283, 284t recessive, 288 tyrosine activity with, 283-285, 284t Oncogene receptor protein, 288, 290t Oncogenesis genes involved in, 290t in thyroid carcinoma, 288-293 multistep hypothesis of, 288, 289f Ophthalmopathy, in Graves' disease, 57, 59f Orphan Annie nuclei, in follicular variant of papillary thyroid carcinoma, 117, 117f Osteitis fibrosa cystica in primary hyperparathyroidism, 386, 398, 419 in secondary hyperparathyroidism, 505 Osteodystrophy, uremic, 505-506 Osteolysis, local, in hypercalcemia of malignancy, 539 Osteoporosis, T score definition of, 427 Oxyphilic tumors, 123. See also Hiirthle cell neoplasms.

P p53 gene, 290t, 292 gene therapy with, for undifferentiated thyroid carcinoma, 336 in anaplastic thyroid carcinoma, 77, 159, 161, 161f, 162,232 in thyroid carcinoma, 157 Pain relief, for pancreatic cancer, 670 Painless thyroiditis, 37-38, 38f Palliative procedures, for aerodigestive invasive thyroid carcinoma, 330 Palpation, intraoperative, of insulinoma, 723 Pamidronate for hypercalcemia, 540 in parathyroid carcinoma, 552 for hypercalcemic crisis, 546 Pancreas anatomy of, 665-670, 667f arterial supply to, 667-668, 668f anomalous, 668-669 body of, 667, 667f cancer of. See also Pancreatic tumors; specific tumor; e.g., Insulinoma. chemotherapy for, 800-802, 801t pain relief for, 670 divisions of, 666-667 ducts of, 669 ectopic, 665 embryology of, 665, 666f endocrine after food intake, 711 historical aspects of, 701 hypoglycemia and, 710 physiology of, 701-711 stress and, 710-711 type 2 diabetes and, 709, 709f exocrine, 665-666 head of, 666-667, 667f hereditary syndromes involving, 774t inflammation of, in kidney transplant recipients, 507 islets of. See Pancreatic islets. lymphatic drainage of, 668f, 669 neck of, 667, 667f nerves of, 669-670 surgical exposure of, 670-671, 670f-671f intraoperative assessment in, 671

Pancreas (Continued) tail of, 667, 667f transplantation of, 697 tumors of. See Pancreatic tumors. uncinate process of, 667, 667f venous drainage of, 668 ventral primordia of, 665, 666f Pancreastatin, 378 production of, by pancreatic islet B cells, 703-704 Pancreatectomy for gastrinomas, 752 for insulinomas, 726, 726f laparoscopic, 727 Pancreatic accessory duct of Santorini, 669 Pancreatic cells, 665-666 Pancreatic duct of Wirsung, 669 Pancreatic islets A cells of, 666, 701-702 glucagon production in, 704 peptide YY production in, 704 anatomy of, 701-702, 702f B cells of, 666, 701, 702-704 biology of, 703f, 707-708 insulin production in, 702 insulin secretion in, 703f, 707-708 islet amyloid polypeptide production in, 703 neurosecretory granules of, 715, 716f pancreastatin production in, 703-704 blood flow in, 705 catecholamine effects in, 706 cholecystokinin nerves in, 706 D cells of, 666, 701 diazepam-binding inhibitor production in, 705 somatostatin production in, 705 F cells of, 666, 701-702 pancreatic polypeptide production in, 705 function of, 701 hormone secretion in, 704t, 707 pulsatility of, 708-709 innervation of, 706 neurotransmitters of parasympathetic effects of, 706 sympathetic effects of, 706 non-B cells of, biology of, 708 peptides and neuropeptides in, 704t sensory nerves in, 707 transplantation of, 697-698, 698f tumors of. See Pancreatic tumors, endocrine. Pancreatic polypeptide, production of, in pancreatic islet F cells, 705 Pancreatic polypeptide-producing tumor (PPoma),770-771 Pancreatic tumors, endocrine, 764-771. See also specific type, e.g., Insulinoma. aggressive, characteristics of, 764-765, 765t chemotherapy for, 728, 800-802, 80lt classification of, 765, 765t combination therapy for, 728 hepatic artery chemoembolization for, 728 in multiple endocrine neoplasia 1,673, 674t, 765-766 background of, 681-682, 681f-682f biochemical screening for, 682-683, 683t imaging of, 683, 683f incidence of, 770t localization studies for, 733-735, 734f surgery for, 683-684, 684t, 741-742, 742f localization studies for, 730-735, 732f-734f, 734t in multiple endocrine neoplasia I, 733-735,734f

Pancreatic tumors, endocrine (Continued) nonfunctioning localization studies for, 735 surgery for, 743 pathology of, 764-765, 765f sporadic, surgery for, 737-739, 738f, 740f, 741 streptozocin for, 728 surgery for, 683-684, 684t, 737-743 principles in, 766 syndromes associated with, 765t Pancreaticoduodenal artery, 667-668, 668f Pancreaticoduodenal vein, 668, 668f Pancreatitis, in kidney transplant recipients, 507 Pancytopenia, risk of, radioiodine therapy and, 156 Papillae, in papillary thyroid carcinoma, 224 Papillary thyroid carcinoma. See Thyroid carcinoma, papillary. Parafollicular (C) cells, in medullary thyroid carcinoma, 129, l30f,229 Paraganglia, 560 Paraganglioma, 169, 170f,629-630 surgery for, 628 Paralysis. See under specific anatomic part. Parathymus, 10 undescended, 481 Parathyroid artery, 441 Parathyroid carcinoma, 371, 371f, 549-553 biologic markers of, 550-551 clinical presentation of, 549 DNA assessments in, 552 histopathologic characteristics of, 550, 55 If, 552t hypercalcemia treatment in, 552 incidence of, 549, 550t localization studies of, 549-550 non-MEN familial hyperparathyroidism with, 497-498, 497t prevalence of, 549 prognosis of, 552 recurrent, 552 treatment of, 551-552 vs. parathyromatosis, 552 Parathyroid cells calcium sensor protein on, 375-376 proliferation of, 377 autocrine regulation of, 377-378 secretion of, autocrine regulation of, 377-378 Parathyroid gland(s). See also Hyperparathyroidism; Hypoparathyroidism. adenoma of, 369-370, 369f-370f CT scan of, 482f fine-needle aspiration of, 433 MR imaging of, 431-432, 431f PRADl oncogene in, 377, 399 reoperation for, 524-525, 524f-525f scintigraphy of, 432-433, 432f-433f surgery for, 451 minimally invasive, 462-466 ultrasonography of, 430, 43 If variants of, 370 vs. hyperplasia, 370t, 453-454 allotransplantation of, 694-695 anatomy of, 11-15, 12f, 14f, 366-368, 367f-368f, 439-441, 440f-44lf, 481, 482f arterial supply to, 14-15,368-369 autotransplantation of, 486-487, 514, 694-695,694f cryopreservation in, 487, 523 indications for, 532-534

Index - - 821 Parathyroid gland(s) (Continued) pocket storage in, 695 biopsy of, during parathyroidectomy, 443 blood supply to, 441 carcinoma of. See Parathyroid carcinoma. cryopreservation of, 487, 530-534 current technique in, 530-531 function of, 531-532, 532t, 533f, 533t historical aspects in, 530 reoperation and, 523, 533-534 research on, 534, 534t technical issues in, 530-531 thawing technique in, 531 variations of, 531, 532t embryology of, 10-11, lOf, 365-366, 366f, 439,481 epithelial cells of, 369, 369f gross features of, 441 hypercellular, 482, 483f hyperplasia of. See Parathyroid hyperplasia. identification of, in thyroid surgery, 213 in neck dissection, 200 inferior, 367, 367f location of, 452, 452f kissing-paired, 367 localization studies of, in recurrent (persistent) hyperparathyroidism intraoperative, 435 invasive preoperative, 43lt, 433-435, 434f,435t noninvasive preoperative, 430-433, 43lf-433f, 431t, 434t location of, 366, 367f, 440-441, 440f-44lf lower, locations of, 441, 441f management of, in medullary thyroid carcinoma, 132-133 missing, troubleshooting for, 444-446, 444f-446f morphology of, 481-482, 483f pathology of, 369-371, 369f-37lf preservation of, in thyroidectomy, 192, 192f relationship between recurrent laryngeal nerve and, 368 reoperation on, 518-525 anatomic site of disease at, 524t approach to, 519-521 cervical exploration in, 521-522 cryopreservation in, 523, 533-534 diagnosis confirmation in, 519 failed initial explorations and, 518-519 illustrative cases of, 524-525, 524f-525f in multiple endocrine neoplasia I patient, 679-681, 679f-680f results of, 681, 68lt indications for, 519 intraoperative PTH assay in, 478, 681 localization tests before, 521, 52lt, 522f localization tests during, 522-523 mediastinal exploration in, 522 medical alternatives to, 521 pathology review before, 520 results of, 523-524, 523t, 524t risks in, 519-520, 520t size, shape, and color of, 367-368, 441 stromal cells of, 369, 369f superior, 366, 367f, 481, 482f location of, 452, 452f supernumerary, 439-440, 481 surgery on. See also Parathyroidectomy. minimally invasive, 462-466 advantages and disadvanteages of, 464-465,465f complications of, 464 indications for, 464

Parathyroid gland(s) (Continued) results of, 465-466, 465t, 466t techniques of, 462-463, 463f radio-guided, in recurrent (persistent) hyperparathyroidism, 435 symmetry of, 367 tissue resection of, in parathyroidectomy, 443-444 tumors of dissection of, 443-444 location of, 452, 452f sites of, 440, 440f upper, locations of, 440, 440f venous drainage of, 15 vs. fat lobules, 368 weight of, 441 xenotransplantation of, 694 Parathyroid hormone, 372-380 assay of. See Parathyroid hormone assay. bone resistance to, in secondary hyperparathyroidism, 503-504 gene for, 373, 374 immunometric assays of, 379 in calcium homeostasis, 419-420 in hypertension, 404-405 in pseudohypoparathyroidism, 528 messenger RNA levels for, 373-374 metabolism of, 378 radioimmunoassays of, 379 secretion of autocrine regulation of, 377-378 calcium in, 372-374, 373f-374f, 419-420 calcium sensor proteins in, 375-376 cyclic adenosine monophosphate in, 374 G proteins in, 375 in fresh vs. cryopreserved tissue, 531, 533f in malignancy-associated hypercalcemia, 539 in primary hyperparathyroidism, 376-377, 385-386 in secondary hyperparathyroidism, 504 intracellular messengers in, 374-375, 374f-375f parathyroid cell proliferation in, 377 physiologic regulation in, 372-374, 373f-374f protein C kinase in, 375 set-point for, in secondary hyperparathyroidism, 504 Parathyroid hormone assay, 378-380 in differential diagnosis of hypercalcemia, 545 in parathyroidectomy intraoperative, 435, 458-459, 459f advantages of, 475-476 blood collection time and processing in, 474-475,475f by fine-needle aspiration, 475 by internal jugular venous sampling, 475-476,476f criterion accuracy in, 478 disadvantages of, 477 established criterion for evaluation of, 473-474, 473f, 474t for sporadic primary hyperparathyroidism, 472-479 limitations of, 476-477 results of, 477-478 shorter operative time and cost savings with, 476 technique of, 475 preoperative venous sampling for, 434-435

Parathyroid hormone receptor, 378 Parathyroid hormone-related protein, 378 in hypercalcemia, 545 in hypercalcemia of malignancy, 384, 536-538, 537f-538f, 538t tumor-releasing, 770 Parathyroid hyperplasia, 370, 370f, 370t etiology of, 482-483 hypercalcemia in, 482 hyperparathyroidism in, 483-484, 484f multiple endocrine neoplasia and, 483 parathyroidectomy for, 481-487 autotransplantation and, 486-487 cryopreservation in, 487 indications for, 483-484, 484f postoperative hypocalcemia after, 486t results of, 487 technique of, 484-486, 485t, 486t surgery for, 451 vs. adenoma, 370t, 451, 453-454 Parathyroid hypertensive factor, 405 Parathyroidectomy, 441-444. See also Parathyroid gland(s), surgery on. after renal transplantation, 510-511, 5llt anemia after, 515 anesthesia for, 442 autotransplantation with, 486-487, 514 before renal transplantation, 510, 51lt bilateral, 449-454 vs. unilateral, 452-454 biopsy during, 443 bone disease after, 515 calcium metabolism after, 515 care before, 511 complications of, 514 dissection in, 442-443 endoscopic, 467-471 algorithm for surgical management in, 469f contraindications to, 468-469, 470t lateral approach to, 468, 468f, 470, 470t pure, 467 results of, 469-470 technique of, 467-468, 468f for double adenoma, 451 for hyperplasia, 451, 481-487. See also Parathyroid hyperplasia, parathyroidectomy for. for medullary thyroid carcinoma, 132-133 for multiple endocrine neoplasia, 452 for primary hyperparathyroidism, 388, 388f-390f, 390. See also Hyperparathyroidism, primary, parathyroidectomy for. bilateral, 449-454 endoscopic,467-471 minimally invasive, 462-466 unilateral, 456-460 for single adenoma, 451 future aspects of, 460 hypertension control with, 405 incision in, 442 closure of, 444 indications for, in secondary hyperparathyroidism, 510-512, 51lt initial, intraoperative PTH assay in, 478 lateral approach to, 446 localization studies in, 511-512 minimally invasive endoscopic, 462, 463f lateral approach to, 463, 463f video-assisted, 462-463, 463f, 467-468 results of, 465-466, 465t, 466t neck exploration in, 442-443

822 - - Index Parathyroidectomy (Continued) NIH-sponsored guidelines for, 419, 421, 42lf PAS scores and, 388, 39Of, 420-421, 42lf-422f positioning of patient for, 442, 442f postoperative care in, 444 premature death after, 406 recurrent (persistent) hyperparathyroidism after in multiple endocrine neoplasia I patients, 677-679, 678t parathyroid hormone assay in, 434-435 selection of procedure in, 512-514, 513t subtotal, 513 for MEN I in hyperparathyroidism, 677 results of, 678t vs. autotransplantation trials, 513, 513t surgical management of, 512 technique of, 441-444 tissue resection in, 443-444 total, autotransplantation with, 514 ultrasonography before, 458 unilateral, 456-460 advantages of, 460 in adenoma vs. hyperplasia, 453-454 intraoperative monitoring in, 458-459, 459f local anesthesia for, 459 localization studies in, 453 preoperative, 458 minimal invasion in, 459-460 principle of, 456 rationale for, 452-453 results of, 457-458 vs. bilateral, 452-454 venous sampling before, 458 Parathyroidectomy Assessment of Symptoms (PAS) scores, 388, 390f, 420-421, 42lf-422f Parathyromatosis, 512 vs. parathyroid carcinoma, 552 Patient selection, for aerodigestive invasive thyroid carcinoma surgery, 320-321 PAX8 gene therapy, for undifferentiated thyroid carcinoma, 336 PAX8-PPAR:yl oncogene, 292 Pemberton's sign, in evaluation of goiter, 27,310 Pendred's syndrome, 5, 775 Peptic ulcer, in gastrinoma, 745, 747 Peptide(s), endocrine, 704t Peptide YY, production of, by pancreatic islet A cells, 704 Percutaneous transhepatic portal venous sampling, of insulinoma, 720, 72lf, 731-732,73lt Peroxisome proliferator-activated receptor y agonist, in thyroid tumor growth inhibition and redifferentiation, 336 Personality changes, in primary hyperparathyroidism, 406 Phagocytosis, in secondary hyperparathyroidism, 507 Pharangeal pouches, parathyroid origin from, 365, 366f, 439 Pharynx, invasive thyroid carcinoma of, surgery for, 329 Phenoxybenzamine, before pheochromocytoma surgery,624,626,627 Phenylacetate, in thyroid tumor growth inhibition and redifferentiation, 336 Phenylbutyrate, in thyroid tumor growth inhibition and redifferentiation, 336

Pheochromocytoma, 621-631 catecholamines in, 621 clinical features of, 621-622, 622f conditions associated with, 631 CT scan of, 623, 623f, 625f diagnosis of, 622 extra-adrenal, 628, 629-630 familial, 776 historical aspects of, 621 hypertension in, 621, 622 imaging of, 580-581, 580f-58lf flow chart in, 582f in children, 631 in multiple endocrine neoplasia 2, 630-631 in multiple endocrine neoplasia 2B, 761-762 in pregnancy, 630 in von Rippel-Lindau disease, 775 incidence of, 621 laparoscopic adrenalectomy for, 648 complications of, 656 localization studies of, 580-581, 580f-58 If, 623-624 malignant, 629, 630f chemotherapy for, 803 MR imaging of, 623, 623f-625f pathology of, 586, 587f, 628-629, 629f preoperative management of, 625, 626 scintigraphy of, 623-624, 624f-625f size of, 622, 628 subclinical, screening for, 589 surgery for anterior approach to, 627-628 ~ blockers before, 626 calcium channel blockers before, 626 care after, 628 doxazosin before, 626 esmolol during, 626 laparoscopic, 626-627 left adrenal exposure in, 627-628 management during, 626 phenoxybenzarnine before, 624, 626,627 posterior approach to, 628, 628f prazosin before, 626 propranolol before, 626 right adrenal exposure in, 627 sodium nitroprusside during, 626 venous sampling in, 581 Phorbol esters, tumor-promoting, 271 Phosphate, retention of, in secondary hyperparathyroidism, 503 Phosphatidylinositol-protein kinase C--<:alcium pathway, in thyroid regulation, 257, 257t, 258f Phosphoinositide turnover phospholipaseprotein kinase C, in thyroid growth regulation, 270-271, 270f Phospholipase in signal transduction, 270 thyroid-stimulating hormone stimulation of, 270-271, 270f Phrenic nerve, injury to, in neck dissection, 203 Physical condition, of patient with aerodigestive invasive thyroid carcinoma, 321 Physical exercise. See Exercise. Pituitary adenylate cyclase activating polypeptide, 706 Pituitary gland adenoma of corticotropin-secreting, Cushing's syndrome from, 612 in Carney's complex, 776

Pituitary gland (Continued) in multiple endocrine neoplasia 1,675, 675f irradiation of, for Cushing's disease, 615 selective transsphenoidal microsurgery of, for Cushing's disease, 615 tumors of, in multiple endocrine neoplasia 1, 674-675,675f treatment of, 675, 676f Plasmacytoma, 168, l69f Platelet-derived growth factor(s), 256 in thyroid growth regulation, 260 Platelet-derived growth factor receptor, 260 Plicamycin for hypercalcemia, in parathyroid carcinoma, 552 for hypercalcemic crisis, 547 Plummer's disease, 311 clinical manifestations of, 65 diagnosis of, 65 epidemiology of, 55t historical aspects of, 54-55, 55f pathogenesis of, 64-65, Mf treatment of, 65-66 Polyglandular autoimmune syndromes, Addison's disease in, 634-635 Polyps, gastrointestinal hamartomatous, 777 Portal venous sampling of gastrinoma, 750 of insulin oma, 720, 72 If, 731-732, 73lt Postpartum thyroiditis, 37, 38f Potassium channels, APT-regulated, 703f, 707 Potassium iodide for Graves' disease, 60 for thyroid storm prophylaxis, 63 Potassium perchlorate, for Graves' disease, 59-60 PPoma (pancreatic polypeptide-producing tumor),770-771 PRADl oncogene, in parathyroid adenoma, 377, 399, 449 Prazosin, before pheochromocytoma surgery, 626 Prednisone, for subacute thyroiditis, 36 Pregnancy hypercalcemic crisis in, 545 hypothyroidism during, 45 pheochromocytoma in, 630 thyroxine therapy in, 69, 70t, 76 Prethyroid fascia, 197 Proinsulin, in insulinoma, 718 Prolactinoma, in hyperaldosteronism, 596 Propranolol before pheochromocytoma surgery, 626 for Graves' disease, 60 for thyroid storm, 218 for thyroid storm prophylaxis, 63-64 Propylthiouracil for Graves' disease, 59 adverse effects of, 60, 601 for thyroid storm, 217 Prostaglandins, in malignancy-associated hypercalcemia, 539 Protein kinase A adenylase cyclase, in signal transduction, 266-269,267f phosphorylation in, 273 Protein kinase C calmodulin kinase and, 274 desensitization by, calmodulin kinase and, 273-274 in parathyroid hormone secretion, 375 elevation of, 376-377 in thyroid growth regulation, 270-271, 270f inhibitors of, 271

Index - -

Protooncogene(s), 288. See also specific protooncogene, e.g., ret protooncogene. definition of, 280 in thyroid carcinoma, 233-236 Provocative tests, for insulinoma, 719, 719f Pruritus, in secondary hyperparathyroidism, 506 Psammoma bodies, in papillary thyroid carcinoma, 106, 106f, 224, 224f Psammomatous melanotic schwannoma, in Carney's complex, 776 Pseudogout, in primary hyperparathyroidism, 409 Pseudohypoparathyroidism, 528 classification of, 529t Pseudopseudohypoparathyroidism, 528 Psychiatric disorders, in primary hyperparathyroidism, 406-407, 407t Psychosis, in primary hyperparathyroidism, 406 PTEN gene, 235, 290t, 292 PTHrP gene, 537, 538

Q Quality of life (QOL) score, in asymptomatic hyperparathyroidism, 420

R Radiation exposure to anaplastic thyroid carcinoma from, 160 thyroid carcinoma from carcinogenesis and, 245 characteristics of, 245, 245t environment and, 243-245, 244f historical aspects of, 27, 240, 24lf in childhood, 240-242, 24lf medical therapy and, 242-243, 242t,243f ionizing, thyroid tissue destruction with, 25 tumorigenic effects of, on child's thyroid, 94 Radiation dose, on radiation-associated thyroid carcinoma, 242, 242t Radiation therapy for anaplastic thyroid carcinoma palliative, 163 postoperative, 162, 162f for bulky or minimal residual disease, in advanced thyroid cancer patients, 330 for Cushing's disease, 615 for endemic goiter, 22 for medullary thyroid carcinoma, 135 for plasmacytoma, 168 for thyroid carcinoma, recurrency prevention with, 183-184 for thyroid lymphoma, 176 therapeutic, thyroid cancer caused by, 27, 242-243,242t, 243f to neck, hypothyroidism due to, 46 Radioimmunoassays, of parathyroid hormone,379 Radioimmunoguided surgery, for medullary thyroid carcinoma, 137 Radioiodine therapy ablative for sporadic nontoxic goiter, 29, 30t postoperative, for papillary thyroid carcinoma, 107-108 side effects of, 29 exposure to, risk of thyroid carcinoma and, 243, 243f for bulky or minimal residual disease, in advanced thyroid cancer patients, 330

Radioiodine therapy (Continued) for childhood thyroid carcinoma, 98-99, 98f-99f complications of, 98t for differentiated thyroid carcinoma, 251-252 for Graves' disease, 60-61, 60t for Hiirthle cell neoplasms, 127 for metastatic thyroid carcinoma, 154, 156, 156f complications of, 156-157 side effects of, 156 for Plummer's disease, 65-66 for thyroid carcinoma, recurrency prevention with, 183 hypothyroidism from, 46 Radionuclide scanning. See Scintigraphy. ras oncogene, 283 in anaplastic thyroid carcinoma, 159, 162, 232 in oncogenesis, 291 in thyroid growth, 26 in thyroid neoplasms, 261, 265, 283, 284t rb gene, 292 in thyroid neoplasms, 261-262 Rectum, carcinoid tumors of, 780 treatment of, 786 Redifferentiating agents, in restoration of differentiated thyroid function, 334-336, 335f,337f Renal calculi in asymptomatic hyperparathyroidism, 419 in normocalcemic hyperparathyroidism, 425-427,426f in primary hyperparathyroidism, 396, 397 in transplanted kidneys, 507 Renal failure chronic, 502 bone disease in, 505 glucose intolerance in, 506 hyperlipidemia in, 507 hyperphosphatemia in, 503 hypertension in, 506-507 insulin secretion in, 506 normochromic, normocytic anemia in, 506 in primary hyperparathyroidism, 399 Renal graft, impaired function of, 504 Renal hyperparathyroidism, 502 Renal transplantation secondary hyperparathyroidism after, 504 clinical manifestations of, 507 secondary hyperparathyroidism before, 502-504 simultaneous pancreas transplantation with, 697 ret protooncogene, 234 germline defects in, 134 in medullary thyroid carcinoma, 351 hereditary, 131, 13 It, 230 in multiple endocrine neoplasia 2,491,674, 758, 759f in multiple endocrine neoplasia 2A, 134,234 in multiple endocrine neoplasia 2B, 134, 234, 758, 758f-759f in papillary thyroid carcinoma, 226 in thyroid neoplasms, 285, 285t RET receptor, 234 Retinoic acid, in enhancing NIS gene expression, 358 Retinoic acid receptor, 334, 335f Retinoid X receptor, 334, 335f Retinoids, in thyroid tumor growth inhibition and redifferentiation, 334-336, 335f, 337f reVptconcogene,234-235,290-291,290t rearrangements of, in carcinogenesis, 245

823

Ribonuclease, bovine seminal, anaplastic thyroid carcinoma and, 164 Ribonucleic acid. See RNA entries. Riedel's thyroiditis, 40-41 RNA, messenger for parathyroid hormone, 373-374 insulin, 702 RNA transcript, of insulin gene, 790 RPMI-I640 culture medium, for crypopreservation of tissue, 530-531

S Salt iodination for goiter prophylaxis, 21 for hypothyroidism prophylaxis, 51 Sarcoma, of thyroid, 169 SASI (selective arterial secretin injection) test, for gastrinorna, 750, 750t Scandinavian studies, on long-term mortality after surgery for hyperparathyroidism, 413-415, 414t Schmidt's syndrome, 46 Schwannoma, 587f psammomatous melanotic, in Carney's complex, 776 Scintigraphy DMSA, of medullary thyroid carcinoma, 148 for Cushing's syndrome, 589 iodine 131 of adrenal glands, 566 of intrathoracic goiter, 312-313, 312f of metastatic thyroid carcinoma, 153, 155f of papillary thyroid carcinoma, 142-143, 145f of recurrent thyroid carcinoma, 184-185

MillG of adrenal glands, 566, 577 of medullary thyroid carcinoma, 147-148 of pheochromocytoma, 580-581, 58lf, 623-624, 624f-625f of adrenal glands, 576-577 of adrenocortical carcinoma, 607 of aldosteromas, 580 of Cushing's syndrome, 614, 615f of lungs, after childhood thyroidectomy, 98, 99f of medullary thyroid carcinoma, 136-137 of thyroid nodules, 86-87, 87f sestamibi, of parathyroid glands, 678-679, 679f-680f somatostatin receptor of carcinoid tumors, 784, 784f of gastrinoma, 733, 733f, 734t, 749 of insulinoma, 722, 723f, 723t technetium 99m sestarnibi for recurrent (persistent) hyperparathyroidism, 432-433, 432f-433f of papillary thyroid carcinoma, 143-144, 146f3 thallium 201 of papillary thyroid carcinoma, 143-144, 146f of recurrent thyroid carcinoma, 185 thallium 201-technetium 99m pertechnetate, for recurrent (persistent) hyperparathyroidism, 431-432 Sclerosis, tuberous, 778 Secretin injection test, for gastrinoma, 748, 748t Selective arterial secretin injection (SASI) test, for gastrinoma, 750, 750t Sensory nerves, in pancreatic islets, 707 Sepsis, endocrine pancreas and, 710-711

824 - - Index Serotonin secretion, by carcinoid tumors, 783 Severe combined immunodeficiency (SCID) mice, transplantation of adrenocortical cells into, 696-697, 696f Sex hormone status, thyroid carcinoma and, 246 Sex steroids, synthesis of, 573 Sheenan's syndrome, 47 Signal transduction, 265-274 desensitization of, 273-274, 273f system interaction (crosstalk) in, 274 system(s) for, 265-273, 266t AC-PKA, 266-269, 267f, 268f calcium-calmodulin-dependent protein kinase, 271 growth factor-tyrosine kinase, 271-272, 272f PI tumover-phospholipase-PKC, 270-271, 270f Silent thyroiditis, 37 Skin lesions/rashes in Carney's complex, 776 in glucagonoma, 768 Small cell carcinoma, of thyroid, vs. anaplastic thyroid carcinoma, 161,230-231 Smoking carcinogenic effect of, 246 hypothyroidism from, 45 Sodium iodide, intravenous, for thyroid storm, 218 Sodium nitroprusside, during pheochromocytoma surgery, 626 Sodium-iodide symporter (NIS) gene therapy. See also NIS gene. for undifferentiated thyroid carcinoma, 336-337 Somatostatin, 269 for hypoglycemia in insulinoma, 727 isotope-labeled analysis of, in insulinoma, 722, 723f, 723t production of, in pancreatic islet D cells, 705 Somatostatin receptors, in neuroendocrine tumors, 722, 723t Somatostatinoma, 766-767 characteristics of, 767t duodenal, 765f surgery for, 739 Spinal accessory nerve, in neck dissection, 201-202 Spindle cells, in anaplastic thyroid carcinoma, 160, 16lf, 23lf Splanchnic nerves, 669 Splenic arteries, 667, 668f Squamous cell carcinoma, of thyroid, 170 Standardized meal test, for gastrinoma, 748 Sternocleidomastoid muscle, in neck dissection, 200, 202 Sternohyoid muscle, 194 Sternothyroid muscle, 194 Sternotomy for recurrent thyroid carcinoma, 204 in intrathoracic goiter surgery, 194, 314, 314t Steroids. See also specific steroid. exogenous, Addison's disease from, 635-636 Stomach. See also Gastric entries. carcinoid tumors of, 781 treatment of, 785 Stones, kidney. See Renal calculi. Strap muscles, division of, in intrathoracic goiter removal, 194 Streptozocin for insulinomas, 728 for islet cell tumors, 802

Stress Addison's disease and, 636 endocrine pancreas and, 710-711 hemorrhagic, increased plasma glucose during, 710 in bilateral adrenal hemorrhage, 637 Sturge-Weber syndrome, pheochromocytoma in, 631 Suicide gene therapy, for differentiated thyroid carcinoma, 338-339 Supportive care, for myxedema coma, 221 Suprarenal arteries, 562 branches of, 562-563 Suprarenal glands, 560 Suprarenal veins, 563 Surgery. See also specific procedure, e.g., Thyroidectomy; under specific disorder. Addison's disease in, 635, 637 causes of, 634, 635t conservative, for multinodular goiter, goiter recurrence after, 304-305 Sympathogonia, primitive, neuroblastoma of, 560

T T 3. See Triiodothyronine (T3)' T4 • See Thyroxine (T4) . Tamoxifen, for Riedel's thyroiditis, 41 Teratoma, of thyroid, 170 Testicular tumors, in Carney's complex, 776 Thiocyanate, 25 Thoracic duct lesions, as complication in thyroid surgery, 208-209, 209f Thoracic inlet obstruction, large goiter with, 20, 2lf, 27 Thoracotomy, in intrathoracic goiter surgery, 315-316 Thymus, embryology of, 10-11, IOf Thyrocytes iodide uptake in, 355, 356f regulation of, in multinodular goiter, 73 Thyroglobulin, serum levels of in metastatic thyroid carcinoma, 152-153, 153f in recurrent thyroid carcinoma, 184 Thyroglossal duct, 9 Thyroid artery bleeding of, in thyroid surgery, 208 inferior, 12, 12f in thyroidectomy, 189-190, 19lf superior, 11-12, 12f in thyroidectomy, 190-192, 191f division of, 194 Thyroid carcinoma. See also Thyroid neoplasms. aerodigestive invasion by, 318-332 incidence of, 319t local and distant disease in, preoperative assessment of, 318-320, 319f-320f physical and mental condition of patient with, 321 surgery for, 321-330 additional treatment with, 330 cervical exploration in, 322, 322t complications of, 329-330 disease progression and, 321 en bloc resection in, 327 hospital lethality in, 329, 329t incision in, 322 intraoperative frozen section in, safety margins of, 327 laryngotracheal resection in, 324 types of, 324-327, 325f, 325t, 326f, 328f

Thyroid carcinoma (Continued) local resectability and, 320-321, 320f long-term results of, 330-331, 331t mediastinal tracheal resection in, 327, 329 palliative local procedures in, 330 patient intubation in, 322 patient selection in, 320-321 pharyngoesophageal invasion and, 329 postoperative care in, 329 radical resection technique in, 322, 323f-326f, 324-327, 328f, 329-330 recurrent laryngeal and vagal nerve protection in, 327 shaving procedures in, 327 window resection in, 327, 329t tumor-invaded structures in, 322t types of cancer in, 321t aggressiveness of clinical indicators of, 253-254 epidemiologic factors in, 248-249, 249f pathology in, 249 predictors of, 248-254 risk group classification in, 250-251 anaplastic, 159-165 bone morphogenic protein and, 164 bovine seminal ribonuclease and, 164 BRAF mutations and, 164-165 CA4P and, 164 ~-catenin activation in, 159 chemotherapy for, 163,804 clinical course of, 232 clinical presentation of, 159-160 comparative genomic hybridization in, 349-351, 350t, 35lf-352f, 352t cytokeratin 20 expression in, 165 cytologic features of, 88f diagnosis of, 160 gene therapy for, 165 giant cell, 160, 160f, 231f metastatic, 160 multimodality therapy for, 162-163 p53 mutations in, 159, 161, 161f, 162,232 pathology of, 160f-162f, 231-232, 23lf patient categorization in, 159 prognosis of, 164 radiation exposure and, 160 radiation for palliative, 163 postoperative, 162, 162f ras mutations in, 159, 162,232 recurrence of, 184, 184f research investigation in, 164-165 spindle cell, 160, 161f, 231f squamoid variant of, 160 surgery for, 162, 163 survival in, 164 after radiation with and without chemotherapy, 164t treatment of, 162-163 vs. lymphoma, 161 vs. small cell carcinoma, 161,230-231 benign nodular disease associated with, 246 changing presentation of, 252 chemotherapy for, 803-804 childhood, 93-99. See also Children, thyroid carcinoma in. columnar cell, 171-172, I7lf diagnosis of, role of thyroid iodide uptake in, 1,356f dietary influences on, 245, 245t familial adenomatous polyposis-associated, 235-236, 235f

Index - - 825 Thyroid carcinoma (Continued) follicular adenomatous, 116, 116f adjuvant therapy for, 120 aggressiveness of, 250 capsular invasion in, 117, 117f, 227 clinical features of, 118 comparative genomic hybridization in, 347 cytologic features of, 88f fine-needle aspiration of, 118, 118f incidence of, 115,227-228 localizations tests for, 142-147 lymph node metastases in neck dissection for, 199 complications of, 203 operative technique of, 200-203, 201£-202f therapeutic strategy in, 204 prognostic significance of, 198 management of, 120-121, 121£ pathologic features of, 116-118, 117f-118f, 226-228, 227f prevalence of, 115, 227 prognosis of, 118, 119t surgery for, 119-120 survival in, 119t vascular invasion in, 117, 117f, 227 well-differentiated, 228 genes and protooncogenes in, 233-236 incidence of in intrathoracic goiter, 311, 31lt non-radiation factors affecting, 245, 246t insular, 170-171, 171£ intermediately differentiated, 170-174, 171£-174f invasion of, 295-301 epidermal growth factor in, 299-300, 300f implications for clinical therapeutics in, 301 metalloproteinases in, 298-299, 299t molecular crosstalk in, 300-301 multistep process of, 295, 296f proteases in, 298-300, 299t, 300f regulators of, 300 urokinase plasminogen activator in, 299 iodide uptake in, 355 iodine 131 therapy for, recurrency prevention with, 183 lifestyle factors in, 245-246 localization tests for, 142-149 lymph node dissection in, 196-197 lymph node metastases in, 197 incidence of, 197 localization of, 197 neck dissection for choice of, 198-200 complications of, 203 technique of, 200-203, 201£-202f therapeutic strategy in, 203f, 204 recurrence of, 204 medullary, 129-139 anti-CEA monoclonal antibody imaging of, 148 C (parafollicular) cells in, 129, 130f,229 calcification of, 147, 149 clinical presentation of, 129-132, 130t, 13lf,13lt comparative genomic hybridization in, 351 hereditary, 129, 131£ genetic testing for, 134 ret mutations in, 131, 131t

Thyroid carcinoma (Continued) hypercalcitoninemia in, persistent or recurrent, 135 image diagnosis of, 147-148, 147f in multiple endocrine neoplasia 2,129-130, 130f-I31£, 130t, 13lt, 230, 760-761, 760f-761f preventive surgery for, 134-135 lymph node metastases in, 197 neck dissection for, 199-200 complications of, 203 operative technique of, 200-203, 201£-202f therapeutic strategy in, 203f, 204 prognostic significance of, 198 metastatic disease in, 129, 130f palpable disease in, surgery for, 132-134, 132t, 133f, 133t pathology of, 229-230, 229f persistent or recurrent chemotherapy for, 135-136 CT scan of, 136 diagnostic laparoscopy for, 137, 137f localization of, 136-137 nuclear imaging studies of, 136-137 radiation therapy for, 135 selective venous catheterization for, 136 surgery for, 137-139, 138f ultrasonography of, 136 prognosis of, factors influencing, 132 reoperation for, 137-139 calcitonin levels after, 138, 138f scintigraphy of DMSA,148 MIBG, 147-148 surgery for, 132-134, 132t, 133t parathyroid management in, 132-133 regional node management in, 133-134, 133f ultrasonography of, 147, 147f metastatic diagnostic procedures for, 152-153 distant, 252-253 FDG-PET imaging of, 148-149 iodine 131 body scan in, 153 location of, 152, 153t prognosis of, 157 radioiodine therapy for, 154, 156, 156f complications of, 156-157 side effects of, 156 serum thyroglobulin levels in, 152-153, 153f surgery for, 154, 154f-155f molecular carcinogenesis in, 245 mucoepidermoid, 172 new therapeutic approach(es) to, 334-338 cytotoxic agents in, 338 gene therapy in, 336-338, 338-339 metalloproteinase inhibitor in, 339-340 redifferentiating agents in, 334-336, 335f, 337f tyrosine kinase receptors in, 339, 339f vascular endothelial growth factor inhibitors in, 340 NIS gene in, 357-358. See also NIS gene. oncogenesis in, 288-293 papillary AGES grading system of, 226 aggressiveness of, 250 classification of, 224 comparative genomic hybridization in, 346-347, 347t cytologic features of, 88f

Thyroid carcinoma (Continued) diffuse sclerosing variant of, 172-173, 172f,226 fine-needle aspiration of, 104 follicular variant of, 117, 117f, 225 hemithyroidectomy for, 102-108 advantages and disadvantages of, 103-104, 104t considerations in, 102-103, 103t lymph node dissection with, 106-107, 107f-108f postoperative adjuvant therapy with, 107-108 rationale and indications for, 104-106, 105f-106f survival rates in, 104t, lOSt, 106 high-risk classification of, 110, Ill, lIlt treatment of, 108 histology of, 224, 224f invasion of, to other organs, 144-146, 146f lobectomy for, 110 low-risk, 104, 104t classification of, 110, Ill, lIlt lymph node metastases in, 197 neck dissection for, 199 complications of, 203 operative technique of, 200-203, 201£-202f therapeutic strategy in, 203f, 204 prognostic significance of, 198 macrofollicular variant of, 226 minimal, 225 morphologic findings in, 224-225 papillae in, 224 pathology of, 224-226, 224f psammomatous bodies in, 106, 106f, 224, 224f recurrence of, 106 ret/pte oncogenes in, 226 scintigraphy of radioiodine, 142-143, 145f technetium 99m sestamibi, 143-144, 146f3 thallium 201, 143-144, 146f solid/trabecular variant of, 173-174, 174f tall cell variant of, 173, 173f, 225 total thyroidectomy for, 104, 104t, 106,108 benefits of, 112 rationale for, 110-112, lIlt technique of, 112 ultrasonography of, 142, 143f-144f preoperative recognition of, recurrency prevention by, 181-182 radiation therapy for, 251-252 recurrency prevention with, 183-184 radiation-associated carcinogenesis in, 245 characteristics of, 245, 245t environmental, 243-245, 244f historical aspects of, 27, 240, 241f in childhood, 240-242, 24lf medical therapy in, 242-243, 242t, 243f recurrent, 181-186,252 classification of, 181 diagnosis of, 184-185 immunohistochemical staining of, 185 in lymph nodes, treatment of, 204 incidence of, 185-186 iodine 131 scintigraphy of, 184-185 local, 181 management of, 186

826 - - Index Thyroid carcinoma (Continued) metastases in, 185-186, 186f MR imaging of, 184f prevention of, 181-184 adjuvant iodine 131 therapy in, 183 preoperative recognition of malignancy in, 181-182 radiation therapy in, 183-184 thyroid-stimulating hormone suppression in, 182-183 total thyroidectomy in, 182 serum thyroglobulin levels in, 184 site of, 185 thallium 20 I scintigraphy of, 185 sex hormone status and, 246 squamous cell, 170 surgery for, 251. See also Lobectomy, thyroid; Thyroidectomy, total. thyroid growth factors and, 77, 77t thyroidectomy for. See Thyroidectomy, total. thyroid-stimulating hormone suppressive therapy for, 77-78 recurrency prevention with, 182-183 unusual types of, 168-174, 169t Thyroid cork, 28 Thyroid crisis. See Thyroid storm. Thyroid cysts, fine-needle aspiration of, 89 Thyroid function tests after hemithyroidectomy, 103 preoperative, in intrathoracic goiter, 313 Thyroid gland. See also Hyperthyroidism; Hypothyroidism. aberrant tissue of, 10 adenoma of follicular, 116, 116f pathology of, 223-224 allografts of, 692--693 anatomy of, 11-15, 12f, 14f surgical, 61--62, 6lf autotransplantation of, 691--692, 692f carcinoma of. See Thyroid carcinoma. cyst of, fine-needle aspiration of, 89 diseases of cryopreserved parathyroid transplantation for, 533 non-MEN familial hyperparathyroidism in, 494 embryogenesis of, 3, 4f embryology of, 9-10, lOf enlargement of. See Goiter(s). function of restoration of gene therapy in, 336-338 redifferentiating agents in, 334-336, 335f,337f treatments independent of, 338-340 cytotoxic agents in, 338 gene therapy in, 338-339 metalloproteinase inhibitor in, 339-340 tyrosine kinase receptors in, 339, 339f vascular endothelial growth factor inhibitors in, 340 growth regulation of epidermal growth factor-transforming growth factor-a in, 258-259 fibroblast growth factors in, 259, 259f hepatocyte growth factors in, 260 insulin-like growth factors in, 259 mitogenic pathways in, 256-257, 258f platelet-derived growth factors in, 260 stimulatory and inhibitory factors in, 256, 257t thyrotropin in, 257-258 hereditary syndromes involving, 774t

Thyroid gland (Continued) homeostasis of, 256 Hiirthle cell neoplasms of, 123-127. See also Hurthle cell neoplasms. hyperplasia of, 260-261, 260f. See Thyroid gland, growth regulation of. somatic mutations in, 261, 26lf intermediately differentiated carcinomas of, 170-174,17lf-174f lymphatic drainage of, 13-14, 14f, 196 lymphoma of. See Thyroid lymphoma. metastases to, 176-177, 176f neoplasms of. See Thyroid neoplasms. paraganglioma of, 169, 170f physiology of, 3-7 plasmacytoma of, 168, 169f sarcoma of, 169 squamous cell carcinoma of, 170 surgery on, 207-213. See also Thyroidectomy. bleeding in, 208 complications of, 207-208 general, 208 specific, 208-213 dyspnea after, 211 edema in, 208 hoarseness after, 211 hypoparathyroidism after, 212-213 hypothyroidism after, 213 infection in, 208 lymphatic lesions in, 208-209, 209f recurrent laryngeal nerve in damage to, 208f-209f, 209-210 identification of, 210 superior laryngeal nerve in, damage to, 211-212,211f-212f vascular lesions in, 208 wound healing disorders in, 208 teratoma of, 170 xenografts of, 693 Thyroid growth factor(s), 77t in thyroid carcinoma, 77 Thyroid growth-inhibiting factors, 77t, 260 Thyroid growth-promoting factors, 26, 77t Thyroid growth-promoting immunoglobulin, 269 in endemic goiter, 19 in multinodular goiter, 73 Thyroid hormone. See also Calcitonin; Thyroxine (T4) ; Triiodothyronine (T3) . autoregulation of, 7 degradation of, hypothyroidism from, 47 for Hashimoto's thyroiditis, 40 peripheral action of, 5--6, 6f physiology of, 3-7, 5 regulation of, 6-7, 6f release of, 4, 4f resistance to, hypothyroidism from, 47 synthesis of, 4-5, 4f-5f transport of, 5 Thyroid hormone receptors, 6, 6f Thyroid hormone replacement therapy, for myxedema coma, 221 Thyroid hormone response element, 6 Thyroid hyperplasia, 260-261, 260f. See also Thyroid gland, growth regulation of. somatic mutations in, 261, 26lf Thyroid lymphoma, 174-176 chemosensitive, 176 clinical features of, 174, 175f clinical presentation of, 232-233 diagnosis of, 175 in Hashimoto's thyroiditis, 46 marginal zone, 232

Thyroid lymphoma (Continued) pathology of, 174-175,232-233, 233f, 249 radiosensitive, 176 stages of, 175 survival in, 176 treatment of, 175-176 Thyroid neoplasms. See also Thyroid carcinoma. benign, 261, 262f bilateral, nodal metastasis in, 133t comparative genomic hybridization in digital image acquisition and analysis in, 345-346, 346f DNA extraction in, 344 limitations and difficulties of, 351, 353 metaphase spreads in, 344, 345f technique of, 344-345, 345f cytokines in, 269 factors predisposing to, 240-254. See also specific factor, e.g., Radiation. gsp gene mutations in, 265, 282, 282f,283t multistep mutation theory of, 280, 28lf oncogenes in, 280-286 ras mutations in, 261, 265, 283, 284t rb mutations in, 261-262 signal transduction in, 265-274 desensitization of, 273-274, 273f system interaction (crosstalk) in, 274 system(s) for, 265-273, 266t AC-P~, 266-269, 267~ 268f calcium-calmodulin-dependent protein kinase, 267f, 271 growth factor-tyrosine kinase, 271-272, 272f PI turnover-phospholipase-PKC, 270-271,270f trk oncogene in, 265 tumor development in, 280, 28lf unilateral, nodal metastasis in, 132t Thyroid nodule(s), 85-91. See also Goiter(s). autonomous (hot), 26 benign, associated with thyroid carcinoma, 246 benign colloid, 86, 88f dominant, 86f fine-needle aspiration of, 295 Hurthle cells in, 124f in children, 96 prevalence of, 68 solitary, 86f clinical evaluation of, 85-86, 86f, 86t diagnosis of, 86-89 fine-needle aspiration of, 87-89 cytologic features in, 88f-89f formation of, 26 incidence of cancer in, 85 malignant potential of, 86, 89 medical treatment of, 89-90 risk factors for, 86t schematic of management of, 90f scintigraphy of, 86-87, 87f spontaneous resolution of, 5 surgery for, 90-91, 90f indications for, 90 thyroid-stimulating hormone suppressive therapy for, 71, 72t thyroxine for, 72-73, 72f ultrasonography of, 87, 87f Thyroid peroxidase, 4 antibodies to in Hashimoto's thyroiditis, 40, 44 in painless thyroiditis, 37, 38 Thyroid rests, ectopic, midline, 9

Index - - 827 Thyroid storm, 63, 216-219 adrenergic depletion for, 218 antithyroid therapy for, 217-218 Bayley's symptom complex in, 216 ~ blockers for, 218 clinical manifestations of, 216 coexisting illnes with, treatment of, 218, 219f diagnosis of, 216-217 Burch and Wartofsky's criteria for, 217t iodide therapy for, 217-218 pathophysiology of, 217 precipitants of, 217t prevention of, 218-219 prophylactic management of, 63-64 systemic decompensation in, 218 treatment of, 217-218 Thyroid transcription factor I, in carcinoid tumors, 782 Thyroid vein, bleeding of, in thyroid surgery, 208 Thyroidectomy, 188-194. See also Thyroid gland, surgery on. access in, 188, 189, 189f-190f accuracy of, 188 anatomic structures in, identification of, 188-189 bleeding control in, 189 completion for follicular thyroid carcinoma, 119-120 for recurrent goiter, 307-308 complications of, 308, 308t diathermy in, restricted use of, 189 fascia incision in, 190f for anaplastic thyroid carcinoma, 162, 163 for Graves' disease, 61-64 anatomic considerations in, 61-62, 6lf hypoparathyroidism after, 62 indications for, 6lt for plasmacytoma, 168 for sporadic nontoxic goiter, 29-30, 30t hemi-. See Hemithyroidectomy. incisions in, 189f isthmectomy in, 189. See also Isthmectomy. isthmus in, division of, 194 laryngeal nerve in recurrent, 189-190, 19lf dissection of, 192-193, 193f superi04 190-192, 191f lobectomy in, 189. See also Lobectomy. parathyroid gland preservation in, 192, 192f principles of, 188-189 strap muscle division in, 194 subcutaneous fat division in, 190£ subtotal for Graves' disease, types of, 63, 63f for hyperparathyroidism. See also Hyperparathyroidism, surgery for. for papillary thyroid carcinoma, 103, 104t hypothyroidism from, 46 prevention of, 51 thyroid artery in inferior, 189-190, 19lf superior, 190-192, 19lf division of, 194 thyroid-stimulating hormone suppressive therapy after, 75 thyroid-stimulating hormone suppressive therapy for, 79, 79f T incision in, 194 total, 193 for childhood thyroid carcinoma, 96-97 complications of, 97-98, 97t extent of disease at, 96t

Thyroidectomy (Continued) for follicular thyroid carcinoma, 119-120 for Hiirthle cell neoplasms, 126 for papillary thyroid carcinoma, 104, 100t, 106,108 benefits of, 112 rationale for, 110-112, 11lt technique of, 112 for thyroid carcinoma, recurrency prevention with, 182 hypothyroidism from, 46 with central neck dissection, 200-201, 20lf with lateral neck dissection, 201-203, 202f wound closure in, 193 Thyroiditis, 34-41 acute (suppurative), 34-35, 35f chronic, 38-41 classification of, 35t definition of, 34 etiology of, 35t granulomatous, 36, 36f Hashimoto's. See Hashimoto's thyroiditis. Riedel's, 40-41 subacute painful (de Quervain's) clinical presentation of, 36 diagnosis of, 36, 37f differential diagnosis of, 36 etiology and pathogenesis of, 35-36 histologic features of, 36, 36f treatment of, 36-37 painless, 37-38 clinical course of, 38, 38f variants of, 38 Thyroid-stimulating hormone, 6-7, 6f, 256 in endemic goiter, 19 in sporadic nontoxic goiter, 25-26 in thyroid growth regulation, 257, 257t, 258f, 267-268, 268f Thyroid-stimulating hormone receptor, 267-268 in thyroid neoplasms, 257 mutations in, 280-281, 288, 290t Thyroid-stimulating hormone suppressive therapy, 68-79. See also Levothyroxine; Thyroxine (T4 ) . after thyroidectomy, 75 algorithm for, 79, 79f complications of, 70 for benign goiters, 75-76 for diffuse goiter, 74-75, 75t for follicular thyroid carcinoma, 120, 121 for multinodular goiter, 73-74, 74t for nodular goiter, 73 for papillary thyroid carcinoma, 103 postoperative, 108 for solitary thyroid nodule, 71, 72t, 89-90 for thyroid carcinoma, 77-78 recurrency prevention with, 182-183 history of, 68-69 in post-thyroidectomy patient, 75 lipid profile in, 70-71 physiologic goals of, 69-70 postoperative, recurrence of goiter from, 305 Thyroid-stimulating hormone test, for hypothyroidism, 48 Thyroid-stimulating immunoglobulins, 269 Thyrotoxic crisis. See Thyroid storm. Thyrotoxic storm. See Thyroid storm. Thyrotoxicosis after iodination, 21 in Plummer's disease, 65

Thyrotropin, 265, 296. See also Thyroid-stimulating hormone. in thyroid growth regulation, 257-258 Thyrotropin-releasing hormone, 6f, 7 Thyroxine (T4 ) . See also Levothyroxine; Thyroid-stimulating hormone suppressive therapy. bioavailability and dosage of, factors affecting, 69-70, 70t for diffuse goiter, 74-75, 75t for endemic goiter, 22 for hypothyroidism, 48-49 adverse effects of, 49 in neonates, 51 maintenance dose of, 49 for metastatic thyroid carcinoma, 157 for multinodular goiter, 73-74, 74t nontoxic, 74 for solitary thyroid nodule, 72-73, 72f for sporadic nontoxic goiter, 29, 30t for thyroid carcinoma, 78 iodide uptake in, 355, 356f ischemic heart disease and, 71 lipid metabolism and, 70-71 metabolism of, 5 physiology of, 69 postoperative suppplementation with, recurrent goiter after, 305 serum free, in hypothyroidism, 48 suppressive doses of, prior to intrathoracic goiter surgery, 313 synthesis of, 4f, 5 T incision, in thyroidectomy, 194 Tissue thawing, in parathyroid crypopreservation, 531 Tissue viability, in parathyroid crypopreservation, 532t TNM scoring system, for recurrent thyroid carcinoma, 181 Tongue, ganglioneuromatosis of, 759f Trachea collapse of, after intrathoracic goiter surgery, 316 papillary thyroid carcinoma invasion of, 145-146, 146f Tracheomalacia, after intrathoracic goiter surgery, 316 Transcription factors, in parathyroid and thyroid development, 3 Transforming growth factor-a, 256 Transhepatic portal venous sampling, percutaneous, of insulinoma, 720, 721f, 731-732,73lt Transplantation. See also Allotransplantation; Autotransplantation; Renal transplantation; Xenotransplantation. islet cell, 697-698, 698f pancreas, 697 Transsphenoidal microsurgery, selective, for Cushing's disease, 615 Trapezius muscle in neck dissection, 201-202 paralysis of, 203 Trastuzumab,301 Trichostatin A, increased NIS gene expression with, 358-359, 358f-359f Triiodothyronine (T3) for hypothyroidism, 48-49 coronary bypass surgery and, 50-51 for myxedema coma, 221 iodide uptake in, 355, 356f metabolism of, 5 physiology of, 69 pituitary production of, 69

828 - - Index Triiodothyronine (T3) (Continued) synthesis of, 4f, 5 trk oncogene, 290t, 291 in thyroid neoplasms, 265, 285, 285t Trousseau's sign, in hypocalcemia, 444, 528 ITF-I gene therapy, for undifferentiated thyroid carcinoma, 336 Tuberculosis, Addison's disease in, 635 Tuberous sclerosis, 778 Tubulin, 295 Tumor(s). See under anatomy; specific tumor. Tumor necrosis factor, in thyroid growth regulation, 269 Tumor suppressor genes, 290t, 292. See also specific gene, e.g., p53 gene. Tumorigenesis, multistep, proposed model of, in thyroid carcinoma, 334, 335f Tumor-promoting phorbol esters, 271 Tyrosine kinase receptor( s) for differentiated thyroid carcinoma, 339, 339f in thyroid regulation, 257, 257t, 258f mutations in, 290-291, 290t

U Ulcer, peptic, in gastrinoma, 745, 747 Ultrasonography endoscopic of gastrinoma, 749-750 of insulinoma, 722-723, 724f, 730, 731t for recurrent (persistent) hyperparathyroidism intraoperative, 435 preoperative, 430-431, 43 If intraoperative of gastrinoma, 733, 734f of insulinoma, 723, 724f-725f laparoscopic, in adrenalectomy, 657 of adrenal glands, 566, 577 of gastrinoma, 732, 732f, 734t, 749 of insulinoma, 720 of medullary thyroid carcinoma, 136, 147, 147f of papillary thyroid carcinoma, 142, 143f-144f of sporadic nontoxic goiter, 27 of subacute thyroiditis, 36, 37f of thyroid nodules, 87, 87f

Uremic osteodystrophy, 505-506 Urokinase plasminogen activator, in invasive thyroid carcinoma, 299

Von Recklinghausen's disease, 777-778 variant of, 757. See also Multiple endocrine neoplasia 28 (MEN 28).

V Vagal nerve, protection of, in thyroid carcinoma surgery, 327 Vanillylmandelic acid, in pheochromocytoma, 589 Vascular endothelial growth factor inhibitor(s), for differentiated thyroid carcinoma, 340 Vascular lesions, in thyroid surgery, 208 Vasoactive intestinal polypeptide (VIP), 706 Vasoactive intestinal polypeptide tumor (VIPoma), 767-768, 768f characteristics of, 767t chemotherapy for, 801 surgery for, 739, 801 Venography, of adrenal glands, 577 Venous catheterization, for medullary thyroid carcinoma, 136 Verner-Morrison syndrome, 767 VHL syndrome paraganglioma in, 629 pheochromocytoma in, 631 Video-assisted parathyroidectomy, minimally invasive, 462-463, 463f, 467-468 results of, 465-466, 465t, 466t Vimentin, 296 VIP (vasoactive intestinal polypeptide), 706 VIPoma (vasoactive intestinal polypeptide tumor), 767-768, 768f characteristics of, 767t chemotherapy for, 801 surgery for, 739 Vitamin A, preoperative, adrenalectomy and,642 Vitamin 8 12 injections, after total gastrectomy, 753 Vitamin D. See 1,25-Dihydroxyvitamin D. Vocal cord paralysis after surgery for recurrent goiter, 308, 308t as manifestation of compartment syndrome, 306 intrathoracic goiter and, 309-310 Von Hippel-Lindau disease, pheochromocytoma in, 775-776

W Weiss criteria, for adrenocortical malignancy, 605t Werrner's syndrome, 673, 745. See also Multiple endocrine neoplasia I (MEN 1). Whipple procedure, for insulinomas, 726 Whipple's triad, definition of, 795 Wilms' tumor, in hereditary parathyroidism-jaw tumor syndrome, 775 Wolff-Chaikoff effect, 25, 356 World Health Organization (WHO) classification, of endemic goiter, 20, 20f Wound closure, in thyroidectomy, 193 Wound infections in neck dissection, 203 in thyroid surgery, 208 X Xenotransplantation, 691 of parathyroid tissue, 694 of thyroid tissue, 693

Z ZDl839 (Iressa), 301 Zollinger-Ellison syndrome. See also Gastrinoma. diagnosis of, 747 duodenotomy in, 733, 738 evaluation of patients with, 747-748 gastrectomy in, follow-up after, 753 gastric carcinoid tumors in, 781 history and evolution of, 745 liver metastases in, 754 multiple endocrine neoplasia 1 in, 734-735 surgery for, 684-686, 685f, 741-742, 742f pathophysiology of, 745-746, 746f Zona fasciculata, 564, 565f Zona glomerulosa, 564, 565f Zona reticularis, 564, 565f Zuckerkandl fascia, of adrenal glands, 561-562