ELSEVIER SAUNDERS 1600 John F. Kennedy Blvd., Ste 1800 Philadelphia, PA 19103-2899 TEXTBOOK OF ENDOCRINE SURGERY ISBN 0-7216-0139-1
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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.
13
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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0.80
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iii
~~
o~
~E C/l ._
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o... J:. >- 0.10
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-----
Antibody-positive (fitted model)
='0 .0 ._ III 0 .0'" (5
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0.2
0.5
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2
Observed data (smoothed) Antibody-negative (fitted model)
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.
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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.
49
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-
40. 41.
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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
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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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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
Childhood Thyroid Carcinoma - -
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
103
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
110
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
100 90 -+-11• • •- - - - - - - - - - · · - - - - - - - - - - 80 c: 70
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.9 '0 60 til o 50 c. 0
S! 40 c. ~ 0
-t-.......-.t. . . . . . . . .t - - . . . - - - - - - - - - - - - - - - - - - - . - - - . - - - .
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
30 20 10 O~=
meen
cured
mel
233 2.2 3.4
n.do... y_",
nouptake
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
163
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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Thyroid Gland
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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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
Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - - 169
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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Thyroid Gland
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.
Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - -
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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Thyroid Gland
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
184 - -
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.)
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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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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,
207
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
<,_--""][------r--------~
~ctl E (])
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.
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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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o
Total
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Females
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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CJ
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.c E
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:l
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1988
1989
1990
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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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1986 1987 1988 1989 1990 1991 1992 1993 1994
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.
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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
25 ~
's;
20
r-
U til
Mean±SEM
~ 15
til
~
T
'iii 10 lIJ
.L
til
£en
I-
5
o
I
I
Normal
Benign
n =59
n=20
P< .0001
I
T
..L
I
CarcinomaStage 1
CarcinomaStage 2
n = 25
n=6
P< .006
P< .02
I
--
I
Carcinoma- Medullary Stage 3,4 Carcinoma n = 11
n=3
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
First 4th
CON
Second 30 min
CON~""'""'i""""",,.:. >. :>J
121 LNM 1 EJ LNM 2
o Primary Tumor
TSH CON~~~~~
o
2
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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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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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
c 0
"00
ctl
> .5
E CIl l:
invasion."
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,
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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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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
