The Handbook of
ENDOCRINE
SURGERY
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The Handbook of
ENDOCRINE
SURGERY Rebecca S. Sippel Herbert Chen
University of Wisconsin School of Medicine and Public Health, USA
World Scientific NEW JERSEY
•
LONDON
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SINGAPORE
•
BEIJING
•
SHANGHAI
•
HONG KONG
•
TA I P E I
•
CHENNAI
Published by World Scientific Publishing Co. Pte. Ltd. 5 Toh Tuck Link, Singapore 596224 USA office: 27 Warren Street, Suite 401-402, Hackensack, NJ 07601 UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE
British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library.
THE HANDBOOK OF ENDOCRINE SURGERY Copyright © 2012 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the Publisher.
For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy is not required from the publisher.
ISBN-13 978-981-4293-19-8 ISBN-10 981-4293-19-9
Typeset by Stallion Press Email:
[email protected] Printed in Singapore.
JQuek - The Handbk of Endocrine.pmd
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We dedicate this book to our endocrine surgery mentors
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Contents
Contributors Foreword Preface
xix xxxv xxxvii
I. THYROID
1
A. Evaluation Chapter I.A.1: Thyroid Evaluation — Laboratory Testing Jennifer L. Poehls and Rebecca S. Sippel
3
Thyroid Function Tests Thyroid Antibodies Thyroid Tumor Markers Selected References
3 9 11 13
Chapter I.A.2: Thyroid Imaging James E. Wiseman, Lilah F. Morris and Michael W. Yeh
15
Introduction Ultrasound Computed Tomography (CT) Magnetic Resonance Imaging (MRI) Radionuclide Scanning Positron Emission Tomography (PET) and PET/CT Selected References Chapter I.A.3: Thyroid Evaluation — FNA Jennifer B. Ogilvie FNA Technique FNA Results and Significance vii
15 16 21 22 22 23 25 27 27 31
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Recommendations Selected References
32 38
B. Clinical Management Chapter I.B.1:
Chapter I.B.2:
Chapter I.B.3:
Evaluation of a New Thyroid Nodule Adrienne L. Melck and Sally E. Carty
39
Epidemiology History Physical Examination Laboratory Investigations Imaging Indications for Fine Needle Aspiration Biopsy Thyroid Nodule Management after FNAB Molecular Testing of FNA Specimens Management of a Benign Thyroid Nodule Management of Thyroid Cysts Selected References
39 39 40 42 43 44 45 46 46 47 48
Management of Papillary Thyroid Cancer Dina M. Elaraj and Cord Sturgeon
49
Global Treatment Strategy Controversies in Surgical Management Management of Nodal Metastases Radioactive Iodine TSH Suppression Long-Term Followup Management of Recurrent Disease Selected References
49 49 51 54 56 57 58 60
Management of Medullary Thyroid Cancer Scott N. Pinchot and Rebecca S. Sippel
63
Introduction Management of Sporadic MTC Management of Hereditary MTC Genetic Basis of Hereditary MTC Long-Term Followup Management of Recurrent Disease Selected References
63 64 66 69 73 76 78
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Chapter I.B.4:
Chapter I.B.5:
ix
Management of Follicular and Hurthle Cell Cancer Christopher R. McHenry and Scott M. Wilhelm
79
Introduction Operative Management Postoperative Management Long Term Followup Treatment of Metastatic Disease Selected References
79 81 82 84 86 87
Management of Aggressive Variants and Anaplastic Thyroid Cancers Marlon A. Guerrero and Electron Kebebew
89
Overview 89 Tall Cell Variant of Papillary Carcinoma 91 Insular Thyroid Cancer 93 Columnar Cell Variant of Papillary Carcinoma 94 Diffuse Sclerosing Variant of Papillary Carcinoma 95 Anaplastic Thyroid Cancer 96 Poorly Differentiated Thyroid Cancer 99 Selected References 100 Chapter I.B.6:
Chapter I.B.7:
Management of Thyroid Lymphomas, Metastatic Lesions and Other Rare Tumors N. Gopalakrishna Iyer and Ashok R. Shaha
101
Overview Thyroid Lymphomas Metastatic Disease to the Thyroid Gland Rare Tumors of the Thyroid Gland Selected References
101 101 106 107 108
Hyperthyroidism Geeta Lal and Sonia L. Sugg
109
Introduction Treatment Options Specific Conditions Thyroid Storm Selected References
109 109 116 122 123
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Chapter I.B.8:
Chapter I.B.9:
II.
Handbook of Endocrine Surgery
Management of Complications of Thyroidectomy 125 Jason Long and Peter Angelos Postoperative Hoarseness Recurrent Laryngeal Nerve (RLN) Injury External Branch of the SLN Injury Selected References Neck Hematoma Selected References Postoperative Hypocalcemia/Hypoparathyroidism Selected Reference Management of Injury to the Thoracic Duct or Chyle Leakage Selected References Other Nerves at Risk of Injury During Thyroidectomy Selected References
125 127 128 128 129 131 131 132 133
Thyroid Hormone Replacement/Adjustment Meei J. Yeung and Jonathan W. Serpell
137
Thyroid Hormone Replacement/Adjustment Selected References
137 143
PARATHYROID
134 134 136
145
A. Evaluation Chapter II.A.1:
Parathyroid Laboratory Testing Denise Carneiro-Pla
147
Introduction Sporadic Primary Hyperparathyroidism (SPHPT) Differential Diagnosis Secondary Hyperparathyroidism Tertiary Hyperparathyroidism Familial Hyperparathyroidism Parathyroid Cancer Bone Mineral Density in Parathyroid Disease Selected References
147 147 150 153 154 154 155 156 156
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Chapter II.A.2:
xi
Parathyroid Imaging Christine S. Landry, Elizabeth G. Grubbs, Beth S. Edeiken-Monroe, Thinh Vu, E. Edmund Kim and Nancy D. Perrier
159
Introduction Imaging Modalities Specific Questions for the Endocrine Surgeon Conclusion Selected References
159 161 167 169 169
B. Clinical Management Chapter II.B.1:
Chapter II.B.2:
Clinical Management of Primary Hyperparathyroidism Joel T. Adler, Rebecca S. Sippel and Herbert Chen
171
Introduction Indications Minimally Invasive Parathyroidectomy Bilateral Exploration Ectopic Glands Intraoperative Nerve Monitoring Conclusions Selected References
171 171 173 175 176 176 177 177
Secondary Hyperparathyroidism Mohamed O. Abdelgadir Adam, Patrick H. Pun and John A. Olson, Jr.
179
Definition Historical Background Epidemiology Pathophysiology Genetic Etiologies Clinical Manifestations Diagnosis Medical Therapy Indications for Parathyroidectomy in SHPT
179 179 180 181 182 183 184 185 187
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Chapter II.B.3:
Chapter II.B.4:
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Preoperative Assessment Preoperative Localization Surgical Strategies Intraoperative PTH Monitoring Surgical Outcomes Disease Persistence/Recurrence Type of Parathyroidectomy Percutaneous Ethanol Injection Summary Selected References
188 188 189 191 191 192 192 193 194 194
Tertiary Hyperparathyroidism Steven E. Rodgers, John I. Lew and Carmen C. Solórzano
203
Introduction Diagnosis Surgical Treatment Management of Recurrent Disease Summary Selected References
203 203 204 207 208 208
Parathyroid Carcinoma Elliot J. Mitmaker and Wen T. Shen
211
Introduction Demographic Data Etiology Clinical Presentation Localization Studies Pathology Operative Management Medical Management and Adjuvant Therapies Prognosis and Outcomes Selected References
211 211 212 212 214 215 217 219 220 220
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Chapter II.B.5:
Chapter II.B.6:
Chapter II.B.7:
xiii
Hyperparathyroidism in Familial Disease Charles Tuggle, Julie Ann Sosa and Robert Udelsman
223
Overview Multiple Endocrine Neoplasia 1 (MEN1) Multiple Endocrine Neoplasia 2A (MEN2A) Familial Isolated HPT (FIHPT) HPT-Jaw Tumor Syndrome (HPT-JT) Neonatal Severe HPT (NSHPT) and Autosomal Dominant Mild HPT (ADMH) Neurofibromatosis Type 1 (NF1) Family Screening and Genetic Testing Genetic Testing and Counseling Selected References
223 223 227 229 231 233 237 238 239 239
Management of Hypercalcemic Crisis Carrie C. Lubitz and Antonia E. Stephen
241
Etiology Definition Clinical Manifestations Acute Treatment Options Selected References
241 242 242 243 247
Postoperative Hypocalcemia Daniel Levin and Jacob Moalem
249
Introduction Thyroid Surgery Parathyroid Surgery Reoperative Neck Surgery Pathophysiology Postoperative Monitoring Treatment of Postoperative Hypocalcemia Summary Selected References
249 249 250 252 252 253 254 260 260
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Chapter II.B.8:
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Cryopreservation and Autotransplantation of Parathyroid Tissue Jennifer McAllaster and Mark S. Cohen
265
Introduction Indications for Parathyroid Autotransplantation and Cryopreservation Methods for Cryopreservation of Parathyroid Tissue Long Term Storage, Viability, and Thawing of Cryopreserved Glands Autotransplantation of Parathyroid Tissue Post-Operative Management Following Parathyroid Autotransplantation Reoperation for Hyperfunctional Autografts Selected References
265 266
III. ADRENAL
266 268 270 271 274 274 277
A. Evaluation Chapter III.A.1:
Chapter III.A.2:
Adrenal Incidentaloma Rashmi Roy and James A. Lee
279
Overview Laboratory Evaluation Radiographic Assessment Selected References
279 279 284 286
Cushing’s Syndrome: Laboratory and Imaging 287 Evaluation Geoffrey B. Thompson and William F. Young , Jr. Introduction Case Detection for Endogenous Hypercortisolism: Who Should be Evaluated for Cushing’s Syndrome? Laboratory Evaluation Subtype Evaluation and Imaging Selected References
287 288
289 291 297
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Chapter III.A.3:
Chapter III.A.4:
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Pheochromocytoma Goswin Y. Meyer-Rochow and Stan B. Sidhu
299
Introduction Laboratory Testing Genetic Testing Imaging Evaluation Selected References
299 299 306 309 312
Evaluation and Diagnosis of Hyperaldosteronism Xavier M. Keutgen, Rasa Zarnegar and Thomas J. Fahey III
315
Introduction Diagnosis Additional Laboratory Tests Additional Imaging Studies Selected References
315 316 319 324 327
B. Clinical Management Chapter III.B.1:
Chapter III.B.2:
Laparoscopic Adrenalectomy Avital Harari and Quan-Yang Duh
329
Laparoscopic Transabdominal Approach Retroperitoneal Laparoscopic Approach Selected References
329 337 340
Preoperative and Perioperative Management of Adrenal Lesions Tricia A. Moo-Young and Richard A. Prinz
341
Overview Pheochromocytoma Hyperaldosteronism Cushing’s Syndrome (Hypercortisolism) Adrenal Insufficiency Selected References
341 341 348 350 353 355
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Chapter III.B.3:
IV.
Adrenal Cortical Cancer Daniel T. Ruan and Matthew A. Nehs
357
Diagnosis of Adrenal Cortical Cancer Prognostic Factors and Determinants of Resectability Operative Management Evaluation and Management of Patients with Metastatic Disease Selected References
357 360
ENDOCRINE PANCREAS
361 362 365 367
A. Evaluation Chapter IV.A.1: Evaluation of Carcinoid Tumors Katherine Heiden and Mira Milas Overview Laboratory Evaluation Imaging Evaluation Summary Selected References Chapter IV.A.2: Evaluation of Insulinoma Jui-Yu Chen, Yi-Fang Tsai, Ling-Ming Tseng and Chen-Hsen Lee Introduction Laboratory Evaluation Imaging Evaluation Selected References Chapter IV.A.3: Evaluation of Gastrinoma Adam S. Brinkman and Clifford S. Cho Introduction Presentation Diagnosis Localization
369 369 370 373 375 375 377
377 378 382 390 391 391 391 392 395
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Chapter IV.A.4: Evaluation of “Other” Neuroendocrine Tumors of the Pancreas Rachel Adams Greenup, Tracy S. Wang and Douglas B. Evans Introduction Glucagonoma Clinical Syndrome of Glucagonoma (Think Catabolism!) Serum Glucagon Levels Vipoma Somatostatinoma PPOMA Selected References
xvii
397
397 397 398 399 399 401 403 403
B. Clinical Management Chapter IV.B.1:
Chapter IV.B.2:
Clinical Management of Midgut Carcinoid Tumors Thomas W. T. Ho and Janice L. Pasieka
405
Overview Midgut Small Bowel Carcinoids Appendiceal Carcinoids Goblet Cell Carcinoids Selected References
405 406 420 421 422
Clinical Management of Insulinoma David T. Hughes, Gerard M. Doherty and Paul G. Gauger
423
Preoperative Considerations Operative Planning and Approach Intraoperative Localization Operative Technique Postoperative Management Special Circumstances Medical Management Selected References
423 423 425 425 426 427 429 429
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Chapter IV.B.4:
Index
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Contents
Clinical Management of Gastrinoma Steven K. Libutti
431
Overview Medical Management of Primary Gastrinomas Selected References
431 440 441
Clinical Management of Nonfunctional Neuroendocrine Tumors and Management of Metastatic Disease Jennifer Rabaglia, Shelby Holt and Fiemu Nwariaku
443
Overview Preoperative Evaluation Operative Management of nfPNETS Management of Metastatic and Recurrent Disease Selected References
443 444 448 449 453 455
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Contributors
Mohamed O. Abdelgadir Adam, MD Resident in Surgery Department of Surgery Duke University DUMC 2945 Durham, NC 27710, USA Joel T. Adler, MD Resident, General Surgery Massachusetts General Hospital 55 Fruit Street, GRB-425 Boston, MA 02114, USA Peter Angelos, MD, PHD, FACS Professor and Chief of Endocrine Surgery University of Chicago 5841 S. Maryland Ave, MC 4052 Chicago, IL 60637, USA Adam S. Brinkman, MD Surgical Resident University of Wisconsin School of Medicine and Public Health 600 Highland Avenue Madison, WI 53792, USA
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Contributors
Denise Carneiro-Pla, MD, FACS Assistant Professor of Surgery/Endocrine Surgery Department of Surgery Medical University of South Carolina 25 Courtenay Dr., Suite 7018 Charleston, SC 29425, USA Sally E. Carty, MD Professor of Surgery University of Pittsburgh 3471 Fifth Ave., Suite 101 Kaufmann Bldg. Pittsburgh, PA 15213, USA Herbert Chen, MD, FACS Professor, Chairman of General Surgery University of Wisconsin School of Medicine and Public Health K3/703, Clinical Science Center 600 Highland Avenue Madison, WI 53705, USA Jui-Yu Chen, MD Attending Physician and Instructor National Yang-Ming University Department of Surgery, Division of General Surgery Taipei Veterans General Hospital No. 201, Sec. 2, Shipai Rd., Beitou District Taipei City, Taiwan 11217, R.O.C. Clifford S. Cho, MD Assistant Professor University of Wisconsin School of Medicine and Public Health K4/752, Clinical Science Center 600 Highland Avenue Madison, WI 53792, USA
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Mark S. Cohen, MD, FACS Associate Professor of Surgery and Pharmacology Toxicology and Therapeutics Chief of Endocrine Surgery, Vice Chair for Research and Director Surgical Simulation and Skills Laboratory University of Kansas Medical Center 3901 Rainbow Boulevard Mailstop 2005, Room 4008 Murphy Building Kansas City, KS 66160, USA Gerard M. Doherty, MD Norman W. Thompson Professor of Surgery University of Michigan Medical School University of Michigan Hospital 1500 East Medical Center Drive Taubman Center 2920B Ann Arbor, MI 48109-0331, USA Quan-Yang Duh, MD Professor of Surgery University of California, San Francisco and VA Medical Center, San Francisco 4150 Clement Street San Francisco, CA 94121, USA Beth S. Edeiken-Monroe, MD Professor MD Anderson Cancer Center 1500 Holcombe Blvd. Houston, TX 77030, USA Dina M. Elaraj, MD, FACS Assistant Professor Section of Endocrine Surgery Department of Surgery Northwestern University 676 North St. Clair Street, Suite 650 Chicago, Il 60611, USA
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Douglas B. Evans, MD Chairman, Department of Surgery Donald C. Ausman Family Foundation Professor of Surgery Medical College of Wisconsin 9200 W. Wisconsin Avenue Milwaukee, WI 53226, USA Thomas J. Fahey III, MD, FACS Professor of Surgery Weill Cornell Medical College 525 East 68th Street, Room A-1027 New York, NY 10021, USA Paul G. Gauger, MD William J. Fry Professor of Surgery University of Michigan Medical School University of Michigan Hospital 1500 East Medical Center Drive Taubman Center 2920D Ann Arbor, MI 48109-0331, USA Rachel Adams Greenup, MD, MPH Chief Resident, General Surgery Medical College of Wisconsin 9200 W. Wisconsin Avenue Milwaukee, WI 53226, USA Elizabeth G. Grubbs, MD Assistant Professor MD Anderson Cancer Center 1400 Hermann Pressler Drive, Unit 1484 Houston, TX 77030, USA Marlon A. Guerrero, MD Assistant Professor University of Arizona Arizona Health Science Center 1501 N. Campbell Ave. Tucson, AZ 85724-5131, USA
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Avital Harari, MD Assistant Professor of Surgery University of California, Los Angeles 10833 Le Conte Ave, Suite 72-232 CHS Los Angeles, CA 90095, USA Katherine Heiden, MD Assistant Professor of Surgery Rush University Medical Center 1725 W. Harrison, Suite 818 Chicago, IL 60612, USA Thomas W. T. Ho, MD Resident-Surgical Oncology Department of Surgery/North Tower University of Calgary 1403 29th Street NW, Calgary Alberta, Canada T2N2T9 Shelby Holt, MD Associate Professor of Surgery University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas, TX 75390-9156, USA David T. Hughes, MD Assistant Professor of Surgery Albert Einstein College of Medicine Montefiore Medical Center 1400 Bainbridge Ave. Bronx, NY 10467, USA N. Gopalakrishna Iyer, MBBS, PHD, FRCS Consultant Head and Neck Surgeon National Cancer Centre Singapore 11 Hospital Drive, Singapore 169610
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Contributors
Electron Kebebew, MD, FACS Head Endocrine Oncology, Senior Investigator National Cancer Institute 10 Center Drive Bethesda, MD 20892-1201, USA Xavier M. Keutgen, MD Surgery Resident Weill Cornell Medical College 525 East 68th Street, Room A-1027 New York, NY 10021, USA E. Edmund Kim, MD Professor MD Anderson Cancer Center 1515 Holcombe Blvd. Houston, TX 77030, USA Geeta Lal, MD Assistant Professor University of Iowa Hospitals and Clinics 200 Hawkins Drive, 4641 JCP Iowa City, IA 52242, USA Christine S. Landry, MD Surgical Oncology Fellow MD Anderson Cancer Center 1400 Hermann Pressler Drive, Unit 1484 Houston, TX 77030, USA Chen-Hsen Lee, MD, FACS Dean of Medicine, Professor, School of Medicine National Yang-Ming University Department of Surgery, Division of General Surgery Taipei Veterans General Hospital No. 201, Sec. 2, Shipai Rd., Beitou District Taipei City, Taiwan 11217, R.O.C.
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Contributors
James A. Lee, MD Chief of Endocrine Surgery New York Presbyterian Hospital-Columbia University Columbia University Medical Center Herbert Irving Pavilion Room 819 161 Fort Washington Avenue New York, NY 10032, USA Daniel Levin, MD Surgical Resident University of Rochester Medical Center 601 Elmwood Ave, BOX SURG Rochester, NY 14642, USA John I. Lew, MD Assistant Professor of Surgery University of Miami School of Medicine 1120 NW 14th Street (M875) Miami, FL 33136, USA Steven K. Libutti, MD, FACS Vice Chairman of Surgery Albert Einstein College of Medicine and Montefiore Medical Center 3400 Bainbridge Ave, MAP4 Bronx, NY 10467, USA Jason Long, MD Resident in Surgery University of Chicago 5841 S. Maryland Ave, MC 4052 Chicago, IL 60637, USA
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Contributors
Carrie C. Lubitz, MD Instructor in Surgery Harvard Medical School Massachusetts General Hospital 55 Fruit Street, Yawkey 7B Boston, MA 02114, USA Jennifer McAllaster, MD Chief Resident, Department of Surgery University of Kansas Medical Center 3901 Rainbow Boulevard Mailstop 2005, Room 4008 Murphy Building Kansas City, KS 66160, USA Christopher R. McHenry, MD Vice Chairman, Department of Surgery MetroHealth Medical Center Case Western Reserve University 2500 MetroHealth Drive Cleveland, OH 44109-1998, USA Adrienne L. Melck, MD, MPH Clinical Instructor in Surgery University of British Columbia Rm. C303 – 1081 Burrard Street St. Paul’s Hospital Department of Surgery Vancouver, BC, V6Z 1Y6, Canada Goswin Y. Meyer-Rochow, MB, CHB, FRACS, PhD Waikato Clinical School University of Auckland Waikato Hospital Private Bag 3200 Hamilton 3240, New Zealand
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Mira Milas, MD Associate Professor of Surgery Cleveland Clinic 9500 Euclid Ave Endocrine Surgery F20 Cleveland, OH 44195, USA Elliot J. Mitmaker, MD, MSC, FRCSC Endocrine Surgery Fellow University of California, San Francisco 1600 Divisadero Street, C-347 Mount Zion Hospital, Hellman Building San Francisco, CA 94143, USA Jacob Moalem, MD Assistant Professor, Endocrine Surgery University of Rochester Medical Center 601 Elmwood Ave, BOX SURG Rochester, NY 14642, USA Tricia A. Moo-Young, MD Staff Endocrine Surgeon Northshore University HealthSystems 2650 Ridge Avenue Walgreens Building, Suite 2507 Evanston, IL 60201, USA Lilah F. Morris, MD Longmire Administrative Chief Resident in General Surgery Endocrine Surgical Unit, Division of General Surgery David Geffen School of Medicine at UCLA 10833 Le Conte Ave., 72-229 CHS Los Angeles, CA 90095, USA
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Contributors
Matthew A. Nehs, MD Clinical Fellow in Surgery Harvard Medical School 75 Francis Street, ASBII Boston, MA 02115, USA Fiemu Nwariaku, MD Associate Dean for Global Health Associate Professor of Surgery University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas, TX 75390-9156, USA Jennifer B. Ogilvie, MD, FACS Assistant Professor of Surgery New York University Langone Medical Center 530 First Avenue, Schwartz Health Care Center, 6H New York, NY 10016, USA John A. Olson, Jr., MD, PhD Associate Professor of Surgery Chief, Section of Endocrine and Oncologic Surgery Department of Surgery Duke University DUMC 2945 Durham, NC 27710, USA Janice L. Pasieka, MD, FRCSC, FACS Clinical Professor of Surgery and Oncology Department of Surgery/North Tower University of Calgary 1403 29th Street NW, Calgary Alberta, Canada T2N2T9
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Nancy D. Perrier, MD Professor MD Anderson Cancer Center 1400 Hermann Pressler Drive, Unit 1484 Houston, TX 77030, USA Scott N. Pinchot, MD General Surgery Resident University of Wisconsin-Madison H4/7, Clinical Science Center 600 Highland Avenue Madison, WI 53792, USA Jennifer L. Poehls, MD Department of Medicine Division of Endocrinology, Diabetes and Metabolism University of Wisconsin 2226 UW Health West Clinic 451 Junction Road Madison, WI 53717, USA Richard A. Prinz, MD Vice-Chair of Surgery, Staff Endocrine Surgeon Northshore University HealthSystems 2650 Ridge Avenue Walgreens Building, Suite 2507 Evanston, IL 60201, USA Patrick H. Pun, MD, MHS Assistant Professor of Medicine Department of Medicine (Nephrology) Duke University Medical Center DUMC 2747 Durham, NC 27710, USA
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Contributors
Jennifer Rabaglia, MD Assistant Professor of Surgery University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas, TX 75390-9156, USA Steven E. Rodgers, MD, PhD Assistant Professor of Surgery University of Miami School of Medicine 1120 NW 14th Street (C232) Miami, FL 33136, USA Rashmi Roy, MD Endocrine Surgery Fellow Department of Endocrine Surgery Johns Hopkins University School of Medicine Johns Hopkins Hospital 600 N. Wolfe Street Blalock 6th Floor, Room 606 Baltimore, MD 21287, USA Daniel T. Ruan, MD Instructor in Surgery Harvard Medical School 75 Francis Street, ASBII Boston, MA 02115, USA Jonathan W. Serpell, MBBS, MD, FRACS, FACS Professor, Monash University Endocrine Surgery Unit Alfred Hospital, Melbourne, Victoria, Australia Department of General Surgery, Level 6 Centre Block Alfred Hospital, Commercial Road, Prahran 3181 Melbourne, Victoria, Australia Ashok R. Shaha, MD, FACS Professor of Surgery Jatin P Shah Chair in Head and Neck Surgery Memorial Sloan Kettering Cancer Center 1275 York Avenue New York, NY 10065, USA
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Wen T. Shen, MD, MA Assistant Professor University of California, San Francisco 1600 Divisadero Street, C-347 Mount Zion Hospital, Hellman Building San Francisco, CA 94143, USA Stan B. Sidhu, MD, BS, PhD, FRACS Associate Professor, Endocrine Surgical Unit University of Sydney 202/69 Christie St St Leonards, NSW 2065, Australia Rebecca S. Sippel, MD, FACS Assistant Professor, Chief of Endocrine Surgery Department of Surgery University of Wisconsin School of Medicine and Public Health K3/704, Clinical Science Center 600 Highland Avenue Madison, WI 53792, USA Carmen C. Solórzano, MD Associate Professor of Surgery Vanderbilt University School of Medicine 597 PRB, 2220 Pierce Ave Nashville, TN 37232, USA Julie Ann Sosa, MD, MA Associate Professor of Surgery (Surgical Oncology and Endocrine Surgery) Department of Surgery Yale University School of Medicine TMP 204, 333 Cedar Street New Haven, CT 06520-8062, USA Antonia E. Stephen, MD Instructor in Surgery Harvard Medical School Massachusetts General Hospital 55 Fruit Street, Yawkey 7B Boston, MA 02114, USA
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Contributors
Cord Sturgeon, MD, MS, FACS Associate Professor Director of Endocrine Surgery Department of Surgery Northwestern University 676 North St. Clair Street, Suite 650 Chicago, I1 60611, USA Sonia L. Sugg, MD Associate Professor University of Iowa Hospitals and Clinics 200 Hawkins Drive, 4646 JCP Iowa City, IA 52242, USA Geoffrey B. Thompson, MD Chief, Endocrine Surgery Mayo Clinic 200 1st St SW Rochester, MN 55905, USA Yi-Fang Tsai, MD Attending Physician and Instructor National Yang-Ming University Department of Surgery, Division of General Surgery Taipei Veterans General Hospital No. 201, Sec. 2, Shipai Rd., Beitou District Taipei City, Taiwan 11217, R.O.C. Ling-Ming Tseng, MD Attending Physician and Assistant Professor National Yang-Ming University Department of Surgery, Division of General Surgery Taipei Veterans General Hospital No. 201, Sec. 2, Shipai Rd., Beitou District Taipei City, Taiwan 11217, R.O.C.
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Charles Tuggle, BS Department of Surgery Yale University School of Medicine PO Box 208062, 333 Cedar Street New Haven, CT 06520-8062, USA Robert Udelsman, MD, MBA William H. Carmalt Professor of Surgery and Chair Department of Surgery Yale University School of Medicine Surgeon-in-Chief, Yale-New Haven Hospital FMB 102, 310 Cedar Street New Haven, CT 06510, USA Thinh Vu, MD Assistant Professor MD Anderson Cancer Center 1515 Holcombe Blvd. Houston, TX 77030, USA Tracy S. Wang, MD, MPH Assistant Professor, Division of Surgical Oncology Medical College of Wisconsin 9200 W. Wisconsin Avenue Milwaukee, WI 53226, USA Scott M. Wilhelm, MD University Hospitals of Cleveland 11100 Euclid Avenue Cleveland, OH 44106, USA James E. Wiseman, MD Earl Gales Research Fellow in Endocrine Surgery Endocrine Surgical Unit, Division of General Surgery David Geffen School of Medicine at UCLA 10833 Le Conte Ave., 72-229 CHS Los Angeles, CA 90095, USA
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Contributors
Michael W. Yeh, MD Assistant Professor of Surgery and Medicine (Endocrinology) Endocrine Surgical Unit, Division of General Surgery David Geffen School of Medicine at UCLA 10833 Le Conte Ave., 72-228 CHS Los Angeles, CA 90095, USA Meei J. Yeung, MBBS, FRACS Monash University Endocrine Surgery Unit Alfred Hospital, Melbourne, Victoria, Australia Suite 6, 243 New Street, Brighton 3186 Melbourne, Victoria, Australia William F. Young, Jr., MD, MSC Vice Chair, Division of Endocrinology Mayo Clinic 200 1st St SW Rochester, MN 55905, USA Rasa Zarnegar, MD, FACS Assistant Professor of Surgery Weill Cornell Medical College 525 East 68th Street, Room A-1027 New York, NY 10021, USA
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Handbook of Endocrine Surgery
Foreword
I am honored to be invited to write the foreword for this outstanding and up-to-date book titled Handbook of Endocrine Surgery and edited by Rebecca Sippel, MD and Herb Chen MD. The editors, who are expert endocrine surgeons at the University of Wisconsin, Madison, have assembled a talented group of endocrine surgeons from the USA and Australasia as authors. This very practical and clinically oriented book provides valuable information for surgeons who care for patients with endocrine surgical problems. The authors present concise information regarding the preoperative evaluation, surgical technique, approach and decisions on how to avoid complications, and how to manage postoperative problems when they occur. Endocrine surgery is a rapidly evolving specialty of general surgery and head and neck surgery. Recent publications document that patients operated upon by surgeons who perform more endocrine surgical operations have fewer complications than when the same operations are performed by less experienced surgeons. Most major medical centers in the USA and worldwide now have endocrine surgical teams that work closely with endocrinologists, nuclear medicine physicians, radiation therapists, cytologists, pathologists and basic scientists. National and International Endocrine Surgical meetings have been established and are growing rapidly. We must be thankful for the contributions to endocrine surgery by Drs. Theodor Kocher, William Halsted, Harvey Cushing, George Crile, Frank H. Lahey. Charles Mayo, Oliver Cope, Selwyn Taylor, Richard Wellbourn, Per-Ola Granberg, Leon Goldman, Oliver H. Beahrs, Norman Thompson, Charles Proye, Hans Roeher, Thom Reeves, Samuel A. Wells,
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Edwin Kaplan and many other surgeons who have helped to improve the care of patients with endocrine surgical disorders. This book by Drs. Sippel and Chen helps follow this rich tradition.
Orlo H. Clark, MD Professor of Surgery University of California San Francisco
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Handbook of Endocrine Surgery
Preface
While endocrine surgery is a field that demands meticulous operative technique and close attention to detail, it requires just as much if not more in the preoperative and postoperative management of patients. As endocrine surgeons we are not merely technicians removing a thyroid or a parathyroid, but physicians that are curing diseases of the endocrine system through surgery. What separates us from other surgeons that may do the same technical operation is that we understand the diseases we are operating on and how to determine who needs an operation, what operation should be done, and how to best care for the patient before and afterwards. Much of what we know about the practice of endocrine surgery isn’t learned from reading journal articles or book chapters; it was learned from our mentors, who helped to train us in both the art and science of endocrine surgery. It is the clinical pearls that our mentors taught us of “how I do it” that is at the essence of this book. Residents and fellows are taught what tests to order and what is in the differential diagnosis, but when it comes down to interpreting those tests or figuring out how to actually rule out those other conditions in the differential diagnosis they often struggle to find a reference that could help in the actual day to day clinical world. They may know that a patient with suspected Cushing’s syndrome needs to get a dexamethasone suppression test, but don’t really know what that means. When do you give the steroids, when do you check the labs, how do you interpret the results, do you need to stop any medications? There are plenty of books and references that will tell you the correct test to order, but few that tell you exactly how to do it or how to interpret it. Hence the goal of this book is to be a reference that can answer those questions. This book is designed to be a very practical and clinical relevant reference that can guide the
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practicing surgeon through the work up and management of patients with surgical endocrine diseases. The book is divided into four main sections focusing on Thyroid, Parathyroid, Adrenal, and Endocrine Pancreas. Each section is divided into two parts with the first part focusing on diagnosis and the second part focusing on clinical management. The authors of this book are leaders in endocrine surgery both past, present, and future. They share the wisdom of their experience and knowledge, as well as their mentors, and help to shape your understanding of the diseases that they treat. The authors have incorporated the latest tests and techniques and shared their practical experience of “how they do it.” We are grateful to the many contributors to this text. This book represents the efforts of many people whom we consider friends and colleagues as well as leaders in the field. They have put forth a great effort into their contributions and it is our hope that you will appreciate their knowledge and effort and find this text an invaluable resource in your day to day practice.
Rebecca S. Sippel, MD and Herbert Chen, MD
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THYROID
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Chapter I.A.1: Thyroid Evaluation — Laboratory Testing Jennifer L. Poehls, MD and Rebecca S. Sippel, MD, FACS
THYROID FUNCTION TESTS Overview Thyroid-stimulating hormone (TSH) is produced by the anterior pituitary gland and is responsible for thyroid cell growth and hormone production by binding to the TSH receptor on the thyroid cell. TSH secretion is regulated by thyrotropin-releasing hormone (TRH) from the hypothalamus and serum levels of thyroid hormone (T3 and T4). TRH promotes the synthesis and release of TSH. TSH stimulates the production and release of T4 from the thyroid. T4 is converted to T3 in the tissues. High levels of T3 and — to a lesser extent — T4 negatively feed back to the hypothalamus and anterior pituitary to inhibit TRH and TSH secretion. Low levels of thyroid hormone stimulate TRH and TSH release (Fig. 1). TSH (Normal Range 0.4–5.50 mU/L) Serum TSH is the most common test used to screen for thyroid dysfunction, including hypothyroidism and hyperthyroidism. Mild degrees of thyroid dysfunction can be identified with TSH. A normal TSH excludes hyperthyroidism and primary hypothyroidism. Advantages The immunoassay has high sensitivity, wide availability, and low cost, making it a good screening test. 3
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J. L. Poehls and R. S. Sippel _ HYPOTHALAMUS TRH + _ T3
ANTERIOR PITUITARY
Peripheral tissues
TSH + THYROID
Fig. 1
T4 T4/T3
Hypothalamic-pituitary–thyroid axis.
Limitations Changes in serum TSH lag behind changes in T4/T3 levels. In the setting of primary hypothyroidism, TSH should not be checked unless it has been at least 6–8 weeks since the last levothyroxine dose change was made. It may take many weeks to correct the TSH after initiation of treatment for hyperthyroidism, so free thyroid hormone levels should be monitored instead for treatment adjustments. Measuring TSH alone is not appropriate when central hypothyroidism is suspected. Free hormone levels in addition to normal or low TSH are required for diagnosis and for monitoring treatment of central hypothyroidism. Test interpretation (Table 1) Causes of increased TSH: • • • •
Primary hypothyroidism (high TSH, low T4) Subclinical hypothyroidism (TSH of 5–10 with normal T4) TSH-secreting tumor (rare) (high TSH, high T4) Isolated pituitary resistance to thyroid hormone (rare)
Causes of decreased TSH: • •
Hyperthyroidism/thyrotoxicosis (low TSH, high T4/T3) Excess exogenous thyroid hormone (low TSH, normal/high T4)
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Interpretation of thyroid function tests.
Cause Primary hypothyroidism Subclinical hypothyroidism Central hypothyroidism Thyroid hormone resistance TSH-secreting tumor Decreased thyroxine-binding globulin or Drugs: phenytoin, carbamazepine Increased thyroxine-binding globulin or Decreased conversion of T4 to T3 (amiodarone, radiocontrast agents, propranolol) Drugs: glucocorticoids, dopamine Nonthyroidal illness (euthyroid sick syndrome) Subclinical hyperthyroidism or Recently resolved/treated hyperthyroidism or First trimester of pregnancy or Early hyperthyroidism T3 thyrotoxicosis Overt hyperthyroidism (Graves’, toxic multinodular goiter, or thyroiditis)
TSH
Free T4
Free T3
↑ ↑ N or ↓ N or ↑ ↑↑ N
↓ N ↓ ↑ ↑ ↓
N or ↓ N N or ↓ ↑ ↑ N or ↓
N
↑
N or ↓
↓ ↓
N N or ↓
↓ ↓
↓
N
N
↓ ↓
N ↑
↑ ↑
N = normal
• • •
Central hypothyroidism (low TSH, low T4) Subclinical hyperthyroidism (low TSH, normal T4) Drugs which inhibit TSH secretion (corticosteroids, dopamine)
T4 Serum levels of T4 are inversely related to serum TSH. Obtaining a serum T4 level in addition to TSH is usually sufficient to distinguish primary from central hypothyroidism, overt (abnormal TSH and T4) from subclinical (abnormal TSH, normal T4) thyroid disease, or determine the severity of hyperthyroidism. 99.96% of all serum T4 is bound to thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA),
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or albumin. Concentrations of total and free (unbound) T4 are measurable by a variety of assays. Total T4 (Normal Range 5.6–13.7 mcg/dL) This measures both bound and unbound hormones by a radioimmunoassay (RIA), chemiluminometric, or other immunometric technique. Advantages It is widely available and accurate. Limitations Drugs or illness can alter the concentrations of TBG or the binding of TBG with T4, leading to increases or decreases in the total hormone levels, but relatively normal free hormone levels. This can sometimes be the explanation for abnormal thyroid function tests in patients who do not have thyroid dysfunction. Test interpretation Causes of low serum TBG (falsely low total T4): •
Androgens, glucocorticoids, niacin, inherited deficiency of TBG, nephrotic syndrome, cirrhosis
Causes of high serum TBG (falsely elevated total T4): •
Estrogen, tamoxifen, 5FU, methadone, heroin, inherited excess of TBG, pregnancy, hepatitis
Free T4 (Normal Range 0.8–2.7 ng/ml) Several methods are available for measuring free hormone: equilibrium dialysis, free T4 immunoassays, or calculating the free T4 index. With the advent of improved technology, free T4 immunoassays are the most common method used to measure the amount of unbound T4 present.
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Equilibrium dialysis is considered the gold standard for free T4 determination, but it is cumbersome, expensive, and not widely available. Thus, it is best reserved for circumstances in which the diagnosis is not clear. The free T4 index entails measuring the total T4 by immunoassay and estimating the uptake of radiolabeled T3 by plasma proteins and matrix added to the sample. It is calculated as the product of the total T4 multiplied by the percentage of the T3 tracer taken up by the matrix. This “T3 uptake” is unrelated to the T3 level in the serum. Advantages Immunoassays are sufficiently accurate in most settings, automatable, inexpensive, and the most widely used method for free T4 determination. They avoid the confusion related to binding protein abnormalities. Limitations No assay is available to correct for all possible binding protein abnormalities. When there is any doubt about the validity of the value, an equilibrium dialysis measurement should be performed. Test interpretations Free T4 levels can be abnormal in euthyroid patients (normal TSH). Elevated free T4 levels can be seen in patients with unusual plasma-binding protein abnormalities and patients on medications that block T4-to-T3 conversion (IV contrast, amiodarone, glucocorticoids, propranolol). These situations are distinguished from hyperthyroidism by a normal TSH. Decreased levels of free T4 but normal TSH can be seen in patients on antiepileptics like phenytoin and carbamazepine. T3 Serum levels of T3 are also inversely related to serum TSH. They can be useful for recognizing T3 thyrotoxicosis (milder hyperthyroidism with elevated T3 but normal T4), to fully define the severity of hyperthyroidism
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and monitor therapy response. Serum T3 concentrations alone are not accurate for diagnosis of hypothyroidism, because T3 levels are often normal in mild-to-moderate primary hypothyroidism. Most of serum T3 is also bound to TBG, TBPA, and albumin. Concentrations of total and free (unbound) T3 are measurable by similar assays used to measure T4. Total T3 (Normal Range 60–181 ng/dL) This measures both bound and unbound hormones by RIA, chemiluminometric, or other immunometric assay. Advantages It is widely available and accurate. Limitations Drugs or illness altering the concentrations of TBG or the binding of TBG with T3 can lead to increases or decreases in the total hormone levels, but relatively normal free hormone levels. Free T3 (Normal Range 2.3–4.2 pg/mL) This measures only free hormone by immunoassay. Advantages It is sufficiently accurate in most settings, automatable, and inexpensive. It avoids confusion related to binding protein abnormalities. Limitations It is not as widely available as total T3. No assay is available to correct for all possible binding protein abnormalities.
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Reverse T3 (Normal Range 0.19–0.46 ng/mL) Reverse T3 (rT3) is measured by radioimmunoassay. Its concentration is about one-third of the total T3 concentration. There is little or no clinical indication for rT3 measurement. It was previously used to help distinguish thyroid function tests due to nonthyroidal illness from true hypothyroidism, but the assay is not accurate enough.
Clinical Applications • • • •
Screening for thyroid dysfunction = check TSH. Working up a low TSH = check free T4, total T3. Working up a high TSH = check free T4. If on medications or have medical conditions that interfere with TBG, then check free instead of total hormone levels.
THYROID ANTIBODIES Anti-TPO Antibodies (Normal is Negative) Thyroid peroxidase (TPO), formerly known as the microsomal antigen, is an enzyme which catalyzes the iodination and coupling of tyrosine residues within thyroglobulin. The presence of autoantibodies to this antigen suggests the diagnosis of autoimmune thyroid disease, particularly Hashimoto’s thyroiditis. RIA is the most sensitive assay and is generally preferred.
Prevalence • • • • • •
General population 8–27% Graves’ disease 50–80% Autoimmune thyroiditis (Hashimoto’s) 90–100% Relatives of patients with Hashimoto’s 30–50% Type 1 diabetes 30–40% Pregnant women ~14%
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Test interpretation A positive titer suggests thyroid autoimmunity and the propensity for thyroid dysfunction to develop. Patients can have positive anti-TPO antibodies and have normal thyroid function. TSH Receptor Antibodies (Normal < 125% of Basal Activity) TSH receptor antibodies can be stimulating, binding, and inhibiting. Thyroid–stimulating immunoglobulin (TSI) is the most often measured and is present in most patients (90%) with Graves’ disease. Unlike antiTPO, it is rarely detected in patients with other autoimmune thyroid diseases. Usually Graves’ can be diagnosed clinically without measuring TSI. However, in pregnant women with hyperthyroidism TSI is useful for determining the risk of neonatal hyperthyroidism from TSI crossing the placenta. TSI can help differentiate Graves’ from thyroiditis in someone who is unable to receive radioactive iodine, like a breastfeeding mother. TSI can also establish the diagnosis of Graves’ in someone who is euthyroid but has signs of orbitopathy. Prevalence • • • • • •
General population 0% Graves’ disease 80–95% Autoimmune thyroiditis (Hashimoto’s) 10–20% Relatives of patients with Hashimoto’s 0% Type 1 diabetes 0% Pregnant women 0%
Test interpretation The test involves isolating the immunoglobulins, exposing cultured thyroid cells to them, and then measuring their cAMP response compared to reference TSI and TSH standards. • • •
Basal activity is <110%: normal. Basal activity is >125%: positive for Graves’. Basal activity is 110–125%: indeterminant; further studies are indicated.
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Antithyroglobulin Antibodies (Normal < 20 IU/mL) Antithyroglobulin antibodies are a general marker of thyroid autoimmunity. Their presence poses a problem for thyroid cancer patients who rely on thyroglobulin measurements to monitor for recurrence. They interfere with the thyroglobulin assay by binding free thyroglobulin in the serum, decreasing the amount available for detection and negating the value of the serum thyroglobulin determination. Prevalence • • • • • •
General population 5–20% Graves’ disease 50–70% Autoimmune thyroiditis (Hashimoto’s) 80–90% Relatives of patients with Hashimoto’s 30–50% Type 1 diabetes 30–40% Pregnant women ~14%
Test interpretation If present in a nonthyroid cancer present, they are an indicator of thyroid autoimmunity. If present in a thyroid cancer patient, they may interfere with the thyroglobulin assay and lead to difficulties with interpretation. Their presistence in a thyroid cancer patient without thyroid autoimmunity more than one year after thyroidectomy and radioiodine ablation may indicate residual thyroid tissue and increased risk of recurrence. However, in thyroid cancer patients with a prior history of thyroid autoimmunity, these autoantibodies may persist longer (median time to disappearance three years).
THYROID TUMOR MARKERS Thyroglobulin (Normal 3.5–56 ng/mL; After Thyroidectomy < 2 ng/mL) Thyroglobulin is the precursor to thyroid hormones and is synthesized only by thyroid follicular cells, making it a good marker for papillary and
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follicular thyroid cancer recurrence after thyroidectomy. It can be measured in the serum by immunoassay, which is limited by interference caused by the presence of circulating antithyroglobulin antibodies. Thyroglobulin is mainly measured when monitoring for residual or recurrent papillary or follicular thyroid cancers after thyroidectomy. It can also be useful in the differentiation of thyrotoxicosis due to exogenous thyroid hormone from endogenous hyperthyroidism (Graves’, thyroiditis). Most thyroid cancer patients are on thyroid hormone suppression therapy after thyroidectomy and radioactive iodine ablation. Thyroglobulin can be measured while the patient is on thyroid hormone suppression, after recombinant TSH stimulation, or withholding thyroid hormone suppression. Advantages When thyroglobulin is measured after withholding thyroid hormone suppression or receiving recombinant TSH, it has a high degree of sensitivity and specificity to detect thyroid cancer after total thyroidectomy and remnant ablation. Limitations Thyroglobulin levels may be low in aggressive or poorly differentiated disease or elevated in patients at low risk for clinically significant morbidity, so they should be interpreted in the setting of pretest probability of clinically significant residual tumor. Test interpretation Ideally, thyroglobulin levels drawn while on thyroid hormone suppression should be <1 ng/mL. If they are >1ng/mL, further testing with recombinant TSH or withholding thyroid hormone suppression should be performed. A recombinant-TSH-stimulated thyroglobulin level (or after withholding thyroid hormone) of >2 ng/mL is suggestive of recurrent disease. In the differentiation of thyrotoxicosis, endogenous forms of hyperthyroidism cause elevations of thyroglobulin and exogenous thyroid hormone causes suppression of thyroglobulin.
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Calcitonin (Normal Males <8 ng/l; Females <4 ng/l) Calcitonin is the product of thyroid parafollicular or C cells. It is a useful tumor marker for medullary thyroid carcinoma (MTC). Calcitonin levels are usually many times higher than normal in disseminated MTC. Mild elevations of calcitonin are not specific for MTC and calcitonin can be normal in early tumors. In patients with high suspicion for MTC (family history of MTC or MEN2A or MEN2B), provocative testing with pentagastrin (0.5 mcg/kg IV over 5 s) or calcium gluconate (2 mg calcium/kg over 1 min) is recommended if the calcitonin is indeterminate (less than 100).
Test interpretation Screening test: • •
>100 is diagnostic for MTC. If the patient is high-risk and the calcitonin is <100 but >normal, the test is indeterminate and further provocative testing is indicated.
Patients with known MTC: • • •
10–40 is suggestive of nodal disease. >150 is often seen in distant metastatic disease, and frequently the calcitonin is >1000 in this setting. >3000 is suggestive of extensive metastatic MTC.
SELECTED REFERENCES Cooper DS, Doherty GM, Haugen BR, et al. American Thyroid Association Guidelines Taskforce. Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2006;16(2):109–142. Gardner DG, Shoback D. Greenspan’s Basic and Clinical Endocrinology, 8th Edn. McGraw-Hill, 2007. Henderson KE, Baranski TJ, Bickel PE, et al. The Washington Manual Endocrinology Subspecialty Consult, 2nd Edn. Wolters Kluwer/Lippencott Williams and Wilkins, 2009.
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Chapter I.A.2: Thyroid Imaging James E. Wiseman, MD, Lilah F. Morris, MD and Michael W. Yeh, MD
INTRODUCTION It is estimated that 4–7% of the population of North America has palpable thyroid nodules, with an incidence of 0.1% per annum. The superficial location of the thyroid gland contributes to ease in palpation, and clinical assessment of the thyroid is vital to any routine physical examination. The ability of physical examination to detect potentially malignant thyroid masses is limited by a number of factors, including location within the thyroid (posterior lesions being much more difficult to palpate), the size of the nodule, the experience and technique of the examiner, and the physical characteristics of each patient’s neck. Indeed, postmortem studies of patients with clinically normal thyroid glands have reported the presence of grossly visible nodules at autopsy in up to 50% of patients, with 30–40% having lesions larger than 2 cm. The sensitivity of physical examination as a diagnostic tool for thyroid nodules has been reported to be as low as 38%. The prevalence of clinically undetectable thyroid cancer in the United States is estimated to be 0.45–13% based on autopsy data. Moreover, between 4 and 12% of palpable thyroid nodules subsequently demonstrate the presence of malignancy on pathologic evaluation. An overwhelming majority of these “occult” thyroid cancers are of papillary histology, an indolent form of the disease with an excellent prognosis. In fact, up to 35% of thyroid glands removed at autopsy or surgically contain papillary “microcarcinomas” measuring less than 1 cm in diameter, which are generally considered clinically insignificant. Given the prevalence of thyroid nodules, their risk of harboring malignancies, the excellent response of 15
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cancers to current treatment modalities, and the limitations of physical examination, the use of imaging has become vitally important in the evaluation of the thyroid (Fig. 1). In addition, with the general increased use of imaging modalities, many thyroid nodules are incidentally discovered. Surgeons should be familiar with the appropriate imaging modalities for the evaluation of thyroid disease and learn how to interpret imaging results.
ULTRASOUND Ultrasonographic evaluation is currently recommended in the workup of all palpable thyroid nodules by the American Thyroid Association (Cooper et al., 2006). Indeed, they define a thyroid nodule as a discrete lesion that is palpably and/or sonographically distinguishable from the surrounding parenchyma. The principle behind ultrasonography (US) is that differences in density can be detected by analyzing the rate of return of deflected sound waves passed through tissue. The basic unit of ultrasonographic transmission is the completion of one forward and backward wave, commonly referred to as a cycle. Frequency refers to the number of cycles occurring over unit time (cycles per second) — a measure identified as hertz (Hz). Higher frequency corresponds with increased resolution but less depth of tissue penetration. Conversely, lower frequency waves penetrate tissue better but provide lower quality images. US of the thyroid is typically performed with a high frequency transducer (7–13 MHz), resorting to lower frequency transducers (5–7 MHz) when deeper penetration is required, such as in the case of large glands or obese patients. The American Institute of ultrasound in Medicine’s (AIUM) 2007 practice guideline for the performance of thyroid US recommends an optimal frequency of 10–14 MHz (AIUM, 2003). The primary aims of thyroid US in the evaluation of nodular disease are (1) to confirm the presence of a nodule detected by palpation, (2) to identify any additional nodules, and (3) to provide a more accurate measurement of the dimensions and characteristics of these lesions. While benign versus malignant lesions cannot be conclusively discriminated, clues to the histologic behavior of these nodules can be derived from characteristics observed on US (Table 2).
Normal/High TSH
Calcification
Low TSH
“Cold” nodule Diameter <1 cm
“Hot” nodule
Diameter >1 cm
SURVEILLANCE
SURVEILLANCE FNA
Fig. 1
Algorithm for imaging workup of thyroid nodules.
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History/Examination
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Initial Ultrasound Examination Given the prevalence of thyroid nodules in the general population and the uncertainty of their clinical significance, ultrasound has little value as a screening tool. Individuals at high risk for thyroid cancer are an important exception (Table 1), and regular ultrasound screening is recommended. With increasing utilization of sonography to evaluate the neck’s vasculature, an increasing number of nonpalpable nodules, or “incidentalomas,” are being identified. Several nodule features that can be easily defined by US have been studied for their prognostic value. They include the size of the nodule, the sonographic appearance of the margins, the shape of the lesion, echogenicity, and the presence of calcifications (Table 2). Though it may seem counterintuitive, the size of the lesion is of no diagnostic value as benign and malignant disease present equally at all sizes. That said, American Thyroid Association guidelines recommend serial ultrasounds without other workup for asymptomatic, incidentally
Table 1 Risk factors that confer high predisposition on the development of malignant thyroid nodules. Risk factors History of head and neck irradiation Total body irradiation for bone marrow transplantation Family history of thyroid malignancy in a first-degree relative Exposure to radioactive fallout or contamination under 14 years of age
Table 2 Comparison of nodule characteristics seen on US that are suggestive of benign versus malignant disease. US feature Composition Echogenicity Microcalcification “Halo” Margins Central blood flow (color Doppler)
Benign
Malignant
Cystic/mixed Isoechoic Absent Present Well-defined Absent
Solid Hypoechoic Present Absent Ill-defined Present
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discovered nodules <1 cm, as these small nodules have the least potential to become clinically significant cancers. In addition, while the traditional view has been that the existence of multiple nodules favors benign underlying pathology, 10–20% of thyroid cancers are multifocal. Sonographic features suggestive of malignancy include poorly defined or “blurred” margins, a predominantly solid composition, and associated cervical lymphadenopathy. Similarly, hypoechogenicity in a palpable nodule may portend cancer. Most nonpalpable nodules, particularly those less than 1 cm in the greatest diameter, appear hypoechoic on US and the finding is of less diagnostic interest in this setting. While none of these characteristics are independently predictive of malignancy, the demonstration of two or more is highly suggestive (Fig. 2). The presence of a peripheral “halo,” representing a capsule or compressed surrounding parenchyma (no invasion), is suggestive of a benign lesion. Calcification within thyroid nodules is commonly appreciated on US and occurs in a variety of patterns. Frequently described forms include an “eggshell” or rim surrounding the periphery, dense areas of coarse calcification, and tiny, punctate foci known as microcalcifications. Classically, “eggshell” calcification has been associated with multinodular goiter, but this pattern has been reported in papillary and undifferentiated carcinoma and as such should not be considered an absolute indication that a lesion is benign. Similarly, up to half of all nodules demonstrating a coarse pattern of calcification harbor malignancy. Microcalcification is a
Fig. 2 (A) Ultrasound image of a mildly hypoechoic nodule with ill-defined borders (solid arrow) and dense calcifications (double arrows). (B) Ultrasound image of a nodule demonstrating punctate microcalcifications (solid arrow). (C) Ultrasound image of a papillary carcinoma of the tall cell variant, demonstrating irregular, spiculated borders (solid arrows).
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frequent finding in patients with palpable thyroid nodules, although it is often absent from nonpalpable nodules. Microcalcifications seen on US correlate with the calcification of psammoma bodies seen under the microscope, and this phenomenon is the most sensitive and accurate predictor of the presence of malignancy within a nodule. However, any pattern of calcification detected sonographically is potentially indicative of the presence of a cancer and should elicit an appropriate level of suspicion. Ultrasound Surveillance in Differentiated Thyroid Cancer US is used routinely for postoperative monitoring following treatment of differentiated thyroid cancer. In experienced hands, ultrasound can detect lymph nodes as small as 2–3 mm in diameter. While, as with thyroid nodules, no particular finding on cervical ultrasound is pathognomonic for the presence of metastatic or recurrent thyroid cancer, the Antonelli criteria (Antonelli et al., 2003) (Table 3) can be used to identify those nodes that are highly suspicious for malignancy. In addition, ultrasound can pinpoint the location of metastatic disease much more precisely and reliably than nuclear scintigraphy or PET scanning. In our experience, ultrasound examination of cervical lymph node basins has been a crucial tool for ensuring complete clearance of cervical disease at initial operation as well as subsequent procedures for recurrent or persistent disease. When metastatic disease or recurrence is suspected based on symptoms, or in the presence of palpable cervical lymph nodes, ultrasound evaluation should be routinely ordered as an adjunct to examination of the thyroid itself. Table 3 Antonelli’s criteria (Cooper et al., 2006) for ultrasound findings suspicious for cervical lymph node metastasis. Ultrasound findings 1. Node diameter 1 cm or greater 2. Hypoechoic or dyshomogeneous pattern 3. Irregular cystic appearance 4. Presence of internal calcifications 5. Rounded or bulging shape with an increased anteroposterior diameter 6. Length-to-width (or vice versa) diameter ratio greater than 0.7
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Duplex Sonography The use of blood flow (duplex) sonography has become standard in the evaluation of all thyroid nodules. Prior to examination, the ultrasound must be calibrated to assess low-flow vasculature. The detection of central blood flow, or hypervascularity, within a lesion is predictive of malignancy, while visualization of peripheral blood flow alone suggests a benign lesion. However, neither finding is of sufficient sensitivity or specificity to make a definitive distinction.
COMPUTED TOMOGRAPHY (CT) Three-dimensional imaging in the workup of thyroid nodules is rarely indicated. CT scans assist in evaluating large goiters with a substernal, retrotracheal, intrathoracic, or retroclavicular component that cannot be visualized on ultrasound (Fig. 3). In addition, in managing a large goiter, assessing the degree of tracheal deviation and airway abnormalities with CT scans is an invaluable component of the preoperative workup, and is often requested by anesthesiologists.
Fig. 3 Sagittal view of a CT of the chest, demonstrating a large, substernal thyroid nodule.
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MAGNETIC RESONANCE IMAGING (MRI) As with CT scans, there are very few indications for the use of MRI in evaluation of the thyroid. In patients who have had previous thyroid surgery, MRI can be used to better delineate the anatomy of the thyroid bed. In addition, some studies have suggested that MRI is more sensitive than other modalities for detecting recurrent disease. However, it is costly, uncomfortable, and adds little unique information in the diagnostic workup of thyroid disorders.
RADIONUCLIDE SCANNING The utility of radionuclide scanning (scintigraphy) lies primarily in the evaluation of patients with suppressed serum thyrotropin (TSH) levels, who may have solitary nodules, multinodular goiter, or suspected Graves’ disease. This study can be performed using either iodine-based molecules (most commonly 123I) or technetium 99Tc. As a general rule, iodine isotopes are favored as their uptake demonstrates the ability of the nodule to both transport and organify iodide. From a mechanistic standpoint, variable isotope uptake permits tissue discrimination based on differences in metabolic activity. In principle, malignant cells have lost their ability to perform differentiated functions of normal tissue, whereas benign nodules exhibit acceleration of these functions. The result is less isotope uptake in malignant lesions (“cold”) and more activity in benign lesions (“hot”) (Fig. 4). This has been borne out in most studies, and demonstration of hyperfunctionality nearly always indicates a benign lesion. “Cold” nodules have an approximately 5% risk of harboring malignancy, and the overall pretest risk of detecting a cancer with radionuclide scanning is approximately 4%. Consequently, use of this modality for diagnostic purposes is generally not considered to be cost-effective in the initial evaluation of the solitary thyroid nodule, and its use should be reserved for those patients with a nodule in the setting of TSH suppression and indeterminate cytology. When there is suspicion of Graves’ disease, radionuclide scanning may be used to differentiate this condition from thyroiditis. Diffusely increased isotope uptake favors the former diagnosis, whereas the exam is characteristically normal or demonstrates decreased uptake in the setting of thyroiditis.
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Fig. 4 (A) 123I uptake study demonstrating a “cold” right lobe nodule with associated displacement of normal tissue (solid arrow). (B) Similar study demonstrating a cluster of “hot” molecules in the lower left lobe (hollow arrow). Note suppression (photopenia) of the remaining normal thyroid tissue.
POSITRON EMISSION TOMOGRAPHY (PET) AND PET/CT The recent advent of PET has had a major impact on the treatment of many cancers. However, its utility in the treatment of thyroid tumors remains uncertain. PET involves the use of 18-fluorodeoxyglucose positron
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18F-FDG-PET/CT demonstrating increased uptake in the left lobe of the thyroid.
emission tomography (18F-FDG-PET) to detect differences in the uptake of glucose between tissues. In the evaluation of thyroid cancer, well-differentiated carcinomas have generally been found to exhibit increased 131I uptake, but little 18 FDG uptake. The pattern is reversed with poorly differentiated cancers, i.e. little 131I uptake and high 18FDG uptake usually occur (Fig. 5). This “flip-flop” phenomenon, as it has been termed, may manifest a given tumor’s transition to a more aggressive phenotype. Because the great majority of thyroid cancers are slow-growing, PET scanning is not
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recommended during either initial staging or routine surveillance. PET has an emerging role in the evaluation of the differentiated thyroid cancer patient who has an elevated thyroglobulin level and a negative 131I whole body scan. One specialized application of CT scanning in the preoperative evaluation of thyroid nodules involves coregistered data acquisition, in which PET and CT images taken concurrently are superimposed on one another. These images then allow tissues exhibiting increased uptake of glucose to be more precisely localized anatomically. A limitation of 18F-FDG-PET and 18F-FDG-PET/CT is that less than 5% of thyroid nodules demonstrate increased uptake of 18F-FDG. Approximately 50% of focally PET-positive lesions harbor malignancy. In other words, while 18F-FDG-PET/CT is highly sensitive in the identification of malignant lesions, its specificity remains low. Thus, the utility of 18F-FDG-PET/CT in the preoperative evaluation of thyroid nodules is uncertain and the modality is not routinely used for this purpose in most institutions.
SELECTED REFERENCES AIUM Practice Guideline for the Performance of a Thyroid and Parathyroid Ultrasound Examination. J Ultrasound Med 2003;22(10):1126–1130. Antonelli A, Miccoli P, Fallahi P, et al. Role of neck ultrasonography in the follow-up of children operated on for thyroid papillary cancer. Thyroid 2003;13(5):479–484. Cooper DS, Doherty GM, Haugen BR, et al. Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American thyroid association guidelines taskforce. Thyroid 2006;16(2):109. Morris L, Ragavendra N, Yeh M. Evidence-based assessment of the role of ultrasonography in the management of benign thyroid nodules. World J Surg 2008;32(7):1253–1263. Pacini F, Schlumberger M, Dralle H, et al. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 2006;154(6):787–803.
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Chapter I.A.3: Thyroid Evaluation — FNA Jennifer B. Ogilvie, MD, FACS
FNA TECHNIQUE Overview Thyroid fine needle aspiration biopsy (FNA) has high sensitivity and specificity in the diagnosis of papillary thyroid carcinoma, as well as other thyroid malignancies, including medullary and anaplastic thyroid carcinoma. The sensitivity, specificity, and accuracy of thyroid FNA are significantly improved when FNA is performed under ultrasound guidance. When FNA is combined with flow cytometry and immunocytochemistry, it can be an excellent diagnostic tool for primary thyroid lymphoma. Advantages FNA is cost-effective, with high sensitivity and specificity, and is the most widely used diagnostic test in the workup of thyroid nodules. It is welltolerated by patients and can be performed in an outpatient setting with minimal complications. Limitations Successful FNA requires expertise, as well as an expert thyroid cytopathologist. Accurate diagnosis is dependent on adequate specimen sampling. FNA alone cannot distinguish between follicular adenoma and follicular carcinoma or a follicular variant of papillary thyroid carcinoma.
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Indications Any firm, palpable or solitary thyroid nodule, any nodule over 1 cm, or any nodule with suspicious clinical or ultrasonographic features should be considered for FNA. Suspicious clinical features include hoarseness, rapid growth, compressive symptoms, attachment to surrounding structures, or associated cervical lymphadenopathy. Suspicious features on ultrasound include microcalcifications, irregular borders, increased vascularity, and predominantly solid composition. Incidental nodules that are 18FDG-PET-avid have a higher risk of malignancy and should be evaluated by FNA. Contraindications There are very few contraindications to FNA, other than severe bleeding diathesis. Occasionally FNA may not be technically feasible in densely calcified or fibrotic nodules. On these rare occasions, core needle biopsy or diagnostic lobectomy with isthmusectomy may be required for diagnosis. There are several groups of patients who may not gain additional benefit from FNA. Patients with a solitary thyroid nodule and a strong family history of thyroid cancer or a history of radiation exposure to the head and neck have a high risk of thyroid cancer and may proceed directly to thyroidectomy, if indicated. Patients with a solitary hyperfunctioning nodule and suppressed TSH have a low incidence of malignancy and may undergo radioactive iodine ablation or surgery without FNA, as indicated. Patients with thyroid nodules and additional indications for thyroidectomy such as multinodular goiter with compressive symptoms or hyperthyroidism may not necessarily need preoperative FNA; however, FNA can be helpful in planning the extent of surgery and lymph node dissection if malignancy is identified. Technique Equipment • •
Alcohol 25-gauge needle
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10 cc syringe Slides
Positioning • • •
The patient is positioned in a supine or semirecumbent position, with the neck gently extended; The neck is cleaned with alcohol; Ultrasound is performed and the nodule localized.
Sampling • •
• •
Under ultrasound guidance, the needle is inserted into the nodule; Using gentle suction, the needle is moved rapidly up and down within the nodule (Fig. 1) for 2–5 s or just until blood appears in the needle hub; Suction is released and the needle is removed; Gentle pressure is held over the aspiration site.
Fig. 1 Ultrasound-guided thyroid FNA. The needle can be seen entering the nodule on the upper right.
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Slide preparation • • •
The aspirate is divided between 2–4 slides; Each slide is smeared with a duplicate slide to make 4–8 samples; Slides are placed into 95% alcohol for Papanicolaou staining or are air-dried for Romanowsky staining.
Complications • • •
FNA complications are rare and usually minor, including local discomfort, vasovagal reactions, bleeding, and hematoma. Infection is extremely rare. Therapeutic anticoagulation, NSAIDS and aspirin are not contraindications to FNA.
Notes • • • • • •
• •
Local anesthesia is not necessary but, if used, 0.5–1.5 ml 2% lidocaine can be injected subcutaneously (not intradermally) 1 min prior to FNA. A pistol grip syringe holder such as Cameco (Precision Dynamics, San Fernando, CA) can assist with aspiration. FNA may also be performed without suction (capillary aspiration or Zajdela technique). Large nodules may require 2–4 passes to achieve adequate sampling. For cystic nodules, all fluid should be drained and sent for cell block, and the solid component should be biopsied using FNA. To rule out thyroid lymphoma, dilute the aspirate in several cc of cold RPMI or normal saline and send for flow cytometry and immunohistochemistry. Clear colorless cyst fluid can suggest a parathyroid cyst and should be sent for cell block and PTH level. On-site FNA evaluation by cytopathology can decrease the rate of nondiagnostic specimens and often provide immediate diagnosis.
Core Needle Biopsy Thyroid core needle biopsy (CNB) can occasionally be helpful in the diagnosis of thyroid nodules with extensive fibrosis or calcification.
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CNB can also be useful for suspected anaplastic thyroid carcinoma, metastatic carcinoma to the thyroid, or medullary thyroid carcinoma, when specific immunostains are required to confirm the diagnosis. CNB has not been shown to be superior to FNA for flow cytometry and immunocytochemistry in the diagnosis of primary thyroid lymphoma, as long as an adequate sample is obtained.
Limitations CNB is associated with increased patient discomfort and risk of bleeding. It should only be performed by an experienced operator. Injuries to the trachea and recurrent laryngeal nerve have been reported. CNB alone cannot distinguish between follicular adenoma and follicular carcinoma or a follicular variant of papillary thyroid carcinoma. Lastly, CNB can produce post-needle-biopsy histologic alterations, potentially complicating the histopathologic diagnosis of surgical specimens. In general, CNB is not recommended as part of the initial evaluation of a thyroid nodule.
FNA RESULTS AND SIGNIFICANCE FNA Report Components • • • • • •
Demographics Clinical indication Thyroid nodule location and size Specimen adequacy assessment FNA diagnosis Immunocytochemical and molecular markers (if performed)
FNA Adequacy Assessment All FNA reports should include an assessment of the adequacy of the specimen. The criteria for adequacy of FNA specimens vary among cytopathologists. Commonly used adequacy criteria are at least six groups of follicular cells on two slides, with 10–20 cells in each group. FNA
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reports should state whether the sample was adequate for interpretation, less-than-optimal or nondiagnostic. Samples that do not contain follicular cells should be considered nondiagnostic, even if the statement “no malignant cells seen” is present. Preventable causes of nondiagnostic FNA: • • • •
Poor cell preservation due to delay in fixation Hemodilution from excessively bloody aspirates Cell damage due to poorly prepared smears Lack of ultrasound guidance
FNA Diagnostic Classification The division of thyroid FNA into diagnostic categories is the subject of much debate. The purpose of FNA is to determine which patients need surgical intervention, and this principle should guide diagnostic terminology and classification. Table 1 and Figs. 2 to 7 demonstrate the most commonly used FNA diagnostic categories and representative cytopathology. All physicians involved in the care of patients with thyroid nodules should understand FNA terminology, adequacy criteria, and diagnostic categories used at their own institution to avoid misinterpretation. Multidisciplinary conferences where FNA and histopathologic results are discussed can also improve the clinical management of patients with thyroid nodules.
RECOMMENDATIONS • • • •
Thyroid FNA is an essential tool in the management of thyroid nodules. Ultrasound guidance significantly improves FNA diagnostic accuracy. An experienced thyroid cytopathologist and clear diagnostic classification are critical to accurate FNA interpretation. Molecular markers such as BRAF and RAS may help refine the accuracy of FNA, especially in indeterminate nodules.
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Common FNA Diagnostic Categories
FNA diagnosis
Alternate FNA diagnoses
Notes
Colloid nodule Nodular goiter Hyperplastic nodule Lymphocytic thyroiditis
Observe1
3% false negative
Indeterminate
Follicular lesion of undetermined significance, atypia of undetermined significance
Follicular adenoma, benign nodule, follicular carcinoma, follicular variant of papillary thyroid carcinoma
Repeat FNA vs. 5–10% diagnostic lobectomy malignant with isthmusectomy
Follicular neoplasm, Follicular/Hürthle adenoma, Diagnostic lobectomy benign nodule, follicular/ with isthmusectomy Hürthle3 cell neoplasm Hürthle carcinoma, follicular/Hürthle variant of papillary thyroid carcinoma
20–30% malignant
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Unsatisfactory Less than optimal
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Benign nodules that are >4 cm, symptomatic, enlarging or cystic and recurrent have a higher risk of malignancy and should be considered for diagnostic lobectomy with isthmusectomy or thyroidectomy. 2 Repeat FNA should be performed under ultrasound guidance, with cytopathology present for the most accurate diagnosis. Nodules that are repeatedly nondiagnostic have a slightly higher risk of malignancy and should be considered for diagnostic lobectomy with isthmusectomy or thyroidectomy. 3 Hürthle cell lesions (neoplasms) are also termed “oncocytic lesions” (neoplasms). 4 Features suspicious for papillary thyroid carcinoma include nuclear elongation, chromatin clearing, and nuclear grooves. 5 The extent of resection should take into consideration the rate of malignancy in the suspicious category at each institution.
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Papillary thyroid carcinoma Total thyroidectomy Medullary thyroid carcinoma Poorly differentiated carcinoma Anaplastic thyroid carcinoma Primary thyroid lymphoma Metastasis to the thyroid
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Papillary thyroid carcinoma4 Thyroid lobectomy with 50–75% Medullary thyroid carcinoma intraoperative frozen malignant Poorly differentiated carcinoma section or total Anaplastic thyroid carcinoma thyroidectomy5 Primary thyroid lymphoma Metastasis to the thyroid
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Malignant
Suspicious for malignancy
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Alternate FNA diagnoses
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Fig. 2 Benign colloid nodule. Uniform, round follicular cells (small arrow) and dense colloid (large arrow). (Romanowsky 60X). Reprinted from: Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006;40:223–238; with permission from Elsevier.
Fig. 3 Follicular neoplasm. Uniform clusters of follicular cells with identifiable microfollicles and no colloid (Romanowsky 60X). Reprinted from: Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006;40:223–238; with permission from Elsevier.
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Fig. 4 Hürthle cell (oncocytic) neoplasm. Enlarged oncocytic cells with abundant cytoplasm, round nuclei, and prominent nucleoli. No colloid. (Romanowsky 60X). Reprinted from: Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006;40:223–238; with permission from Elsevier.
Fig. 5 Lymphocytic thyroiditis. Hürthle (oncocytic) cells and numerous small round lymphocytes (Romanowsky 60X). Reprinted from: Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006;40:223–238; with permission from Elsevier.
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Fig. 6 Medullary thyroid carcinoma. Large, plasmacytoid cells (small arrow) and amyloid (large arrow). (Romanowsky 60X). Reprinted from: Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006;40:223–238; with permission from Elsevier.
Fig. 7 Papillary thyroid carcinoma. Enlarged, irregular nuclei with prominent intranuclear cytoplasmic pseudoinclusion (arrow). (Romanowsky 60X). Reprinted from: Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006;40:223–238; with permission from Elsevier.
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SELECTED REFERENCES Baloch ZW, LiVolsi VA, Asa SL, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36(6):425–437. Pitman MB, Abele J, Ali SZ, et al. Techniques for thyroid FNA: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36(6):407–424.
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Chapter I.B.1: Evaluation of a New Thyroid Nodule Adrienne L. Melck, MD, MPH and Sally E. Carty, MD
EPIDEMIOLOGY A thyroid nodule is defined as a discrete lesion within the thyroid gland that is palpably and/or ultrasonographically distinct from the surrounding parenchyma. Thyroid nodules are a common clinical finding, being palpable in 4–7% of the North American adult population and being prevalent on cervical ultrasound in at least 50–67% of adults. They are four times more common in women than in men. Other than gender, factors associated with an increased risk of having a thyroid nodule include older age, prior exposure to head and neck irradiation, and iodine deficiency. Fortunately, only 4–5% of thyroid nodules are malignant. Cancer risk is equivalent for palpable and nonpalpable nodules of the same size, and for solitary nodules and nodules within a multinodular goiter. The differential diagnosis of a thyroid nodule includes thyroiditis, benign colloid nodule, colloid cyst, benign follicular neoplasm (functioning or nonfunctioning), thyroid cancer, parathyroid gland, and lymph node.
HISTORY The important historical information to be ascertained from a patient with a thyroid nodule can be conceptualized in two categories. First, an attempt to characterize the nodule can be established by asking the patient how it was first detected and how it may have evolved since the initial detection. In particular, it is important to ask if there has been a change in nodule size; a sudden increase in size usually indicates hemorrhage into a colloid nodule or benign follicular adenoma, but more rarely may suggest an 39
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aggressive lesion such as thyroid lymphoma or anaplastic cancer. The patient should also be asked about associated symptoms; for example, if the nodule is large enough to be compressing surrounding structures, the patient may complain of dysphagia to solids, dysphonia, cough, and/or dyspnea that is pronounced in a particular position (e.g. supine or with their head tilted forward or their arms elevated). Symptoms of either hypo- or hyperthyroidism should be investigated, especially considering the possibility of a functioning nodule as in Plummer’s disease. The second line of questioning revolves around determining the presence of known risk factors for thyroid carcinoma. The patient should be asked whether there is a family history of thyroid cancer or other endocrine tumors, or a personal history of exposure to head and neck irradiation. Both Gardner’s and Cowden’s syndromes are also associated with thyroid cancer, and thus colorectal and breast cancer within the patients’ personal or family history are of interest. “B” type constitutional symptoms, including weight loss, fever, and night sweats, may be present in the setting of thyroid lymphoma. The patient should also be asked about any prior neck or thoracic surgery. This becomes particularly important if thyroidectomy is indicated, because laryngoscopy to investigate the status of the vocal folds preoperatively is advisable in the reoperative setting, as it is for any patient presenting with dysphonia.
PHYSICAL EXAMINATION Examination of the patient should begin with vital signs and inspection of their general status. Tachycardia, tremor, restlessness, and a flushed complexion may indicate hyperthyroidism, while loss of the lateral eyebrows, thickened forearm skin, and pretibial edema may indicate hypothyroidism. Brisk or delayed deep tendon reflexes may also indicate hyper- or hypothyroidism, respectively. Carefully listening to the patient’s speaking voice can yield important information about the status of their recurrent laryngeal nerves. On closer inspection of the head and neck, one should look for exophthalmos, lid lag, and jugular venous distension, and the anterior neck should be palpated for tracheal deviation, tenderness, lymphadenopathy, or any juxtathyroidal nodularity. Pemberton’s sign is the development of
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facial flushing, inspiratory stridor, and jugular venous distension when both arms are raised above the patient’s head, and this sign can indicate superior vena cava syndrome as may occur with substernal goiter. Examination of the thyroid gland itself should ascertain its size, contour, and mobility with deglutition. Any palpable nodule should be assessed for fixation to surrounding structures, tenderness, and degree of firmness/ballotability. The most inferior palpable extent of the gland should be determined, as well as any palpable extent below the sternal notch, indicating a mediastinal component. Repeating the exam in the supine position allows the clinician to assess for symptomatic cervical disk disease, kyphoscoliosis, extent of posterior neck extension, and anterior neck access, which is particularly important in patients with obesity or large breasts. Clinical features suggestive of thyroid malignancy are summarized in Table 1. Table 1
Clinical and radiologic features suggestive of thyroid cancer.
History • • • • • • • •
Extremes of age Male gender History of head and neck irradiation Family history of thyroid cancer Family history of endocrine tumor syndrome (MEN 2A and 2B) Hoarseness Dysphagia Rapid growth
Physical exam • Cervical lymphadenopathy • Firm nodule • Fixation to surrounding structures • Vocal cord paralysis Ultrasound characteristics • • • • • •
Hypoechogenicity Taller-than-side shape Microcalcifications Intranodular vascularity Irregular margins Size >4 cm
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LABORATORY INVESTIGATIONS Basic laboratory investigations should include an assessment of thyroid function, including measurement of the serum thyroid-stimulating hormone (TSH). Free thyroxine (T4), free tri-iodothyronine (T3), and free thyroxine index (FTI) measurements are employed to further evaluate patients with an abnormal TSH. Hyperthyroid patients are managed with an alternate algorithm (Fig. 1). Any patient requiring thyroid surgery should also have measurement of a fasting serum calcium level, given that
Thyroid Nodule History / Physical Exam / TFTs Hyperthyroid
Hypothyroid / Euthyroid
Scintigraphy
Ultrasound
Hot
Warm / Cold
>1 cm / Suspicious features
Treat Thyrotoxicosis
FNAB Cancer / Suspicious for Cancer
Total Thyroidectomy +/- CCND FN/HN/FLUS† Lobectomy or Total Thyroidectomy∗ Nondiagnostic† Repeat FNAB Benign <4 cm Serial Follow-Up
Fig. 1
≥4 cm Diagnostic Lobectomy
Management algorithm for evaluation of thyroid nodules.
TFTs = thyroid function tests; CCND = central compartment node dissection; FN = follicular neoplasm; HN = Hürthle cell neoplasm; FLUS = follicular lesion of undetermined significance. *Indications for total thyroidectomy: family history of thyroid cancer, personal history of head and neck irradiation, hypothyroidism, symptomatic goiter, contralateral dominant nodule. † Add molecular testing if available.
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up to 52% of patients with primary hyperparathyroidism have concomitant nodular thyroid disease. Although an elevated antithyroid peroxidase antibody level in a hypothyroid patient confirms the diagnosis of Hashimoto’s thyroiditis, routine thyroid antibody titers add little to the evaluation of a euthyroid nodule. Measurement of baseline serum calcitonin has not been proven to be cost-effective in the US other than in patients with a family history of medullary thyroid cancer. There is no role for thyroglobulin measurement in the initial evaluation of thyroid nodules.
IMAGING Cervical ultrasonography provides useful information regarding not only the nodule in question but also the anatomy of the entire thyroid gland. The size of the thyroid and either the homo- or heterogeneous nature of the parenchyma should be documented. Any nodules detected should be characterized in terms of location, size, and consistency (solid, cystic, or mixed solid and cystic). A number of ultrasonographic features have been associated with an increased malignancy risk (summarized in Table 1) but cannot definitively distinguish benign from malignant nodules. Suspicious central and lateral compartment lymph nodes should be sought. Ultrasound is also essential in guiding accurate fine needle aspiration biopsy (FNAB). Computed tomography (CT) is useful if there is clinical suspicion of a substernal goiter, as it allows the surgeon to evaluate the precise degree of thoracic extension and to document the presence of any tracheal compression preoperatively. When ordered, CT should be performed without the use of intravenous iodinated contrast, which blocks iodine uptake by thyrocytes and therefore delays adjuvant administration of radioactive iodine ablation, should ablation become necessary in the postoperative management of a thyroid cancer. In the modern era, use of thyroid scintigraphy is limited mostly to the evaluation of hyperthyroid patients with suppressed TSH. Unless it is quite large (>4 cm), an isolated functioning (“hot”) nodule in a hyperthyroid patient is almost always benign and such patients require only medical management of thyrotoxicosis provided that there are no other concerning features. As multinodularity is common, it is also vital that the
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clinician confirm that a functioning nodule seen on radionuclide imaging corresponds precisely to the one seen on ultrasound before deferring its further cytologic evaluation. The details of thyroid imaging (ultrasound, CT, and scintigraphy) are discussed in detail elsewhere in this book.
INDICATIONS FOR FINE NEEDLE ASPIRATION BIOPSY Due to its safety, accuracy, and cost-effectiveness, fine needle aspiration biopsy (FNAB) has become the gold standard for evaluation of thyroid nodules; its routine use has demonstrably decreased the rate of unnecessary thyroid surgery while increasing the yield of carcinoma in surgical specimens. Performance of FNAB is discussed in detail in another chapter. The American Association of Clinical Endocrinologists (AACE) guidelines recommend that FNAB should universally be done under ultrasound guidance. The American Thyroid Association (ATA) guidelines stress the importance of ultrasound guidance, particularly for lesions that are >50% cystic or located posteriorly in the gland. One challenge for clinicians is deciding which thyroid nodules should be subjected to FNAB. FNAB should be considered for any nodule in a patient with a family history of thyroid cancer or a personal history of radiation exposure, or with concerning ultrasound characteristics (Table 1), including associated lymphadenopathy. In the absence of these concerning features, there is controversy as to the size cutoff that warrants FNAB. The National Cancer Comprehensive Network (NCCN) clinical practice guidelines recommend biopsy of solitary nodules >1 cm, whereas the ATA currently recommends FNAB for any nodule >1–1.5 cm. Multinodular goiters present a particular challenge and there is evidence to suggest that in this setting, ultrasound characteristics are superior to nodule size in determining which nodules are more likely to be malignant and should therefore be biopsied; if no nodule exhibits the concerning sonographic attributes listed in Table 1, then it is appropriate to aspirate only the largest nodules. In this era of the routine use of positron emission tomography (PET) scans for staging and surveillance of cancer patients, it is not uncommon for an incidentally detected thyroid nodule to come to attention. The
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NCCN guidelines recommend that any FDG-avid thyroid lesion be evaluated with FNAB, as up to 50% will be thyroid cancer.
THYROID NODULE MANAGEMENT AFTER FNAB The category of results of FNAB determines thyroid nodule management. Although the topic is covered in detail in another section, in general there are four categories for results of thyroid FNAB: benign, malignant, indeterminate, and inadequate yield. In 2007, the National Cancer Institute sponsored the Thyroid Fine-Needle Aspiration State of the Science Conference, at which a new nomenclature for FNAB diagnoses was proposed, and this is hoped to provide cytopathologists and clinicians with a more uniform and effective way of reporting and communicating malignancy risk (summarized in Table 2). As with the older systems, under this new six-level system it is predicted that the majority of thyroid nodules will fall into the benign category, while 5–15% of FNABs will be nondiagnostic, 10–15% will be indeterminate, and the remaining 5% will be cancer. While FNAB cytology results in the malignant, suspicious, or indeterminate categories prompt thyroidectomy for treatment and/or definitive diagnosis, and benign nodules <4 cm are generally managed nonoperatively (see below), there is controversy about management of FNAB results with inadequate yield for diagnosis. At our institution all such nodules are subjected to short-interval rebiopsy, and if the results are again inadequate, diagnostic thyroid lobectomy is advised. Some clinicians will attempt a third FNAB before proceeding to surgery. Table 2 National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Cytology classification Benign Follicular lesion of undetermined significance Follicular or Hürthle cell neoplasm Suspicious for malignancy Malignant Nondiagnostic
Risk of malignancy <1% 5–10% 20–30% 50–75% 100% N/A
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MOLECULAR TESTING OF FNA SPECIMENS Molecular pathology analysis of FNAB specimens is an exciting area at the forefront of thyroid nodule analysis, and it may one day obviate the need for any diagnostic thyroidectomy. Histologic analysis of resected thyroid tissue has already shown BRAF mutation in papillary thyroid cancer to correlate with poor prognostic factors such as extrathyroidal extension, tall cell morphology, lymphovascular invasion, and lymph node metastasis. At our institution, molecular testing has been performed routinely on all indeterminate, suspicious, malignant, or inadequate FNAB specimens since early 2007. We are finding that positive results for BRAF mutation, RAS mutation, and RET/PTC and PAX8-PPARγ rearrangements are highly predictive of both the presence and the histologic type of thyroid cancer at thyroidectomy. This is particularly true with FNAB testing for BRAFV600E, which was recently shown by several groups to correlate strongly with the presence of papillary thyroid cancer; our recent prospective evaluation of BRAF in FNAB specimens yielded sensitivity and specificity rates of 70% and 100%, respectively. We have also observed that RAS point mutations correlate with the presence of thyroid cancer in about 85% of cases. Although extensive discussion of the available data with patients is required, we consider BRAF- or RAS-positive FNAB results to prompt a recommendation for initial total thyroidectomy.
MANAGEMENT OF A BENIGN THYROID NODULE The treatment of benign hyperfunctioning nodules is addressed in the hyperthyroidism chapter. In the euthyroid or hypothyroid patient, the optimal management of an asymptomatic, cytologically benign thyroid nodule (and one that is negative for molecular markers) is not yet clear, largely because the natural history of solitary thyroid nodules has been poorly understood. Because benign FNAB results have a 1–4% false negative rate, patients do require some serial followup to exclude missed malignancy. The ATA provides a level B recommendation that after benign FNAB, if a repeat ultrasound at 6–18 months shows no interval enlargement, the subsequent interval to repeat followup may be longer
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(e.g. every 3–5 years). A nodule that is increasing in size on serial imaging or acquires suspicious sonographic characteristics should undergo repeat FNAB and/or diagnostic resection, but there is yet no consensus as to what degree of nodule growth matters. The ATA guidelines propose a 20% increase in diameter with a minimum increase in ≥2 dimensions of at least 2 mm or no more than a 50% change in nodule volume as reasonable definitions of nodule growth. There is no evidence that levothyroxine suppression of TSH is effective at sustainably reducing nodule size in iodine-sufficient regions of the world and it is therefore not currently recommended for the treatment of benign thyroid nodules. Recent prospective evidence suggests that for thyroid nodules >4 cm, benign FNAB results are associated with an unacceptably high false negative rate of up to 13%, missing clinically significant thyroid cancer in 13% of such patients. For large thyroid masses >4 cm the false negative rate is as high as 50% when follicular and Hürthle cell neoplasms are included in the analysis. Thus, diagnostic lobectomy, despite apparently benign cytology results, is increasingly being recommended by several institutions for thyroid nodules >4 cm in size. FNAB should still be pursued for nodules >4 cm, because results positive for thyroid cancer will indicate an initial total thyroidectomy.
MANAGEMENT OF THYROID CYSTS Thyroid cysts are common findings on cervical ultrasound. FNAB should be pursued for symptomatic cysts and any cyst with a solid component to confirm that they are cytologically benign. For complex cysts , ultrasound guidance for FNAB is crucial for ensuring that cellular material and not just cystic fluid is included in the specimen. Only the minority of simple cysts will resolve spontaneously, and thus these lesions should be serially monitored with ultrasound. Most clinicians will reaspirate a cyst up to three times, but after that surgery is generally recommended for any reaccumulation of fluid. Alternatively, percutaneous ethanol injection has up to an 85% success rate for cyst obliteration, but the patient must be aware of the associated potential complications, including bleeding, local pain, transient recurrent laryngeal nerve injury, and hypotension.
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SELECTED REFERENCES American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract 2006;12:63–102. Baloch ZW, LiVolsi VA, Asa SL, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36:425–437. Cooper DS, Doherty GM, Haugen BR, et al. The American Thyroid Association Guidelines Taskforce. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006;16:109–142. Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin Endocrinol Metab 2008;22(6):901–911. Hegedus L. The thyroid nodule. New Engl J Med 2004;351:1764–1771. McCoy KL, Jabbour N, Ogilvie JB, et al. The incidence of cancer and rate of false-negative cytology in thyroid nodules greater than or equal to 4 cm in size. Surgery 2007;142(6):837–844. NCCN Clinical Practice Guidelines in Oncology™ Thyroid Carcinoma (v.1.2009). © 2009 National Comprehensive Cancer Network, Inc. Available at NCCN.org. Accessed August 29, 2009. Nikiforov YE, Steward DL, Robinson-Smith TM, et al. Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab 2009;94(6):2092–2098. Pinchot SN, Al-Wagih H, Schaefer S, et al. Accuracy of fine-needle aspiration biopsy for predicting neoplasm or carcinoma in thyroid nodules 4 cm or larger. Arch Surg 2009;144(7):649–655. Yip L, Nikiforova MN, Carty SE, et al. Optimizing surgical treatment of papillary thyroid carcinoma associated with BRAF mutation. Surgery 2009;146: 1215–1223.
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Chapter I.B.2: Management of Papillary Thyroid Cancer Dina M. Elaraj, MD and Cord Sturgeon, MD
GLOBAL TREATMENT STRATEGY The global treatment strategy for papillary thyroid cancer (PTC) can be divided into four chief components: 1. Surgical extirpation of the primary tumor and any multifocal or extracapsular disease including nodal metastases; 2. Selective use of radioiodine ablation of the thyroid remnant +/− occult micrometastatic disease; 3. Suppression of the endogenous release of thyroid-stimulating hormone (TSH) through the administration of supraphysiologic doses of levothyroxine; 4. Longitudinal surveillance and treatment for cancer persistence or recurrence.
CONTROVERSIES IN SURGICAL MANAGEMENT There is general agreement that total or near-total thyroidectomy is the optimal surgical strategy for high-risk PTC patients. For years there was debate over the proper extent of surgery for small, low-risk tumors. Most clinicians now agree that total or near-total thyroidectomy is the proper initial operation for PTC ≥1 cm. Utilization of total or near-total thyroidectomy for PTC ≥1 cm has steadily risen in the United States over the past three decades and, since 1993, has plateaued at approximately 90%. Most clinicians also perform total or near-total thyroidectomy for PTC <1 cm, though this can still be considered a controversial area. 49
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Proponents of total or near-total thyroidectomy cite the following data in favor of more extensive surgery: (1) In the hands of experienced surgeons, thyroidectomy has a less than 2% rate of permanent hypoparathyroidism or recurrent laryngeal nerve (RLN) injury; (2) papillary cancer has been found to be multifocal in up to 80% of cases and bilateral in approximately 60% of cases when thorough pathological examination is performed; (3) bilobar resection obviates the need for reoperative neck surgery to remove the opposite lobe; (4) radioiodine administration following hemithyroidectomy is usually ineffective at simultaneously ablating both the residual normal tissue and thyroid cancer; furthermore, radioiodine is most effective for ablation of microscopic disease when the thyroid remnant is small; (5) the tumor marker, thyroglobulin (Tg), is most sensitive when all normal thyroid tissue has been resected and ablated; (6) radioiodine whole body scanning is a more sensitive modality for detecting residual or recurrent PTC after resection and ablation of normal thyroid tissue; (7) more extensive thyroidectomy is associated with an improvement in the recurrence rate and mortality from PTC. Proponents of hemithyroidectomy cite the following arguments to support limited resection in low-risk PTC patients: (1) There are no randomized prospective trials on the extent of surgery for PTC; (2) most low-risk cancers have an excellent prognosis regardless of the extent of thyroidectomy; (3) complications increase with the extent of surgery, and most thyroid operations in the United States are performed by nonexperts or low-volume thyroid surgeons who might have higher complication rates; (4) radioiodine ablation may not have a role in low-risk patients; (5) it is not known if multicentric or bilateral subcentimeter cancers are clinically relevant; (6) some patients will not or cannot comply with lifelong thyroid hormone replacement. The most actively debated controversy in the surgical management of PTC is the extent of nodal resection at the time of thyroidectomy. Some experts promote routine or prophylactic central neck (level VI) dissection for all patients with PTC. Proponents of this strategy cite the following arguments: (1) 20–90% of patients with PTC will have cervical nodal metastases (often micrometastases) at the time of initial cancer diagnosis; (2) cervical nodes harboring micrometastases will often
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appear normal on visual inspection; (3) some studies have suggested that bilateral central neck dissection is associated with reduced local recurrence and increased survival compared to historical controls, Opponents of this strategy argue that (1) prophylactic neck dissection has not consistently been shown to reduce mortality or local recurrence; (2) central neck dissection may be associated with an increased risk of surgical morbidity; (3) there may be no significant clinical relevance to occult micrometastases; (4) micrometastatic disease may be effectively treated with radioiodine. Further study will be required to effectively address these ongoing controversies in the surgical management of PTC.
MANAGEMENT OF NODAL METASTASES Overview The nomenclature to describe the cervical lymph node compartments has been standardized by the American Head and Neck Society and the American Academy of Otolaryngology–Head and Neck Surgery. These compartments are called “levels” and are formally designated by Roman numerals and occasionally subdivided into two regions (A and B): • •
•
•
Submental (level IA) and submandibular (level IB) triangle nodes Lateral neck (levels II, III, and IV) nodes — bounded by the skull base (superiorly), clavicle (inferiorly), posterior border of the sternocleidomastoid muscle (laterally), and the lateral border of the sternohyoid muscle (medially) Upper jugular nodes (level II) from skull base to hyoid bone IIA (anterior) and IIB (posterior) to the spinal accessory nerve Middle jugular nodes (level III) from hyoid bone to cricoid cartilage Lower jugular nodes (level IV) from cricoid cartilage to clavicle Posterior triangle (level V) nodes — bounded by the anterior border of the trapezius muscle (laterally), posterior border of the sternocleidomastoid muscle (medially), and clavicle (inferiorly) Central neck (level VI) nodes — bounded by the hyoid bone (superiorly), suprasternal notch (inferiorly), and common carotid arteries (laterally)
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Superior mediastinal (level VII) nodes — bounded by the suprasternal notch (superiorly) and brachiocephalic vessels (inferiorly).
Nodal metastases from papillary thyroid cancer are most commonly found in the nodal basins of the central and lateral neck. Practically speaking, the superior mediastinal lymph nodes can be considered an extension of the central neck. Metastases to the submental, submandibular, or posterior triangle compartments are rare. Assessment for Nodal Metastases Nodal metastases from papillary thyroid cancer are common, particularly in young patients, although their clinical significance is controversial. Metastases usually occur in a stepwise fashion, first involving lymph nodes of the ipsilateral central neck, and then lymph nodes of the ipsilateral lateral neck, followed by contralateral metastases. Skip metastases are unusual but can occur. Assessment for nodal metastases should begin with physical exam and preoperative cervical ultrasound. Ultrasound has high sensitivity and specificity for the detection of nodal metastases. It is less sensitive for evaluation of the central neck, since the lymph nodes may be obscured by their depth, or their proximity to the thyroid gland, trachea, or esophagus. Suspicious ultrasound characteristics include: • • • • • •
Round (vs. oval) shape Hypoechoic echotexture Hypervascularity Loss of hilar architecture (a fatty hilum is indicative of a benign lymph node) Hyperechoic punctations or microcalcifications Cystic appearance
Suspicious-appearing lymph nodes should be interrogated by ultrasoundguided fine needle aspiration (FNA) biopsy if the results will change the operative plan. Sending the aspirate for a thyroglobulin level may also increase the sensitivity and specificity of the test.
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Management of Nodal Disease Biopsy-proven nodal metastases should be managed by therapeutic compartment-oriented lymph node dissection. “Berry-picking” should not be done, since this leaves lymph nodes behind that are at risk for developing recurrent disease, which would then be more difficult to remove from a reoperative field. Central neck dissection requires removal of the node-bearing fibrofatty tissue within the boundaries of the central neck. This involves skeletonizing the recurrent laryngeal nerve along its entire cervical course, and carefully identifying the parathyroid glands and preserving their blood supply. The lower parathyroid gland is frequently devascularized during this procedure and usually requires autotransplantation. Frozen section analysis to confirm parathyroid tissue and exclude malignancy is prudent prior to autotransplantation. Modified radical neck dissection (also known as functional or lateral neck dissection) entails resection of the fibrofatty tissue within the boundaries of the lateral neck compartments. Practically speaking, this usually involves dissection of levels IV, III, and most of level IIA. The following nerves are potentially at risk during a lateral neck dissection: spinal accessory, phrenic, vagus, cervical sensory, cervical sympathetics, marginal mandibular branch of the facial, greater auricular, hypoglossal, and brachial plexus. Chyle fistula is a potentially lethal complication which can occur from injury to the thoracic duct on either side of the neck. If the internal jugular vein is invaded by PTC unilaterally, it should be resected.
Practical Advice •
•
The functional status of the recurrent laryngeal nerve and parathyroid glands should always be taken into consideration in the management of the central and lateral neck nodal basins. Central neck dissection and modified radical neck dissection are technically challenging procedures that should be performed only when there is known benefit to the procedure and by surgeons with substantial experience in the safe performance of the procedure.
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If metastatic disease is found in the ipsilateral lateral neck preoperatively, the minimal required operation is a near-total thyroidectomy with ipsilateral central neck dissection and ipsilateral modified radical neck dissection. If metastatic disease is found preoperatively in the lateral neck bilaterally, the proper operation is a near-total thyroidectomy, bilateral central neck dissection, and bilateral modified radical neck dissection. If intraoperative clinical evaluation of the central neck reveals bulky lymphadenopathy, especially ipsilateral to the primary tumor, a formal central neck dissection should be performed. If frozen section confirms metastatic lymphadenopathy in the central neck, formal dissection of the central neck compartment should be performed.
RADIOACTIVE IODINE Overview Radioactive iodine remnant ablation is an adjuvant treatment for selected patients with PTC. The isotope used for ablation is I-131, which is administered as sodium iodide in an oral form and has a half-life of eight days. It is usually administered 1–3 months after total or near-total thyroidectomy and appropriate nodal clearance, and its purpose is to destroy any remnant thyroid tissue as well as to treat occult or unresectable metastatic disease. In the United States, most patients with well-differentiated PTC will receive adjuvant radioiodine ablation. A controversy in the use of radioactive iodine ablation is that while some studies have shown a reduction in locoregional recurrences and distant metastases, other studies have shown no benefit. The benefit in low-risk patients, in particular, is unclear. The 2009 American Thyroid Association (ATA) consensus guidelines recommend remnant ablation or selective use of radioactive iodine for all but the lowest-risk patients (those with unifocal or multifocal, <1 cm tumors that are well-differentiated, confined to the thyroid gland, and without any lymph node or distant metastases). The 2011 National Comprehensive Cancer Network (NCCN) guidelines recommend a TSHstimulated whole body radioiodine scan for all patients 2–12 weeks
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postthyroidectomy, but if all gross disease has been removed, radioiodine ablation is unnecessary if the stimulated Tg is <1 ng/ml (with negative antiTg antibodies) and the radioiodine scan is negative. In addition to the controversy regarding the benefit of radioactive iodine ablation, some studies have shown an increase in the risk of developing secondary malignancies after its administration, particularly leukemia and other hematologic malignancies. This risk is thought to be dose-related. Consensus guidelines recommend a dose of 30–100 mCi for those patients with low-risk papillary thyroid cancer, with higher doses (100–200 mCi) recommended if residual microscopic disease is suspected or documented, or if a more aggressive histologic type (i.e. tall cell, columnar cell, or insular variant) is present. Preparation for Treatment In preparation for radioiodine ablation, most clinicians recommend a lowiodine diet for 1–2 weeks before I-131 administration. Foods that should be avoided include: • • • • • • •
Foods that contain iodized salt or sea salt Dairy products (including chocolate) Eggs and egg-containing products Seafood Soybeans and soybean-containing products Iodine-containing vitamins Foods containing red dye #3
Before I-131 administration, the TSH concentration should be >30 mU/l in order to stimulate intracellular uptake of the isotope. This can be achieved by either discontinuing levothyroxine for 4–6 weeks (also called “thyroxine withdrawal”) or administering recombinant human TSH (rhTSH; also called “rhTSH stimulation”). rhTSH stimulation is performed by administering 0.9 mg of rhTSH intramuscularly on two consecutive days, followed by radioactive iodine treatment on the third day. A whole body scan should be obtained in approximately five days to evaluate for percent uptake and metastatic disease. It should be noted that the
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United States Food and Drug Administration (FDA) has approved rhTSH only for thyroid remnant ablation in patients who have undergone neartotal thyroidectomy and who do not have evidence of metastatic disease. The Tg and anti-Tg antibody concentrations should be measured when the TSH is maximal (usually 72 hours after rhTSH administration). Side Effects and Precautions Women cannot be pregnant at the time of ablation, nor should they plan to become pregnant for 6–12 months following treatment. A pregnancy test is required for all women of childbearing age before I-131 administration. Men should observe paternity precautions for at least six months following treatment. After I-131 administration, radiation precautions are dictated by dose administered, institutional protocols, and state and federal law, and are beyond the scope of this chapter. Side effects are usually transient and dose-dependent, and include sialadenitis, xerostomia, changes in taste and/or smell, and conjunctivitis.
TSH SUPPRESSION TSH exerts a trophic effect upon thyrocytes and differentiated thyroid cancers of follicular cell origin. Both retrospective series and metaanalysis have shown that suppressing endogenous TSH secretion by administering supraphysiologic doses of levothyroxine is associated with greater disease-free and overall survival for patients with PTC. Oversuppression has been associated with an increased risk of atrial fibrillation and osteoporosis, and therefore the levothyroxine dose should be titrated to a relatively precise TSH response. A dose of 1 µg of levothyroxine per pound lean body weight per day is usually adequate for TSH suppression, and is a good initial dose for many healthy adults. Older patients and those with cardiac disease are usually started on a lower dose and carefully titrated. Because of the risk of developing osteoporosis associated with chronic TSH suppression, the NCCN guidelines recommend a daily intake of 1200 mg of calcium and 800 units of vitamin D. There are no precise data to guide the management of TSH levels, though, in general, levels are guided by patient risk categories.
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•
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High risk patients (those with incomplete tumor resection, macroscopic tumor invasion into adjacent structures, I-131 uptake outside the thyroid bed on a whole body scan, or distant metastases): Both the 2009 ATA guidelines and the 2011 NCCN guidelines recommend initial suppression of TSH to <0.1 mU/l. Low risk patients (those with no macroscopic residual disease at the time of thyroidectomy, no locoregional invasion, no vascular invasion, no aggressive histologic subtype, no I-131 uptake outside the thyroid bed on a whole body scan, and no distant metastases): Both the 2009 ATA guidelines and 2011 NCCN guidelines recommend initial suppression of TSH to or slightly below the lower limit of normal (0.1–0.5 mU/l). Patients with persistent PTC : The 2009 ATA guidelines recommend suppression of TSH <0.1 mU/l indefinitely.
For long-term management, the NCCN guidelines state that patients who have been disease-free for several years can probably have their TSH levels maintained within the reference range.
LONG-TERM FOLLOWUP The long-term followup of patients with well-differentiated PTC is designed to provide accurate surveillance for recurrent disease, and consequently allow more timely intervention. Patients with more aggressive tumors or who are at a higher risk of recurrence should be monitored more aggressively. Initial risk stratification is primarily achieved by tumor/node/metastasis (TNM) staging and consideration of histologic information such as margin status and the presence of an aggressive histologic subtype. Surveillance is done via a combination of blood tests and radiographic imaging. Tg is the most sensitive tumor marker for differentiated thyroid cancers, but measurement or interpretation can be confounded by the presence of anti-Tg antibodies, the serum TSH concentration, or the presence of nonablated thyroid tissue. Cervical ultrasound is a highly sensitive test for detecting metastatic lymphadenopathy. Whole body radioiodine scanning is very sensitive for the detection of iodine-avid disease, and is
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probably the best test for pulmonary or bony metastatic disease. Crosssectional imaging modalities also have a role in selected patients. Fluorodeoxyglucose positron emission tomography (FDG-PET) is often negative in well-differentiated PTC. However, in less well-differentiated cases, radioiodine scanning can be negative despite a relatively large tumor burden, and for these patients PET imaging may demonstrate the site of metastatic disease. When local recurrence or metastasis is suspected, an evaluation for resectability should be performed. The following points cover the key issues in surveillance: • • • •
• • •
AJCC/UICC staging and stratification into a risk category is recommended for all patients with PTC. Perform physical exam and measure serum Tg, anti-Tg antibodies, and TSH every 6–12 months. Obtain cervical ultrasound to evaluate the central and lateral compartments at 6 and 12 months and then annually for at least 3–5 years. For low-risk patients who have undergone thyroidectomy and RAI ablation, and have an undetectable unstimulated Tg and negative cervical ultrasound, stimulated Tg should be measured 12 months after the initial RAI ablation. If, in the above scenario, the stimulated Tg is undetectable, a diagnostic whole body radioiodine scan is unnecessary. In high- or intermediate-risk patients, a whole body radioiodine scan should be performed at 6–12 months after the initial RAI ablation. In patients with noniodine-avid disease and a stimulated Tg ≥10 ng/ml, a FDG-PET scan should be performed to attempt to localize the recurrent disease.
MANAGEMENT OF RECURRENT DISEASE The general strategy for management of recurrent disease is as follows: • • •
Maintenance of TSH suppression Surgical resection, if possible Radioiodine ablation, if the cancer remains iodine-avid
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External beam radiation Watchful waiting with TSH suppression / best supportive care Cytotoxic chemotherapy or experimental protocols
Locoregional Recurrence Local or nodal recurrence is ideally treated surgically. Radioiodine should not be expected to ablate bulky nodal disease. Adjuvant radioiodine is usually given, however, for iodine-avid disease following surgical resection. External beam radiation should be considered if the recurrent disease is unresectable and/or not radioiodine-avid.
Pulmonary Metastases Radioiodine-avid pulmonary metastases are usually treated with radioiodine ablation. Pulmonary pneumonitis and fibrosis can develop following high-dose radioactive iodine treatment, and can limit further treatment options. For patients with diffuse pulmonary radioiodine uptake, the 2009 ATA guidelines recommend dosimetry studies in order to limit whole body retention at 48 h to 80 mCi and limit 200 cGy to the red bone marrow. Surgical resection can be considered for limited macronodular metastases or for pulmonary metastases that are not radioiodine-avid. Endobronchial laser ablation and external beam radiation may also be employed in selected cases.
Bone Metastases Bone metastases may be treated with resection, radioiodine, or external beam radiation, depending on location, symptoms, and iodine avidity. Complete surgical resection of isolated metastasis has been associated with improved survival, as has radioiodine ablation of iodine-avid bone lesions. For unresectable or nonradioiodine-avid lesions, treatment decisions are made based on risk and consequences of pathologic fracture. External beam radiotherapy is used in conjunction with corticosteroids in an attempt to minimize the probability of complications from acute tumor
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expansion. Bisphosphonate therapy and embolization may also be used for painful lesions. Central Nervous System Metastases Corticosteroids are usually started at the time of diagnosis. Because most thyroid cancer metastases are slow-growing and long-term survival has been reported following surgical resection of isolated brain metastasis, resection is the preferred treatment. Stereotactic radiosurgery is another option that has shown promise, and may be preferred when conventional resection would lead to unacceptable morbidity due to the location or number of metastases. Other forms of external beam radiotherapy, such as whole brain or spine irradiation, may be considered for multiple metastases. Radioiodine may also be beneficial for iodine-avid metastases, but should be used with rhTSH stimulation and steroid prophylaxis to minimize swelling and tumor growth at the time of treatment. The results of radioiodine have been disappointing. Chemotherapy has not been a recommended treatment option. Other Sites of Metastatic Disease In general, surgical resection is favored for enlarging or symptomatic resectable metastases. Radioiodine is usually given if the tumor remains iodine-avid and the patient has not met the exposure limits. Dosimetry is recommended to achieve the maximal tumor dose. External beam radiotherapy is usually chosen for unresectable disease that is not responsive to radioiodine. Although cytotoxic chemotherapy has been found to have a minimal effect at best, this line of treatment might be considered, especially when associated with an ongoing clinical trial. Although not FDA-approved for treatment of thyroid cancer, the 2011 NCCN guidelines state that small molecule kinase inhibitors (such as sorafenib or sunitinib) can be considered if clinical trials are not available or appropriate.
SELECTED REFERENCES 1.
Bilimoria KY, Bentrem DJ, Ko CY, et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg 2007;246(3):375–381.
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3.
4.
5.
6.
7.
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Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association Management Guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19(11):1167–1214. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994; 97:418–428. McGriff NJ, Csako G, Gourgiotis L, et al. Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer. Ann Med 2002;34:554–564. NCCN Clinical Practice Guidelines in Oncology™. Thyroid Carcinoma (Version 2.2011). © 2011 National Comprehensive Cancer Network, Inc. Available at www.NCCN.org. Accessed 10 April 2011. To view the most recent and complete version of the NCCN Guidelines, go to www.NCCN.org Robbins KT, Clayman G, Levine PA, et al. Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology–Head and Neck Surgery. Arch Otolaryngol Head Neck Surg 2002;128(7):751–758. Sawka AM, Thephamongkhol K, Brouwers M, et al. Clinical review 170: a systematic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer. J Clin Endocrinol Metab 2004;89(8):3668–3676.
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Chapter I.B.3: Management of Medullary Thyroid Cancer Scott N. Pinchot, MD and Rebecca S. Sippel, MD, FACS
INTRODUCTION Medullary carcinomas of the thyroid are neuroendocrine neoplasms derived from the parafollicular cells, or C cells, of the thyroid and account for nearly 5–10% of thyroid malignancies. In nearly all cases of medullary thyroid cancer (MTC), the C cells secrete calcitonin (Ct), a specific and highly sensitive biomarker whose measurement plays an important role in the diagnosis and postoperative followup of patients. Less common, MTC cells elaborate other polypeptide hormones, including vasoactive intestinal peptide (VIP), serotonin, somatostatin, and carcinoembryonic antigen (CEA), the last of which has been shown to be associated with a worse prognosis. The majority of MTCs are sporadic, but up to 25% of MTC cases result from a germline-activating mutation in the REarranged-duringTransfection (RET) proto-oncogene. Hereditary MTCs occur in the setting of multiple endocrine neoplasia (MEN) syndrome type 2 (2A or 2B) or as familial MTC (FMTC) without an associated MEN syndrome. In sporadic MTC, patients most commonly present in the fifth or sixth decade with a palpable cervical lymph node or a solitary thyroid nodule. Fine needle aspiration (FNA) biopsy of the mass and the presence of an elevated serum Ct are diagnostic of MTC. Unlike sporadic MTC, most patients with hereditary disease are identified by genetic testing of at-risk family members for the germline mutation of the RET gene. As such, hereditary MTC tends to present at an earlier age than sporadic disease and is typically multifocal and bilateral (Table 1).
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Table 1 Clinical syndromes of sporadic and hereditary medullary thyroid carcinoma. Sporadic MTC Associated mutation Disease distribution C cell hyperplasia (>6 C cells/follicle or >50 cells/lpf Age of onset Common presentation Radioiodine scanning Lymph node metastases Extranodal metastatic sites
Familial MTC
Somatic RET mutation (codon met918thr most common) Unifocal No
Germline RET mutation
Fourth Decade Isolated thyroid nodule
<20 years old Positive family history of MTC or PHEO Nonspecific Common
“Cold” thyroid nodule Common (80% of palpable lesions or lesions >1 cm) Liver, bones, lungs
Multifocal and bilateral Yes
Liver, bones, lungs
MANAGEMENT OF SPORADIC MTC Characteristics Sporadic MTC is most commonly not associated with germline RET proto-oncogene mutations, C cell hyperplasia, or a family history suggestive of MTC or pheochromocytoma. Although largely undefined, it is thought to arise de novo as a result of one or more somatic mutations of the RET proto-oncogene in a single parafollicular cell. The most commonly identified mutation is codon met918thr, which is associated with a very aggressive form of sporadic MTC and a significant reduction in survival when compared to other mutations. Metastases to neck and mediastinal lymph nodes occur frequently and may be inapparent to the surgeon and pathologist unless each node removed is carefully studied. Common patterns of lymph node metastases are to the ipsilateral nodes in levels II–IV of the neck, although contralateral nodal metastases may occur in up to 40% of patients with palpable primary tumors.
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Surgical Treatment Currently, the only possible curative treatment for MTC is complete surgical resection when the disease is confined to the neck. Patients with clinically evident sporadic MTC are best treated with a minimum of total thyroidectomy and bilateral central (levels VI and VII) neck dissection. Ipsilateral lateral neck dissection (levels II–V) should be considered if the primary tumor is >1 cm in diameter, if there is evidence of positive nodal disease in the central neck, or if suspicious lymphadenopathy is seen on preoperative ultrasound. Contralateral lateral neck dissection should be reserved for patients with bilateral primary tumors or extensive lateral adenopathy on the side of the primary tumor (Fig. 1).
Fig. 1 Treatment algorithm for clinically apparent medullary thyroid cancer. From: Sippel RS, Kunnimalaiyaan M, Chen H. Current management of medullary Thyroid cancer. Oncologist 2008;13:539–547.
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Central neck nodal disease is present in nearly 80% of patients with palpable tumors, and an adequate central neck dissection offers a cure rate that is higher than that seen with thyroidectomy alone. Caveats regarding the adequacy of central neck dissection include: • • • •
Complete clearance of all lymph nodes and fibrofatty tissue from the level VI compartment Dissection and removal of level VII lymph nodes in patients with significant level VI disease or locally advanced tumors Careful dissection of the recurrent laryngeal nerve along its entire length, especially in level VI lymphadenectomy Meticulous dissection of the parathyroid glands with potential need for sternocleidomastoid or forearm autotransplantation
MANAGEMENT OF HEREDITARY MTC Characteristics Hereditary MTC manifests as part of the MEN2 syndrome, which is transmitted as an autosomal dominant trait. As such, the hereditary form commonly occurs in individuals younger than 20 years of age. Frequently, a positive family history suggestive of MTC or pheochromocytoma is also present. MEN type 2A (MEN2A) is the most common form of hereditary MTC, accounting for nearly 80% of MEN2 cases, and is characterized by multicentric MTC in 90% of gene carriers, unilateral or bilateral pheochromocytomas in 50% of gene carriers, and primary hyperparathyroidism in 15% of carriers. There are three variants of MEN2A: • • •
MEN2A + Hirschprung disease MEN2A + cutaneous lichen amyloidosis MEN2A + FMTC (least aggressive variant)
MEN type 2B (MEN2B) makes up approximately 20% of cases of MEN2 and is characterized by MTC in 100% of gene carriers; pheochromocytomas in 50% of carriers; mucosal ganglioneuromas of the lips, tongue, eyelids, and gastrointestinal tract in more than 90% of carriers;
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and a marphanoid body habitus in nearly all gene carriers. In this kindred, MTC develops at a very young age (infancy) and has a very aggressive course. Therefore, early identification of MTC in MEN2B is essential because metastases have been described in the first year of life. Surgical Treatment The appropriate surgical procedure for a patient with localized hereditary MTC presenting as a clinically apparent thyroid nodule is a total thyroidectomy with central (levels VI and VII) lymph node dissection. Lateral (levels II–V) lymph node dissections should be added to the therapeutic regimen in patients with documented local metastatic disease. Prophylactic Surgery (Fig. 2) Because the penetrance of hereditary MTC is nearly 100%, all individual carriers of a RET mutation should be medically evaluated and treated for MTC. While there is a clear age-related progression from C cell hyperplasia to MTC and ultimately to nodal spread, the age of MTC onset varies between MEN2A, MEN2B, and FMTC kindreds. Therefore, when determining the timing of prophylactic surgery to remove an at-risk thyroid, it is essential that the surgeon balance the risk of clinically significant disease with the risks of surgical intervention. Characteristics and recommendations for the youngest MEN2A, MEN2B, and FMTC patients vary and are summarized as follows: MEN2A or FMTC • •
The age of onset is 3–5 years. More extensive disease is suggested by:
•
Clinical or radiological evidence of lymphadenopathy Thyroid nodules ≥5 mm in size at any age Serum basal serum Ct >40 pg/ml when >6 months old
Patients without evidence of extensive disease should undergo prophylactic thyroidectomy within the first 3–5 years but should not undergo prophylactic level VI compartmental dissection.
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Fig. 2
Initial diagnosis and therapy of preclinical hereditary disease.
MEN2B • • • •
•
The age of onset is <1 year of age. Genetic testing should be done as soon as possible after birth, as foci of MTC may be present in infancy. More extensive disease is suggested by factors similar to those above. Patients without evidence of extensive disease should undergo prophylactic thyroidectomy as soon as possible — within the first year of life, if possible. Prophylactic level VI compartmental dissection may not be necessary in MEN2B patients unless nodal disease is suspected.
Thyroid and parathyroid surgery is associated with a higher morbidity in children than in adults, clearly emphasizing the importance that the surgeon operating on infants be experienced and familiar with the recurrent
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laryngeal nerve and parathyroid gland management in children. Such procedures should therefore be reserved for high volume endocrine surgical centers.
GENETIC BASIS OF HEREDITARY MTC Genetic Alterations A germline point mutation in the RET proto-oncogene on chromosome 10q11.2 is responsible for the uncontrolled growth of the C cells. The encoded RET protein, a receptor tyrosine kinase expressed in neuralcrest-derived cells (i.e. thyroid parafollicular cells, parathyroid cells, adrenal medulla chromaffin cells, and enteric autonomic plexuses), mediates downstream pathways of cell survival and mitogenesis. Because RET is a proto-oncogene, a single activating mutation of one allele is sufficient to lead to constitutive activation of the receptor and cause the autosomal dominant inherited neoplastic transformation seen in MEN2 syndrome and FMTC. The first germline mutation of the RET gene was identified in patients in 1993. The most common mutation, occurring in over 85% of all mutations associated with MEN2A, affects codon 634. A single mutation, a codon 634 cysteine substituted for an arginine (TGC to CGC), accounts for 50% of all MEN2A mutations. In approximately 95% of patients with MEN2B, a single mutation converting a methionine into a threonine at codon 918 (exon 16) has been identified. This mutation is thought to cause receptor autophosphorylation and activation, and it has been implicated in altered signaling pathways responsible for the more aggressive MTC phenotypes. Similarly, other rarer noncysteine mutations located within the intracellular catalytic domain of RET have been described, giving rise to FMTC and MEN 2B (Table 2). Genetic Testing The importance of genetic testing for germline mutations cannot be underestimated, since approximately 25% of patients with MTC have a germline point mutation in the RET proto-oncogene. Advances in the understanding
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Table 2
Frequency of RET mutations associated with familial RET syndromes.
Exon
Codon
Amino acid (wild type → mutant)
Phenotype
Frequency (%), MEN2 cases
8
532, 533, 534 533
Ins-Glu-Glu-Cys Gly-Cys
FMTC FMTC
Rare
10
609
Cys-Arg Cys-Gly Cys-Tyr Cys-Ser Cys-Arg Cys-Tyr Cys-Phe Cys-Trp Cys-Ser Cys-Arg Cys-Gly Cys-Tyr Cys-Ser Cys-Phe Cys-Ser Cys-Arg Cys-Gly Cys-Tyr Cys-Trp
MEN2A/FMTC
0–1
MEN2A/FMTC
2–3
MEN2A/FMTC
3–5
MEN2A/FMTC
6–8
MEN2A/FMTC
0–1
MEN2A
80–90
MEN2A/FMTC MEN2A/FMTC
80–90
611
618
620
11
630
Cys-Tyr Cys-Ser Cys-Phe 634 Cys-Ser Cys-Arg Cys-Gly Cys-Tyr Cys-Ser Cys-Phe Cys-Trp 635, 636, 637, 638 Ins-Thr-Ser-Cys-Ala 637, 638, 639 Ins-Cys-Arg-Thr 648 Val-Ile
MEN2A/FMTC MEN2A MEN2A
Rare
(Continued)
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Exon
Codon
71
(Continued )
Amino acid (wild type → mutant)
Phenotype
Frequency (%), MEN2 cases
13
768 790 791
Glu-Asp Leu-Phe Tyr-Phe
MEN2A/FMTC
Rare
14
804
Val-Met Val-Leu
MEN2A/FMTC
0–1
15
883 891
Ala-Phe Ser-Ala
MEN2B MEN2A/FMTC
Rare
16
918 922
Met-Thr Ser-Tyr
MEN2B MEN2B
3–5 Rare
of MTC molecular carcinogenesis have significant clinical implications and, as such, all patients with a diagnosis of MTC should undergo genetic testing. However, if a genetic test is desired, it is best done with the assistance and support of a certified genetic counselor. Once a patient is found to be positive for a RET mutation, they must be carefully counseled regarding the risks to additional family members. At-risk family members need to be identified and should undergo genetic testing, because patients who are identified as RET mutation carriers can be offered a prophylactic thyroidectomy and need to be screened for other associated conditions. Since the most common mutation is on exon 11 (codon 634) followed by exon 10, these exons should be sequenced and analyzed for the presence of any point mutation. When a patient with suspected familial disease still tests negative, then mutations on exons 13–16 and, less commonly, exons 12 and 8 should be considered. Importantly, if MEN2B is suspected based on clinical presentation, exon 16 should be considered first, as the majority of MEN2B patients (95%) have mutations in codon 918 on exon 16. If no mutations are identified despite a positive family history, it is preferable to sequence the complete gene, since the entire gene sequence is known.
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Timing of Surgery (Table 3) Among RET mutations, there is significant variation in the aggressiveness of the MTC that develops. This has led to the concept of “codon-directed” timing of surgery, in which the timing of prophylactic surgery is specified by the specific genotype. Several authors have proposed the stratification of the risk (highest versus intermediate versus low risk) based on the specific encountered RET mutations. Level 3 mutations (codons 883, 918, and 922) have the highest transforming activity and correlate strongly with the onset of MEN2 within the first years of life. Because of the high risk for malignancy at an early age, thyroidectomy is recommended within the first six months of life — preferably within the first month. Level 2 mutations (codons 611, 618, 620, and 634) are considered intermediate-risk among the RET mutations and the current recommendation is that patients undergo thyroidectomy before the age of five years. Level 1 RET mutations (codons 609, 768, 790, 791, 804, and 891) have been associated with a high risk of early MTC development, but represent the
Table 3 “Codon-directed” timing of surgery based on ret mutations associated with hereditary MTC. Risk level for MTC Level 3 (highest)
Level 2 (higher)
Level 1 (high)
Codon mutation 883 918 922 611 618 620 634 609 630 768 790 791 804 891
Age of prophylactic surgery Within the first 6 months of life (preferably in the first year) By age 5
By age 5–10
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lowest risk of the RET mutations. The biological behavior of MTC in patients with these mutations is variable, but generally MTC grows more slowly and develops at a later age than with the higher-risk mutations. There is no clear consensus regarding the optimal timing of thyroidectomy in this group of patients, although most surgeons recommend surgery before the age of 5–10 years. Importantly, the age of onset of MTC is not always constant and there are always exceptions to the rule. Therefore, many surgeons recommend prophylactic thyroidectomy in all patients with MEN2A by the age of five years whenever possible.
LONG-TERM FOLLOWUP Management of Patients with MTC at Thyroidectomy Patients with sporadic or familial disease confined to the thyroid gland, without nodal disease, have a very low risk for recurrence and rarely die from their disease. Thus, for patients with no evidence of residual disease after initial surgery based on radiographic and biochemical testing, longterm complete remission is a realistic goal. In patients who achieve a complete biochemical cure, defined as postoperative Ct “normalization,” followup should start 2–3 months postoperatively by obtaining new baseline serum Ct and CEA levels. Patients with undetectable serum Ct levels may then be followed annually with biochemical monitoring of serum Ct. In the setting of persistent MTC after appropriate initial surgical resection, the goals of followup are to prevent locoregional complications of residual disease and/or complications of metastatic disease. While early biochemical detection of progressive disease may reduce the likelihood of cervical or distant metastatic complications, it is unlikely that a complete remission will be attained (Fig. 3).
Management of Patients Without MTC at Thyroidectomy Prophylactic surgery removes the at-risk thyroid gland prior to its developing clinically significant disease. As such, the risk of developing persistent or recurrent disease after prophylactic thyroidectomy is very low. Measurement of annual basal serum Ct should be considered, while
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Fig. 3
Long-term followup of patients with MTC at thyroidectomy.
less frequent testing may be considered if there is no evidence of disease after 60 months of followup. Role of Stimulated Serum Calcitonin Testing Although MTCs secrete Ct, some patients with familial forms of MTC have been found to have normal plasma immunoreactive Ct (iCt) concentrations under basal conditions. Among the agents used to promote Ct secretion in stimulation tests have been calcium, glucagon, and pentagastrin (which contains the COOH-terminal tetrapeptide of gastrin). In several historical studies, pentagastrin administration produced higher peak iCt levels than did calcium infusion and glucagon administration. The test is performed as follows: Pentagastrin stimulation test Technique • •
Patients are studied between 8:00 am and 12:00 pm following an overnight fast Pentagastrin (0.5 µg/kg) is administered by a single rapid intravenous push
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Ten ml of venous blood is obtained in heparinized tubes at 0, 1–2, 5, and 10 min after pentagastrin injection The plasma is immediately separated by centrifugation at 4°C and then frozen Radioimmunoassay of Ct is performed.
Side effects • • • •
Sensation of pharyngeal and retrosternal tightening Epigastric fullness Emesis All symptoms are usually mild and transient, lasting only 45–90 s.
A rise in serum Ct after stimulation suggests residual or recurrent disease; however, with improvement in the functional sensitivity of newer Ct assays, those patients with abnormal testing only after stimulation demonstrate very low levels of disease which are unlikely to be seen on anatomic or functional imaging. Likewise, the added benefit of this information is minimal given the low rate of biochemical remission in patients with metastatic disease. Therefore, although controversial, followup stimulated serum Ct testing is not recommended for detection of low levels of residual disease despite undetectable basal Ct values. Management of CEA-Positive, Calcitonin-Negative Patients In the vast majority of patients with MTC, rising CEA levels accompanied by elevated serum Ct measurements are suggestive of progressive disease. Conversely, MTC tumor dedifferentiation has been shown to be associated with a decreased or stable level of Ct accompanied by an elevated or rising CEA level. Several laboratory factors may result in falsely low Ct levels or elevated CEA levels, making interpretation of the CEA-positive, Ct-negative patient challenging. False depression of serum calcitonin (Ct) •
“Hook effect”
If an extremely high antigen concentration is present, the capture and signal antibodies are saturated with the antigen, thus preventing
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a sandwich formation. When the liquid phase is discarded, most of the antigen is lost with the signal antibodies; thus, the antigen concentration measured is falsely low. Heterophilic antibodies (human antibodies that bind animal antibodies)
False elevation of serum carcinoembryonic antigen (CEA) • • • • • •
Cancers of the digestive system, lung, prostate, breast, and ovary Bronchogenic cyst Inflammatory bowel disease Chronic obstructive pulmonary disease Benign pulmonary disease Heterophilic antibodies
Therefore, although in most cases CEA and Ct are similar in MTC, primary and metastatic tumors from patients with invasive disease often demonstrate an inverse relationship between CEA and Ct staining such that the most aggressive disease may present with intense CEA staining but minimal Ct staining.
MANAGEMENT OF RECURRENT DISEASE Multifocal, and often multiorgan, metastases frequently develop early in the course of MTC. Therefore, the ideal goal for all MTC patients to be free of disease and without morbidity is difficult to achieve. More realistic aims of current MTC therapy are palliative and strategically prophylactic. The goals of managing patients with persistent or recurrent metastatic disease include: • • • •
Locoregional disease control Palliation of symptoms related to hormonal excess Palliation of distant metastasis-related symptoms (i.e. pain) Prevention of harm secondary to metastatic disease (i.e. fracture, bronchial obstruction, spinal cord compression)
Detection of persistent or recurrent disease at an early stage is facilitated by serum Ct and stimulated Ct levels.
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Neck Reoperation In the setting of an elevated postoperative Ct level, a careful metastatic evaluation must be performed prior to proceeding with operative intervention. When distant metastases are discovered, one must choose which lesions require therapy. Patients in whom surgical resection should be offered include: • • • • • •
Inadequate initial operation Locoregional disease only Tracheal or mediastinal invasion threatening to cause acute airway obstruction Impending or active central nervous compression Hormonal secretion limiting daily activities Impending or active fracture of weight-bearing bone
With adequate patient selection, neck reoperation has been shown to normalize serum Ct levels in nearly 30% of patients. Careful patient selection, recognition of metastatic disease, and thorough operative planning are the hallmarks of successful reoperative neck surgery. Chemotherapy, Radiotherapy, and Other Treatments for Distant Metastatic Disease Conventional chemotherapy has shown to have very limited efficacy in patients with MTC. Dacarbazine-based chemotherapeutic regimens have been associated with a reduction in tumor size in approximately 30% of patients treated with this agent; however, a complete remission has never been observed, and current chemotherapeutic strategies have been shown to exert no effect on survival rates. Similarly, radiotherapy is routinely used as an adjunctive, palliative treatment for extensive locoregional disease, mediastinal disease, or bony metastases. Strategies employing radiotherapy have been shown to effectively prevent and control complications associated with MTC activity in the neck and mediastinum but, like chemotherapeutic regimens, demonstrate no effect on improving survival time. Tyrosine kinase inhibitors are small molecules that compete with the adenosine-triphosphate-binding site of the catalytic domain of a tyrosine
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kinase. Several small-molecule tyrosine kinase inhibitors have been developed against RET and show promising results both in vitro and in vivo as emerging therapies for the treatment of MTC. These molecules include ZD6474 (vendetanib), SU11248 (sunitinib), BAY 43–9006 (sorafenib), CEP-751 and CEP-701, XL-880, XL-184, and RPI-1. Recently, studies have shown that sorafenib, a multikinase inhibitor of receptor tyrosine kinase, VEGFR, and BRAF kinase, inhibits proliferation of ATC cell lines and inhibits tumor angiogenesis via induction of endothelial apoptosis in an orthotopic anaplastic thyroid carcinoma xenograft model in nude mice. Similarly, the orally administered multitarget tyrosine kinase inhibitor, sunitinib, has been shown to be a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. Many of these agents which are earlier in the development pipeline are capable of inhibiting RET at subnanomolar concentrations and hold significant promise for the treatment and palliation of hereditary MTC.
SELECTED REFERENCES Jiménez C, Hu MI, Gagel RF. management of medullary thyroid carcinoma. Endocrinol Metab Clin N Am 2008;37:481–496. Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009;19(6):565–612. Sippel RS, Kunnimalaiyaan M, Chen H. Current management of medullary thyroid cancer. Oncologist 2008;13:539–547.
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Chapter I.B.4: Management of Follicular and Hürthle Cell Cancer Christopher R. McHenry, MD and Scott M. Wilhelm, MD
INTRODUCTION One of the major challenges in thyroid surgery is the management of a patient with a thyroid nodule and a fine needle aspiration (FNA) biopsy consistent with a follicular or Hürthle cell neoplasm. Approximately 20% of such patients will have a thyroid cancer: a follicular, classic papillary or follicular variant of papillary cancer in patients with a follicular neoplasm or a Hürthle cell cancer in patients with a Hürthle cell neoplasm. FNA cytology is unable to distinguish between a benign and a malignant follicular or Hürthle cell neoplasm. In the absence of lymph node or systemic metastases, it is the presence of capsular or vascular invasion that is necessary for establishing a diagnosis of malignant disease in patients with a follicular or Hürthle cell neoplasm. As a result, a FNA biopsy consistent with the follicular or Hürthle cell neoplasm warrants diagnostic thyroid lobectomy and isthmusectomy. A patient with a follicular or Hürthle cell neoplasm, without a prior history of head or neck radiation or involvement of the contralateral lobe of the thyroid gland, should undergo thyroid lobectomy and isthmusectomy. Frozen section examination is not of value in distinguishing a follicular or Hürthle cell adenoma from a follicular or Hürthle cell carcinoma, because of its inaccuracy in the definitive determination of capsular or vascular invasion. The sensitivity, specificity, and accuracy of frozen section examination are similar to FNA biopsy, and frozen section examination rarely provides more information than FNA biopsy. In fact, a diagnosis of follicular or Hürthle cell neoplasm is usually what is rendered
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on frozen section examination and a definitive diagnosis is deferred until all of the permanent sections have been reviewed. If the final pathology reveals follicular or Hürthle cell carcinoma, a completion thyroidectomy is recommended. Patients with a follicular or Hürthle cell neoplasm and nodular disease ≥1 cm involving the contralateral lobe of the thyroid gland or a prior history of head or neck irradiation are treated with a definitive total thyroidectomy at the initial operation. Follicular cancer accounts for approximately 11% of all cases of thyroid malignancy in the United States and 25–40% of cases in iodine-deficient areas. The incidence of follicular carcinoma is decreasing in the United States — a phenomenon that is related to the increased recognition and more accurate diagnosis of the follicular variant of papillary thyroid cancer and the eradication of iodine deficiency. Follicular cancer may be classified into minimally invasive and invasive variants. Minimally invasive follicular cancer is defined as an encapsulated follicular cancer with a single focus of capsular invasion. Invasive follicular cancer refers to a follicular cancer with angioinvasion or extensive tumor invasion beyond the tumor capsule, with diffuse infiltration of the affected lobe of the thyroid gland. Follicular cancer, in contrast to papillary thyroid cancer, has a propensity for hematogenous spread and is less likely to involve the regional lymph nodes. At the time of diagnosis, systemic metastases are present in 10–15% and lymph node metastases in less than 10% of patients with follicular cancer. Hürthle cell carcinoma (HCC) is the least common of the welldifferentiated thyroid cancers, making up only about 4% of all cases of thyroid malignancy. Although HCC is classified by the World Health Organization as a subtype of follicular carcinoma, it is a distinct clinical entity. It is more often multifocal and bilateral and it more frequently metastasizes to regional lymph nodes than follicular carcinoma. Of all the differentiated thyroid cancers, HCC has the highest incidence of metastases. Ten to 20% of patients will present with metastases and overall approximately one-third of patients will develop metastases. In contrast to papillary and follicular cancers, HCC is radioresistant and has a poorer prognosis, with a 10-year survival rate of approximately 75%. No genetic syndromes have been associated with HCC and the only known risk factor is radiation exposure. At the time of diagnosis, lymph node metastases
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have been documented in 3–56% of patients, and up to 15% of patients may have distant metastases, most commonly to the lung or bone.
OPERATIVE MANAGEMENT Follicular Thyroid Cancer Minimally invasive cancer is an indolent tumor that is treated with thyroid lobectomy and isthmusectomy. Following thyroid lobectomy and isthmusectomy, patients with minimally invasive follicular cancer have a disease-free survival similar to that of patients with a benign follicular adenoma. In contrast, patients with invasive follicular carcinoma have a 10-year disease-specific mortality of 15–28%. Because of its propensity for vascular invasion and systemic metastases, all patients with invasive follicular cancer are treated with total thyroidectomy. Since less than 10% of patients with follicular cancer have lymph node metastases, prophylactic central neck dissection is not a consideration. Central neck dissection and modified neck dissection are reserved for patients having enlarged lymph nodes, with biopsy-confirmed metastatic disease in the central and the lateral neck, respectively.
Hürthle Cell Cancer In the case of HCC, a thyroid lobectomy with isthmusectomy should be the standard initial surgical therapy for patients with a solitary Hürthle cell neoplasm and no history of head/neck irradiation or disease involving the contralateral lobe of the thyroid gland. Exposure to radiation increases the likelihood of having HCC and multifocal disease. Thus, in patients with a prior history of head or neck irradiation, an initial total thyroidectomy is advocated. Some surgeons advocate performing an initial total thyroidectomy for patients 70 years of age or older, males, and patients with follicular or Hürthle cell neoplasms ≥4 cm due to a potentially higher likelihood of malignancy. However, this is controversial and additional studies on larger numbers of patients will be required before consensus can be reached on the selection criteria for more aggressive management of patients with follicular or Hürthle cell neoplasms.
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In contrast to follicular carcinoma, the current American Thyroid Association guidelines recommend “considering” a central neck dissection (level VI) in patients with HCC. Because HCC is most often radioresistant, surgical resection affords the best chance for cure. Radioactive iodine treatment is rarely of value. This, along with the fact that HCC is more likely to metastasize to the regional lymph nodes, is the rationale for considering a prophylactic central neck lymph node dissection. However, this remains a subject of controversy. There is consensus that a compartmental lymph node dissection should be performed for patients with abnormal lymph nodes detected on physical exam, sonography or during intraoperative exploration.
POSTOPERATIVE MANAGEMENT Evaluation for Metastatic Disease Both follicular cancer and Hürthle cell cancer produce thyroglobulin. Performing a total thyroidectomy for follicular and Hürthle cell cancer allows the optimal use of serum thyroglobulin for detection of persistent or recurrent disease. A total thyroidectomy also allows the use of iodine-131 for detection and treatment of metastatic disease. Approximately 75% of metastases from follicular cancer concentrate radioactive iodine, compared to only 10–38% of metastases in patients with Hürthle cell cancer. Radioiodine for detection and treatment of metastatic disease is usually effective only when all normal thyroid tissue has been removed. Although Hürthle cell cancer is less likely to concentrate radioiodine, most Hürthle cell cancers produce thyroglobulin. Iodine-131 ablation of residual normal thyroid tissue enhances the value of postoperative serum thyroglobulin measurement for detection of recurrent disease. With the exception of minimally invasive follicular cancer, iodine-131 ablation and whole body scanning are recommended for all patients with follicular or Hürthle cell cancer. The rationale for iodine-131 treatment is to ablate any residual normal thyroid tissue or microscopic malignancy (Table 1). This is important for reducing recurrence and improving survival. Radioiodine ablation also improves the sensitivity of thyroglobulin measurements by eliminating normal thyroid tissue as a source of thyroglobulin
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Radioiodine remnant ablation.
(A) Serum TSH level should be ≥30 µIU/ml to stimulate iodine uptake by residual normal or malignant thyroid tissue. (B) Whole body scanning is delayed for at least six weeks postoperatively, because of the residual circulating thyroid hormone secreted before thyroidectomy. (C) Low iodine diet for two weeks prior to whole body scanning. (D) Remnant ablation is completed following either thyroid hormone withdrawal or recombinant human TSH administration. (E) Postoperatively, to minimize symptoms of hypothyroidism during thyroid hormone withdrawal, patients are started on cytomel (tri-iodothyronine), which has a half-life of 24 h as opposed to levothyroxine, which has a half-life of 7 days. (F) Cytomel is stopped 2 weeks and levothyroxine 4–6 weeks prior to iodine-131 ablation and whole body scanning.
and antithyroglobulin antibody production. Moreover, radioiodine ablation improves the sensitivity of iodine-131 whole body scanning for detection of recurrent disease by eliminating uptake in the thyroid bed. A 30 mCi dose of iodine-131 may be given to an outpatient and is successful in ablation of residual thyroid tissue in 80% of patients who have undergone total thyroidectomy. If all residual thyroid tissue is not successfully ablated, a second 30 mCi dose of iodine-131 can be given in 6–12 months. A whole body scan is obtained 2–5 days after iodine-131 ablation for detection of metastatic disease. Thyroid Hormone Therapy Both follicular and Hürthle cell cancers have thyrotropin (TSH) receptors. TSH stimulates tumor growth, invasion, and angiogenesis. Thyroid hormone is given postoperatively for treatment of hypothyroidism and to inhibit TSH-dependent growth of residual cancer cells. In patients with persistent or metastatic disease, including those with a detectable thyroglobulin level and no demonstrable disease, the serum TSH level should be maintained below 0.1 µIU/ml. In patients with high risk follicular or Hürthle cell cancer (Table 2) who are clinically free of disease, the serum TSH level should be maintained just below the normal range of
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Low risk and high risk differentiated thyroid cancer.
Low risk Age < 45 Well- or moderately differentiated Confined to the thyroid gland No metastases Size < 4 cm
High risk Age ≥ 45 Poorly differentiated Extrathyroidal tumor spread Metastases Size ≥ 4 cm
0.1–0.4 µIU/ml. For patients with low risk follicular or Hürthle cell cancer (Table 2), serum TSH levels are maintained between 0.3 and 2 µIU/ml. A levothyroxine dose of 2 µg/kg is usually required to suppress TSH levels in patients with thyroid cancer.
LONG TERM FOLLOWUP Postoperatively, patients with follicular or Hürthle cell cancer are followed at 3–6 month intervals for the first two years, and annually thereafter if they are free of disease. Followup consists of physical examination and measurement of serum TSH, basal thyroglobulin, and antithyroglobulin antibody levels. A TSH-stimulated thyroglobulin level is obtained at 12 months. This can be obtained following thyroid hormone withdrawal or recombinant human TSH stimulation. Because of the propensity of Hürthle cell cancer to spread to the regional lymph nodes, patients with this cancer should have an ultrasound of the neck performed 6 and 12 months following thyroidectomy, and yearly thereafter. Physical Examination (1) Evaluate the central neck for local recurrence or lymphadenopathy. (2) Evaluate the lateral neck for regional lymphadenopathy. Thyroglobulin (1) Thyroglobulin (Tg) measurement is more sensitive after thyroid hormone withdrawal or recombinant human TSH stimulation.
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(2) Tg <1 mg/ml off thyroid hormone is likely indicative of cure of thyroid cancer. (3) Anti-Tg antibodies, present in 15–30% of patients with thyroid cancer, are a cause of false positive and false negative Tg results, and thus negate the validity of Tg measurement. (4) The presence of anti-Tg antibodies >1 year following thyroidectomy and radioiodine ablation is likely indicative of residual thyroid tissue. (5) Anti-Tg antibodies decrease and eventually disappear with elimination of residual normal or malignant follicular cells. (6) If TSH-stimulated Tg levels at 12 months are less than the institutional cutoff (0.5–3.0 mg/ml) and neck ultrasound is negative, basal serum Tg levels are followed, and a repeat TSH-stimulated Tg level is obtained only if basal Tg levels become detectable. Iodine-131 Whole Body Scan (1) An iodine-131 whole body scan is indicated for patients with an elevated Tg level and a negative neck ultrasound to localize the source of Tg production. (2) Serum Tg is more sensitive than iodine-131 whole body scanning for detection of recurrent disease. (3) Routine iodine-131 whole body scanning is unnecessary for patients with negative Tg levels, negative neck ultrasound, no clinical evidence of disease, and a prior negative iodine-131 whole body scan. Neck Ultrasound (1) Ultrasound is obtained 6 and 12 months following thyroidectomy in patients with Hürthle cell cancer, and annually for 3–5 years thereafter. (2) Ultrasound is important for detection of small lymph node metastases in patients with rare false negative TSH-stimulated Tg levels.
Evaluation of a Patient with Follicular or Hürthle Cell Cancer and an Elevated Serum Tg Level (1) Physical examination for identification of local or regional recurrence. (2) Chest x-ray, ultrasound, and iodine-131 whole body scanning.
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(3) Spiral computed tomographic imaging of the neck, chest, and brain, magnetic resonance imaging of the spine, pelvis, and femurs, and quantitative measurement of FDG uptake are reserved for patients with an elevated stimulated Tg and a negative neck ultrasound, chest x-ray, and iodine-131 whole body scan.
TREATMENT OF METASTATIC DISEASE Microscopic lymph node metastases are treated with high dose iodine131, usually with a dose of 150 mCi. Radioiodine therapy is most effective for microscopic disease. Radioiodine treatment can be repeated in 6–12 months for persistent disease. Macroscopic lymph node metastases in the central neck are treated with a central neck dissection. This entails removal of the prelaryngeal, pretracheal, and paratracheal lymph nodes and the fibrofatty tissue between the right and left common carotid arteries from the hyoid bone superiorly to the inominate artery inferiorly. Macroscopic lymph node metastases in the lateral neck are treated with a modified neck dissection, which refers to the removal of the upper, mid-, and lower cervical lymph nodes (levels 2, 3, and 4) and the posterior cervical and supraclavicular lymph nodes (level 5). Distant metastatic disease is uncommon in well-differentiated thyroid cancer and is generally seen in less than 10–15% of patients with follicular or Hürthle cell carcinoma. The most common sites for metastatic disease are the lung and bone and, less commonly, the liver and central nervous system. In the lung, there are two characteristic patterns of metastatic disease: micronodular disease, which is treated with high dose radioiodine, and macronodular disease, which can be treated with high dose radioiodine or lung resection. Lung resection is reserved for patients with isolated disease and it has been reported to increase the length of survival by up to 50 months in some small series. Micronodular lung metastases seen on iodine-131 whole body scanning in young patients with a normal chest x-ray have an indolent course and are most likely to be responsive to radioactive iodine treatment with a reported 10-year survival of 90%. Treatment of micronodular metastases often requires multiple doses of
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radioiodine, which can be curative in 35–45% of patients, depending on the burden of disease. In contrast, macronodular lung disease, which is seen on chest x-ray, is less responsive to radioiodine and 10-year patient survival is only 11%. Pulmonary fibrosis is a side effect of multiple doses of radioiodine that are concentrated in the lungs. Children are particularly vulnerable. It is important to appropriately limit the cumulative dose of radioiodine, so as to prevent the development of pulmonary fibrosis. In general, bone metastases are less likely to concentrate radioiodine and are associated with a worse prognosis than lung metastases. Overall, 50% of patients with systemic metastases limited to the lung will be alive and disease-free at 10 years, compared to no patients with bone metastases. High dose iodine-131 is used to treat bone metastases that concentrate radioiodine. Survival may be improved when isolated bone metastases are resected. Surgical palliation is recommended for vertebral metastases because of the risk of compression fractures and neurologic sequelae, and for metastases involving weight-bearing extremities because of the risk of fracture. External radiation can be used for palliation of bone pain. Brain metastases account for less than 1% of metastatic thyroid disease and portend an extremely poor prognosis. Patients with brain metastases have a median survival of one year. Treatment of brain metastases is challenging, because radioiodine therapy may induce cerebral edema. Survival can be improved with surgical resection. External radiation can be used for palliation of patients with unresectable brain metastases. Modern radiosurgical procedures using the gamma knife or cyberknife to resect brain metastases have been reported, but the data are limited to a few case reports.
SELECTED REFERENCES Alaedeen DI, Khiyami A, McHenry CR. Fine-needle aspiration biopsy specimen with a predominance of Hürthle cells: a dilemma in the management of nodular thyroid disease. Surgery 2005;138:650. Cooper DS, Doherty GM, Haugen BR, et al. The American Thyroid Association Guidelines Taskforce. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006;16:109–142.
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McHenry CR, Raeburn C, Strickland T, Marty JJ. The utility of routine frozen section examination for intraoperative diagnosis of thyroid cancer. Am J Surg 1996;172:658–661. McHenry CR, Thomas SR, Slusarczyk SJ, Khiyami A. Follicular or Hürthle cell neoplasm of the thyroid: can clinical factors be used to predict carcinoma and determine extent of thyroidectomy? Surgery 1999;126:798–804. Phitayakorn R, McHenry CR. Follicular and Hürthle cell carcinoma of the thyroid gland. Surg Oncol Clin N Am 2006;15:603–623.
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Chapter I.B.5: Management of Aggressive Variants and Anaplastic Thyroid Cancers Marlon A. Guerrero, MD and Electron Kebebew, MD, FACS
OVERVIEW Well-differentiated thyroid cancer is the most common thyroid malignancy and accounts for 90% of all thyroid cancer cases. Improved understanding of the histopathology of thyroid cancer has further delineated a subset of cancers within the spectrum of well-differentiated thyroid cancer that have more aggressive features. These cancers include the tall cell variant of papillary thyroid cancer, the columnar cell variant, insular thyroid cancer, and the diffuse sclerosing variant. Anaplastic thyroid cancer is the most aggressive type of thyroid cancer and is associated with an over 90% mortality within two years of diagnosis. Often, the more aggressive variants of well-differentiated thyroid cancer are diagnosed after resection on final pathology. The clinical management of the variants that are diagnosed preoperatively will be described in this chapter. Hürthle cell carcinoma and medullary thyroid cancer also have a more aggressive behavior than conventional well-differentiated thyroid cancer; these tumors are discussed in detail in Chapters I.B.3 and I.B.4. Central to the management of patients with aggressive variants and anaplastic thyroid cancer is to adequately assess the extent of tumor involvement in order to perform a complete initial surgical resection, when possible, and to judiciously use adjuvant radioiodine ablation therapy, and consider external beam radiation therapy in patients with unresectable and grossly positive tumor margins. All patients should undergo preoperative ultrasound evaluation of the neck to evaluate the 89
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M. A. Guerrero and E. Kebebew Aggressive Variant on FNA US of thyroid and LN + FNA of suspicious LN
CT or MRI neck h andd chest Resectable
Unesectable
Surgical Resection
Neoadjuvant Radiation
Response RAI ablation + TSH suppression
RAI resistant or incomplete resection
Consider EBRT
Consider surgery
No Response
Adjuvant chemoradiation therapy
Adjuvant chemoradiation therapy
Fig. 1 Management algorithm for aggressive variant thyroid cancer. US — ultrasound; LN — lymph node; FNA — fine needle aspiration; CT — computed tomography; MRI — magnetic resonance imaging; TSH — thyroid-stimulating hormone; RAI — radioactive iodine; EBRT — external beam radiation.
thyroid gland and cervical lymph node basins (Fig. 1). Any suspicious lymph nodes in the lateral neck lymph nodes should be biopsied whenever possible, so that an initial lymph node dissection can be performed and to reduce the risk of persistent disease due to inadequate initial surgical treatment. Ultrasonography has limited accuracy for tumors extending deep into the cervical compartment and extending below the thoracic inlet. In these situations, cross-sectional imaging of the neck and chest with computed tomography without intravenous contrast or magnetic resonance imaging should be obtained (Fig. 2). Because intravenous contrast is high in iodine, it delays the use of radioiodine therapy in patients with thyroid cancer of follicular cell origin, and should be avoided.
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CT scan of recurrent thyroid cancer extending into anterior mediastinum.
TALL CELL VARIANT OF PAPILLARY CARCINOMA The most common of the aggressive variants of papillary thyroid carcinoma (PTC) is the tall cell variant (TCV). A wide range in the prevalence of TCV has been reported: 3–17% of all PTC cases. The female-to-male ratio is 2:1 and the mean age at diagnosis is in the sixth decade. Unlike classic PTC, TCV has an aggressive behavior with a higher rate of multifocality, extrathyroidal extension (up to 80%), and lymph node metastases (up to 60%) at presentation, and is associated with a worse prognosis. Treatment All patients diagnosed with TCV should undergo total thyroidectomy and bilateral central (level VI) lymph node dissection. An en bloc resection of involved tissue should also be performed when extrathyroidal extension is present. Patients presenting with clinical or radiologically evident lymphadenopathy should undergo a lateral (levels II–IV) lymph node dissection (Fig. 3), preferably after a tissue diagnosis has been established by preoperative FNA biopsy or when confirmed by frozen section analysis of the suspected lymph nodes. Postoperative radioactive iodine (131I) ablation is also recommended. The amount of 131I should be tailored to the extent of
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Thyroid Tumor Lateral lymph nodes
Fig. 3 Resected thyroid cancer specimen with central neck and left lateral lymph nodes (II–IV) encasing a thrombosed internal jugular vein.
disease and usually ranges between 100 and 200 mCi. A whole-body radioactive iodine scan is performed 5–7 days following the treatment dose to evaluate any sites of distant disease and the amount of uptake in the neck. It is important to note that TCV is frequently radioiodine-resistant (it does not trap 131I) and represents the majority of PTCs that are refractory to RAI. Of those tumors that are refractory to RAI, 80% have extrathyroidal extension. In these patients and in those who have undergone an incomplete resection, postoperative external beam radiation therapy may be helpful for locoregional control. Those patients with metastatic disease should consider enrollment in a clinical trial. All patients should be placed on thyroid hormone suppression at a dose of 2 mcg/kg/day to keep their TSH suppressed below 0.1 mIU/L, as this reduces the risk of recurrence or progression of persistent disease. Followup All patients with thyroid cancer require long-term surveillance. Because TCV is more aggressive than the classic PTC, patients with TCV should be followed every 3–6 months, then annually if the disease is stable for 3 years. Followup studies should include a neck ultrasound to evaluate for
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thyroid bed or cervical lymph node recurrence. Serum thyroglobulin (Tg), Tg antibodies and thyroid-stimulating hormone (TSH) are also checked. To improve the sensitivity of Tg in detecting residual or recurrent disease, Tg measurements after thyroid hormone withdrawal or after the administration of recombinant TSH are helpful. An elevated Tg > 2 ng/mL without TSH stimulation or Tg > 10 ng/mL with TSH stimulation is suspicious for recurrence or persistent disease. Cross-sectional imaging with a CT scan or MRI of the neck and chest should be done annually to exclude metastatic disease. A PET scan is useful in patients with Tg-positive but radioiodinenegative disease, especially when done with TSH stimulation. Any suspicious lesions in the neck by ultrasound should be biopsied to exclude metastatic disease or recurrence. Prognosis Patients with TCV have a worse prognosis than patients with classic PTC. Locoregional recurrence and distant metastases develop in a fourth of patients. The 10-year mortality rate in patients with TCV is up to 25%.
INSULAR THYROID CANCER Insular thyroid cancer (ITC) accounts for 2–7% of all thyroid cancers. Women are affected twice as commonly as men, usually during the sixth decade of life. Patients with ITC have more aggressive disease at presentation. These patients have larger primary tumors, extrathyroidal extension (50%), lymph node metastasis (85%), and more distant metastasis (>50%) than patients with well-differentiated thyroid cancer. Treatment Patients who present with resectable thyroid tumors diagnosed with ITC on FNA should undergo a total thyroidectomy. A bilateral central lymph node dissection should also be performed, given the high rate of lymph node metastases and local recurrence. An ipsilateral lateral neck dissection should be performed if there is either preoperative clinical or radiologic evidence of involvement. All patients should receive TSH
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suppression therapy postoperatively. Although the efficacy of postoperative radioactive iodine ablation has not been established, its use should be considered for all patients. Similarly, although external beam radiotherapy has not been proven beneficial, its use should be considered in patients who present with advanced disease and are deemed unresectable or who undergo incomplete surgical resection in the hope of achieving local control. Prognosis Nearly two-thirds of patients who undergo surgical resection develop either local recurrence or distant metastases. Due to this aggressive behavior, the 5-year and 10-year survival rates for patients with ITC are 72% and 52%, respectively. Prognostic factors associated with a worse prognosis include age >45 years and the presence of distant metastases.
COLUMNAR CELL VARIANT OF PAPILLARY CARCINOMA The columnar cell variant (CCV) is a rare variant of PTC and accounts for less than 0.5% of all PTCs. It affects women twice as often as men and the mean age of diagnosis is in the fifth decade of life. Tumors that are confined to the thyroid gland and are well-encapsulated have a good prognosis. However, tumors that are not well-encapsulated have a higher rate of extrathyroidal extension, distant metastases, and mortality. Nearly a third of patients have extrathyroidal extension and half have lymph node metastases at diagnosis. Treatment Patients diagnosed with CCV should have a total thyroidectomy. When extrathyroidal extension is present an en bloc resection of the involved tissue should be performed. A central and lateral neck dissection should be performed when there is clinical or radiologic evidence of lymph node metastases. Postoperative RAI ablation should be considered in all patients. However, the rarity of this cancer precludes adequate assessment
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of the efficacy of RAI ablation. All patients are placed on TSH suppression therapy. Postoperative radiation therapy should be considered in cases where a complete resection could not be performed. Prognosis Despite adequate surgical resection, a third of patients will suffer locoregional recurrence. An additional 36% of patients will develop distant metastases. Overall, CCV is associated with a worse disease-related mortality (29%) than classic PTC.
DIFFUSE SCLEROSING VARIANT OF PAPILLARY CARCINOMA The diffuse sclerosing variant (DSV) of papillary thyroid cancer is similar to other variants, in that it predominately affects women. Unlike the other variants, patients with DSV are diagnosed at a younger age (mean: third decade) and generally present with diffuse thyroid enlargement and neck pain. Lymph node metastasis is common in DSV and up to 70% of patients have lymph node involvement at diagnosis. The rate of distant metastasis varies in the literature, but it may be present in up to 60% of patients at diagnosis. Treatment As with the other variants of PTC, a total thyroidectomy is the treatment of choice. DSV has a high propensity for extrathyroidal extension (40%), so an en bloc resection of any involved soft tissue should be performed. A bilateral central lymph node dissection is also recommended, given the high rate of lymph node metastases. Radioactive iodine ablation should be considered for all patients following surgery. Lifelong thyroid hormone suppression is also started postoperatively. Prognosis Up to 50% of patients with DSV will develop local recurrence and up to 60% will develop distant metastases following surgery. Despite these
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risks, the overall survival of patients with DSV is comparable to that of patients with classic PTC.
ANAPLASTIC THYROID CANCER Anaplastic thyroid cancer (ATC) accounts for approximately 2% of all thyroid malignancies. It rarely occurs in the young and over 90% of patients are older than 50 years at diagnosis. Unlike well-differentiated thyroid cancers, ATC commonly presents as a rapidly enlarging thyroid mass. The majority of patients present with either lymph node metastases or extrathyroidal extension and nearly two-thirds at diagnosis have distant metastases at presentation. The most common site of distant metastases is the lung, followed by bone, skin, and brain. Less than 10% of patients present with ATC confined to the thyroid gland. Imaging The rapid progression of ATC can result in local compression or tissue invasion. Radiographic imaging is recommended for appropriate staging and to determine resectability (Fig. 4). A computed tomography (CT) scan of the neck with intravenous (IV) contrast is obtained to evaluate for potential tumor involvement of the vasculature (internal jugular vein, carotid artery, and the great vessels), trachea, and esophagus. CT scans of the head, chest, abdomen, and pelvis with IV contrast are recommended to accurately exclude the presence of metastatic disease. Determiniation of recurrent laryngeal nerve involvement by evaluating the vocal cords with a fiberoptic laryngoscope may be performed, since nearly half of patients present with vocal cord paralysis. Treatment Surgery There is no effective treatment option for ATC, and no single treatment modality has been shown to improve survival. Although surgery is the
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ATC diagnosed by FNA
Staging CT: Head, neck, chest, abdomen, l i pelvis Resectable
Surgical Resection
Unesectable
Discuss end of life issues with all patients
Neoadjuvant Radiation
Response
No Response
Adjuvant chemoradiation therapy Consider surgery
Adjuvant chemoradiation therapy
Adjuvant chemoradiation therapy
Fig. 4 Treatment algorithm for anaplastic thyroid cancer. FNA — fine needle aspiration; CT — computed tomography.
treatment of choice for other thyroid cancers, complete surgical resection is rarely possible for ATC. Surgery as the initial treatment is generally reserved for the rare patient with a small and well-localized tumor. In this case, a complete macroscopic resection (total thyroidectomy) should be performed with preservation of the pharynx, trachea, esophagus, and carotid artery. A lymph node dissection should be performed when gross lymphadenopathy is apparent and complete resection of the tumor is achieved. Aggressive surgery is not recommended, since it offers no survival benefit. Surgical intervention may also be required in patients with an impending airway obstruction. Tumor debulking or incomplete tumor resection in a patient without an impending airway obstruction is not recommended, because it does not offer any survival benefit.
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Radiation Radiation therapy (RT) alone has not been shown to improve survival. However, it is frequently used as an adjunct to surgery in patients who have undergone complete tumor resection. In this setting, current protocols recommend a total dose of 30–60 Gy. However, the potential benefit of local control must outweigh the complications associated with RT, including pharyngitis, esophagitis, tracheitis, myelopathy, and skin changes. The use of intensity-modulated RT has reduced the risk of many of the side effects of radiotherapy.
Chemotherapy Chemotherapy is beneficial in the treatment of some cases of ATC. The most frequently utilized chemotherapeutic agent is doxorubicin, because it has a radiosensitizing effect. Unfortunately, neither monotherapy (doxorubicin, bleomycin, etoposide, cisplatin, vincristine, melphalan, methotrexate, or paclitaxel) nor combination chemotherapy has improved the survival of patients with ATC. The dismal response of ATC to chemotherapy may be due, in part, to the expression of the multidrug-resistance-associated protein in ATC cells. Regardless of the underlying mechanism of resistance, chemotherapy as a single therapy is not recommended.
Multimodality therapy There is general consensus that ATC is a systemic disease and that a multimodality treatment approach is better than any single treatment option. However, multimodality therapy has not been shown to improve overall disease-specific survival. Another limitation is that consensus on the specific regimen and timing of administration has not been universally adopted. One of the most frequently used regimens is combined pre- and postoperative radiation in patients with potentially resectable tumors. Hyperfractionated radiation is administered in either 1.0 Gy or 1.3 Gy per fraction (twice daily, five times a week) to a total dose of 30 Gy preoperatively and 16 Gy postoperatively. Another protocol consists in
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administering preoperative radiation to 46 Gy in 29 fractions (1.6 Gy per fraction twice daily). Doxorubicin at a dose of 20 mg IV is administered weekly before the radiotherapy. Though these protocols did not improve survival, they did prevent local recurrence in 31–77% of patients. Other protocols have also been used with different dosages and fractions, but the total dosage usually ranges between 30 Gy and 60 Gy. Given the futility of current treatment regimens, all patients should be considered for enrollment in clinical trials. Prognosis The median survival of all patients with ATC is five months. The overall two-year survival is 9–14%, but age ≤45 years, small tumor size (<5 cm), and localized disease are associated with slightly better outcome. However, ATC is a fatal disease, so end-of-life issues should be discussed with all patients and their families.
POORLY DIFFERENTIATED THYROID CANCER Poorly differentiated thyroid cancer (PDTC) is a rare tumor of intermediate clinical potential that represents approximately 2–3% of all thyroid malignancies. Despite differences in opinion regarding the pathologic interpretation of these tumors, it is generally accepted that these tumors are aggressive follicularly derived carcinomas that behave more aggressively than well-differentiated thyroid cancer, but without the lethality of ATC. Patients with PDTC have a higher rate of extrathyroidal extension (ETE), local tissue invasion, lymph node metastases, and disease recurrence than patients with well-differentiated thyroid cancer. Over half of patients will develop distant metastases. Due to the aggressive behavior, PDTC is best treated with a multimodality approach. Treatment The rarity of PDTC precludes prospective randomized trials to determine the most effective treatment. Patients who present with well-localized, resectable tumors should undergo total thyroidectomy and bilateral central
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neck dissection. Poorly differentiated tumors are less likely to take up 131I. Though they may not respond to RAI, treatment may be attempted. The lack of efficacy of RAI has prompted the use of adjunct radiotherapy for patients with poor prognostic factors, namely ETE, local tissue invasion, lymph node involvement, or residual disease after attempted resection. Additionally, patients with unresectable tumors should also receive external beam radiation. The typical dosage ranges from 50 to 60 Gy. The presence of distant metastases should be a contraindication to radiation therapy and should be limited to palliation of locoregional obstructive symptoms. Chemotherapy can also be used as an adjunct to surgery and may result in tumor regression in up to 50% of patients. Radiotherapy may be added for responsive tumors. Prognosis Patients with PDTC have an intermediate prognosis between welldifferentiated thyroid cancer and ATC. The five-year survival ranges between 62 and 85%. This wide range in survival reflects the various presentation and extent of the disease, as well as the nonuniform histologic interpretation of the disease.
SELECTED REFERENCES Kebebew E, Clark OH. Locally advanced differentiated thyroid cancer. Surg Oncol 2003 Aug;12(2):91–99. Review. PubMed PMID: 12946480. Kebebew E, Greenspan FS, Clark OH, Woeber KA, McMillan A. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 2005 Apr 1;103(7):1330–1335. PubMed PMID: 15739211. Pudney D, Lau H, Ruether JD, Falck V. Clinical experience of the multimodality management of anaplastic thyroid cancer and literature review. Thyroid 2007 Dec;17(12):1243–1250. Review. PubMed PMID: 18177257.
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Chapter I.B.6: Management of Thyroid Lymphomas, Metastatic Lesions and Other Rare Tumors N. Gopalakrishna Iyer, MBBS, PhD, FRCS and Ashok R. Shaha, MD, FACS
OVERVIEW Thyroid lymphomas and metastatic disease to the thyroid gland are uncommon tumors, constitutes less than 5% of all thyroid malignancies. This chapter reviews the approach to these conditions with regards to diagnosis, prognosis and current management strategies based on the available evidence. Other rare thyroid tumors are listed in Table 1; these are usually diagnosed incidentally and management strategies need to be individualized, as evidence is often lacking for these rare conditions.
THYROID LYMPHOMAS Primary thyroid lymphomas represent 1–5% of thyroid malignancies and less than 2% of extranodal lymphomas.
Epidemiology • • • •
Population incidence: 2.1 per million per year More common in women; female:male ratio 3–4:1 Peak incidence at 60 years (range: 50–80) Hashimoto’s thyroiditis major risk factor– relative risk 70–80×
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Pathology Pathologic subtyping is important, as it determines prognosis and directs management of these tumors. Most are B cell non-Hodgkin’s lymphomas, but there are rare reports of Hodgkin’s or T cell lymphomas. B cell lymphomas are broadly divided into two distinct clinical patterns: diffuse large cell (which includes mixed variants) and MALT (mucosa-associated lymphoid tissue) lymphoma, although other subtypes have been recognized. Diffuse B cell lymphomas and mixed variants • • •
50–70% of thyroid lymphomas CD19-, CD20- and CD45-positive Aggressive clinical course
MALT lymphomas • • • •
23–30% of thyroid lymphomas Express surface immunoglobulins CD5-, CD10- and CD23-negative Indolent clinical course with excellent prognosis
Clinical Presentation • •
• • •
Rapidly enlarging neck mass (70%) Compression symptoms and signs, including dysphagia, stridor, hoarseness, choking, cough and pressure sensation in the neck (50%) Classic B type symptoms: fever, night sweats, weight loss (10%) Hypothyroidism (10%) Thyroid mass with generalized lymphadenopathy
Diagnosis As stated above, the correct subtyping of these lymphomas is crucial to prognosis and therapy, i.e. differentiating diffuse B cell from MALT lymphomas. This can be done by the following methods:
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Fine needle aspiration (FNA) • •
•
Accuracy has increased in recent years with advances in diagnostic techniques along with flow cytometry; Requires combination of expert cytomorphologic examination, immunophenotyping and molecular techniques, and these may not be available at all institutions; It may be difficult to differentiate MALT lymphoma from Hashimoto’s thyroiditis.
Core needle biopsy (Tru-cut) • • • •
Useful for large thyroid masses, where FNA is suspicious for lymphoma; to confirm diagnosis and subtype the lymphoma; Very important in patients suspected to have anaplastic thyroid cancer, to rule out lymphoma; Avoids open surgical biopsy and neck incision; Need to submit fresh tissue specimens for histopathology, immunohistochemistry, flow cytometry and other molecular techniques.
Open surgical biopsy • •
Rarely used; Used only if core biopsy is unable to differentiate the subtype or distinguish MALT lymphoma from Hashimoto’s thyroiditis.
Imaging Accurate imaging is important for staging and treatment planning. The following methods are employed:
Ultrasound • • •
Limited role in localizing thyroid lesions; Useful for US-guided FNA biopsy; Can be used to delineate regional nodal status.
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CT (computerized tomography) scans • • •
Better than ultrasound in determining tumor extent and regional nodal status; Homogeneity of thyroid mass may lead to suspicion of lymphoma; CT of chest, abdomen and pelvis to assess locoregional extent and stage of disease.
PET (positron emission tomography) scans • •
Useful in staging lymphomas, especially in combination with CT scans; Functional imaging is also increasingly used for assessment of tumor response to treatment.
Staging and Prognosis Ann Arbor staging classification is used to stage and prognosticate thyroid lymphomas. Apart from the above investigations, bone marrow biopsy needs to be performed to exclude marrow involvement. Stage (incidence) IE (50%) IIE (45%) IIIE IVE
Definition
5-year survival (%)
Confined to thyroid gland Thyroid gland and locoregional lymph nodes Nodes on both sides of diaphragm Disseminated disease
80 50
Other poor prognostic factors: • • • • •
Size greater than 10 cm Mediastinal involvement B symptoms Rapid clinical growth Presence of dysphagia or stridor
<36
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The histologic subtype also has a significant influence on prognosis: Subtype MALT Mixed MALT and diffuse large cell Diffuse large cell alone
5-year survival (%) 100 78 71
Treatment The principles of management depend on accurate evaluation of the extent of the disease, correct staging and subtyping of the lymphoma. Diffuse large B cell lymphoma (including mixed variants) • • •
Combination of chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone) and locoregional radiation; Radiation fields include entire neck and anterior mediastinum; Role of palliative surgery controversial; compressive symptoms often relieved with chemo-RT or tracheal stents (see below).
MALT lymphoma • •
•
Single modality treatment if the tumor is confined to the thyroid gland (83% stage IE) — either surgery or radiotherapy; If diagnosed post thyroidectomy, postoperative radiotherapy should be considered if there is any uncertainty about the completeness of the surgical excision; Combination of chemotherapy and radiation for stages above stage IE, large bulky tumors and mixed diffuse large cell tumors.
Emerging therapies •
Rituximab, a monoclonal antibody against CD20, has been successfully used for increasing survival rates in non-Hodgkin’s lymphomas. Its role in thyroid lymphomas (especially CD20-expressing MALT lymphomas) has not been explored.
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Tracheal stenting has been successfully used in patients with thyroidrelated airway obstruction. It offer immediate relief of symptoms in patients awaiting response to chemoradiation. Tracheostomy may be necessary if the patient presents with acute airway distress. However, most of these patients can be weaned off their tracheostomy tubes after treatment.
METASTATIC DISEASE TO THE THYROID GLAND Despite its being one of the most vascular organs in the body, metastatic disease to the thyroid gland is an extremely rare clinical entity, accounting for 1–3% of thyroid neoplasms. The incidence is higher in autopsy series of patients with disseminated malignancies — up to 25%. The most common primary malignancy that metastasizes to the thyroid gland is renal cell carcinoma. Other primary tumors that have been described include lung, breast and colonic carcinomas and, more rarely, melanomas, neuroendocrine tumors and nasopharyngeal carcinomas. Clinical Presentation • • •
Most commonly, incidental finding during routine followup for the primary cancer; PET scan showing hypermetabolic lesion in thyroid gland and other lesions; Symptoms due to the nodule, including palpable lesion, compressive symptoms, cough, hemoptysis or vocal cord paralysis.
Diagnosis It is important to always consider thyroid metastases when working up patients with a history of malignant disease who present with a thyroid nodule. Fine needle aspiration •
May be difficult to differentiate from poorly differentiated thyroid carcinoma;
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May require immunohistochemical stains, especially thyroglobulin; Cytological comparison with index tumor may be helpful.
Role of imaging • • •
Limited; Ultrasound to determine if solitary or multicentric lesion and neck nodal status; CT or PET scans to distinguish isolated thyroid metastases from disseminated disease, especially for renal cell carcinoma.
Treatment •
• • • •
Surgery offers survival benefit only in patients with isolated thyroid metastases (especially renal cell carcinoma), and total thyroidectomy is the procedure of choice; Otherwise, palliative treatment for disseminated metastases; Tracheal compression may require surgical intervention; Palliative thyroidectomy may be considered to avoid future vocal cord paralysis or tracheal involvement and airway-related issues; Need for surgical intervention has to be weighed against prognosis of disseminated disease.
RARE TUMORS OF THE THYROID GLAND Table 1 lists a number of rare histological tumor types affecting the thyroid gland. The commonest presentation is a thyroid mass with atypical FNA findings, requiring a thyroidectomy. In this scenario, appropriate histopathologic diagnosis is crucial and the following points are important when dealing with these tumors: • • •
Immunohistochemistry is an essential adjunct to routine examination; Histology slides should be reviewed by an expert thyroid pathologist to confirm diagnosis; Serum calcitonin and CEA are helpful in ruling out medullary thyroid cancer;
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Rare tumors of the thyroid gland.
Mucoepidermoid carcinoma Sclerosing mucoepidermoid carcinoma with eosiniphilia Mucinous carcinoma Spindle cell tumor with thymus-like differentiation Carcinoma with thymus-like differentiation (CASTLE) Ectopic thymoma Teratoma Angiosarcoma Smooth muscle tumors Peripheral nerve sheath tumors Paraganglioma Solitary fibrous tumors
• •
Treatment depends on the diagnosis and extent of the disease; Surgical excision is generally the mainstay of treatment.
SELECTED REFERENCES Calzolari F, et al. Surgical treatment of intrathyroidal metastases: preliminary results of a multicentric study. Anticancer Res 2008;28(5):2885–2888. DeLellis R, et al. WHO Classification of Tumors: Pathology and Genetics of Tumors of Endocrine Organs. IARC Press, 2004. Derringer GA, et al. Malignant lymphoma of the thyroid gland: a clinicopathologic study of 108 cases. Am J Surg Pathol 2000;24(5):623–639. Doria R, et al. Thyroid lymphoma: the case for combined modality therapy. Cancer 1994;73:200–206. Mack LA, et al. An evidence-based approach to the treatment of thyroid lymphoma. World J Surg 2007;31(5):978–986. Mirallié E, et al. Management and prognosis of metastases to the thyroid gland. J Am Coll Surg 2005;200(2):203–207. Shimizu K, et al. Clinicopathological study of clear cell tumors of the thyroid: an evaluation of 22 cases. Surg Today 1995;25(12):1015–1022. Widder S, Pasieka JL. Primary thyroid lymphomas. Curr Treat Options Oncol 2004;5(4):307–313. Young NA, et al. Diagnosis of lymphoma by fine-needle aspiration cytology using the revised European–American classification of lymphoid neoplasms. Cancer Cytopathol 1999;87(6):325–345.
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Chapter I.B.7: Hyperthyroidism Geeta Lal, MD and Sonia L. Sugg, MD
INTRODUCTION Hyperthyroidism, or thyrotoxicosis, results from excessive secretion of the thyroid hormones thyroxine (T4) and/or tri-iodothyronine (T3). The effects of thyroid hormone overproduction (Table 1) can be seen upon virtually every organ of the body and may also include symptoms and signs associated with specific etiologies, such as the infiltrative ophthalmopathy seen in patients with Graves’ disease. Although there are many causes of hyperthyroidism (Table 2), this chapter concentrates on the management of diseases most commonly treated by a surgeon: Graves’ disease, toxic multinodular goiter, and solitary toxic adenoma. Hyperthyroidism can be treated by medical therapy, radioactive iodine, or surgery (Fig. 1). The factors important in determining the course of treatment include the etiology of hyperthyroidism, patient characteristics, and patient and physician preference. Following is an overview of the treatment options for hyperthyroidism, and a discussion on the management of specific disease entities.
TREATMENT OPTIONS Medical Management Antithyroid medications The two antithyroid drugs most commonly used in the United States are propylthiouracil (PTU) and methimazole (Tapazole). Both drugs inhibit 109
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Clinical manifestations of hyperthyroidism.
Thyroid
Goiter Thyroid nodule
Constitutional
Weight loss/gain Fatigue Heat intolerance
Psychological
Nervousness/restlessness Emotional lability Insomnia
Cardiovascular
Tachycardia Palpitations/arrythmias Widened pulse pressure
Respiratory
Air hunger
Gastrointestinal
Dysphagia Intermittent diarrhea Increased appetite
Integument
Warm, moist skin Thin, fragile hair Onycholysis Pretibial myxedema (Graves’)
Neuromuscular
Proximal muscle weakness
Skeletal
Increased bone resorption Increased risk of fractures
Hematologic
Lymphadenopathy
Reproduction
Gynecomastia in men Oligomenorrhea/decreased fertility in women
Ophthalmologic
Lid retraction/stare Infiltrative opthalmopathy (Graves’)
From: Costa EE, Sugg SL, Kaplan EL. Hyperthyroidism. In: Surgical Endocrinology, GM Doherty, B Skogseid (eds.). Philadelphia, PA: Lippincott Williams & Wilkins, 2001, pp. 21–36.
the synthesis of T4 and T3, and compete with thyroglobulin for iodination by thyroid peroxidase. Extrathyroidal mechanisms of action include reducing the peripheral conversion of T4 to T3 by PTU but not methimazole. Both drugs are very effective and have similar costs. They are used in the management of hyperthyroidism, either as a maintenance regimen
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Causes of hyperthyroidism.
Graves’ disease Toxic multinodular goiter Toxic adenoma Thyroiditis, including postpartum thyroiditis Jod–Basedow’s syndrome Hydatidiform mole and choriocarcinoma Struma ovarii Thyroid carcinoma Iatrogenic hyperthyroidism Factitious hyperthyroidism Modified from: Costa EE, Sugg SL, Kaplan EL. Hyperthyroidism. In: Surgical Endocrinology, GM Doherty, B Skogseid (eds.). Philadelphia, PA: Lippincott Williams & Wilkins, 2001, pp. 21–36.
Solitary T Toxic i N Nodule d l
Toxic MNG
+//
Surgery P f d Preferred (Lobectomy ( Toxic ffor T i Nodule)
or
Graves’ Disease
Anti-Thyroid (AT) Medications
RAI Preferred -Pregnant Pregnant patient -Cancer/Suspicious nodule C /S i i d l -Large g g goiter -Contraindication Contraindication to AT meds -Patient Patient preference Young age -Young
failed
Repeat RAI
Surgery g y
Fig. 1
Hyperthyroidism treatment algorithm.
or in preparation for definitive treatment. A euthyroid state is typically reached in about 6–8 weeks, although clinical improvement may be seen after two weeks. They are generally tapered to 30–50% of initial doses once euthyroidism is reached.
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PTU • • •
Typically started at doses of 100 mg three times a day; Indicated in severe hyperthyroidism or thyroid storm, where rapid decrease of serum T3 levels is essential; Also preferred during pregnancy and lactation, because of its tight protein binding.
Methimazole • •
Typically started at doses of 10–30 mg once a day; this dosing is associated with improved patient compliance; Avoid in pregnancy, as it causes aplasia cutis (failure in the development of the scalp skin, presenting as ulcers) in newborns.
Monitoring •
•
Serum-free T3 and/or -free T4 should be monitored every 4–6 weeks. Serum TSH does not need to be monitored in the short term, as levels can remain suppressed for several months. Side effects of antithyroid drugs occur in 4–12% of patients and appear mostly in the first two months.
Minor side effects •
Minor side effects include fever, rash, pruritus, skin eruptions, hair loss, lymphadenopathy, headache, arthralgias, and myalgias.
Major side effects •
Major side effects include granulocytopenia, hepatitis with cholestasis, a lupus-like syndrome, and neuritis. Granulocytopenia typically presents with fever, sore throat, and mouth ulcers and occurs at an incidence of 0.5%. Complete recovery can be expected upon discontinuing the medication.
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Beta-adrenergic blockers These medications are highly effective in controlling the peripheral manifestations of hyperthyroidism, including tachycardia, palpitations, increased cardiac output, nervousness, and tremor. In addition to reducing the sensitivity to catecholamines, they inhibit the peripheral conversion of T4 to T3. They are typically used to control thyrotoxic symptoms while waiting for the effect of antithyroid drugs or radioactive iodine, or in preparation for surgery. • • •
Propanolol, atenolol, and metoprolol are the most commonly used medications; Propranolol is typically given in a dosage of 10–40 mg four times a day; Beta blockers are contraindicated in patients with asthma, chronic obstructive pulmonary disease, or heart block.
Iodine Administration of iodine reduces the organification and the release of T4. It also decreases thyroid gland vascularity, and is therefore used by many surgeons to prepare patients for surgery for Graves’ disease. Treatment beyond two weeks is not recommended, due to the loss of effectiveness in blocking T4 release, a phenomenon known as “iodine escape.” Iodine is administered as an aqueous solution in the following formulations in a dosage regimen of 3–5 drops three times a day: • • •
Lugol’s solution (6 mg of iodide per drop); Saturated solution of potassium iodide (38 mg of iodide per drop); Adverse reactions are infrequent and include skin rash, vasculitis, sialadenitis, drug fever, rhinitis, conjunctivitis, and leukemoid eosinophilic granulocytosis.
Other antithyroid drugs •
Lithium carbonate acts in a similar manner to iodine and may be useful in patients allergic to iodine. However, its usefulness is limited by its narrow therapeutic range.
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Corticosteroids inhibit thyroid hormone secretion and the peripheral conversion of T4 to T3. Their activity in the periphery is additive to those of PTU and is presumed to have different mechanisms. Therefore, they are used in combination with SSKI and PTU if rapid decrease of T3 is desired. Iodinated radiographic contrast agents such as sodium ipodate (Oragrafin) and sodium iopanoate (Telepaque) lower T3 levels by inhibiting outer ring deiodinase. They are used primarily in severely ill patients who require a rapid reduction in circulating levels of T3, as in thyroid storm. These agents are not used in long-term treatment because, as with iodine, there is an escape phenomenon.
Novel immunomodulatory agents •
Rituximab is a monoclonal chimeric human/mouse antibody directed against the surface molecule CD20, which rapidly causes B cell depletion in the circulation as well as in the target organs of autoimmune diseases, such as the thyroid. Initial studies indicated that patients with Graves’ disease and associated ophthalmopathy responded with a reduction in both the clinical activity score and the severity score. The effect of rituximab on hyperthyroidism in Graves’ disease is less pronounced. Due to limited experience, cost, side effects, and the availability of alternative therapy, it is not currently recommended for uncomplicated Graves’ disease.
Radioactive Iodine I131 is the typical isotope used for thyroid ablation. Therapy with RAI may occasionally produce radiation thyroiditis and release of stored thyroid hormone 10–14 days after initial dosing. Therefore, elderly patients and other patients susceptible to the effects of hyperthyroidism, including those with pre-existing heart disease or severe systemic illness, should be pretreated with antithyroid drugs to prevent exacerbation. These medications are generally discontinued for at least three days prior to RAI and a low-iodine diet is instituted 2–4 weeks prior to therapy, to ensure good uptake.
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Contraindications to RAI • •
•
Large goiters — RAI may cause transient swelling of the gland after treatment, which may worsen obstructive symptoms. Pregnancy — due to its possible ablative effects on the fetal thyroid. Women of childbearing age must receive a pregnancy test prior to treatment and are encouraged to not become pregnant for at least six months after treatment. Childhood — this is a relative contraindication. The use of RAI in young patients was discouraged due to the potentially increased risk of developing malignancies from RAI. However, several studies have not shown any increased risk and RAI is now more commonly used in young adults and children.
Surgical Management This remains an important treatment modality for hyperthyroidism in a subset of patients. It is primarily used in cases where there is (1) a requirement for rapid treatment of hyperthyroidism, (2) a failure of or contraindication to antithyroid medications or RAI, and (3) patient preference for surgery. The disadvantages of surgery include the risks of general anesthesia and the cosmetic considerations of a scar, as well as the potential for complications (see Chapter 8). However, the morbidity and mortality rates are low, particularly in the hands of an experienced surgeon.
Extent of surgery •
Subtotal thyroidectomy is classified as bilateral subtotal (leaving a posterior rim on each thyroid lobe) and as the Hartley–Dunhill procedure (unilateral total lobectomy with contralateral subtotal lobectomy). The thyroid remnant makes it possible for some patients to maintain adequate thyroid function without thyroid hormone supplementation. However, the remnant predisposes to persistent or recurrent hyperthyroidism, which is problematic since most patients undergo surgery due to some failure or contraindication to medical therapy. Therefore, many endocrine surgeons now
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favor a total/near-total thyroidectomy for Graves’ disease and toxic MNG. Total/near-total thyroidectomy results in permanent hypothyroidism, requiring lifelong thyroid hormone supplementation. There is virtually no persistent or recurrent hyperthyroidism. In patients with severe ophthalmopathy, total or near-total thyroidectomy has been suggested to cause reversal or amelioration of eye changes, though the supporting data are controversial. Lobectomy is the operation of choice for a single hyperfunctioning nodule.
Preoperative preparation •
• • •
It is extremely important to (a) decrease the risk of precipitating a thyroid storm, and (b) decrease the risk of bleeding reducing the vascularity of the thyroid gland. Antithyroid medications are generally given until a euthyroid state is achieved. Iodine is added for 7–10 days prior to surgery, to decrease vascularity and control thyroid function. Propanolol may be utilized to control thyrotoxic symptoms and is favored instead of iodine by some surgeons. In patients who are allergic to antithyroid medications or who require a rapid preparation for surgery, a β blocker may be used alone or with iodine.
SPECIFIC CONDITIONS Graves’ Disease Clinical features Graves’ disease, or toxic diffuse goiter, is the most common cause of hyperthyroidism, accounting for 85% of all cases. The peak age of onset is the fourth decade. Graves’ disease is an autoimmune disorder — antibodies against the TSH receptor stimulate the production of thyroid hormone autonomously, resulting in hyperthyroidism and a diffuse goiter. In many cases, additional physical manifestations occur, most
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commonly infiltrative ophthalmopathy, but pretibial myxedema and acropachy may also be seen. Although a specific gene related to Graves’ disease has not yet been identified, there has long been evidence of a hereditary component in the disease.
Management Antithyroid drugs These are used initially in the treatment of many patients, especially those who are children and adolescents, have associated pregnancy, or if the goiter and hyperthyroidism are both moderate. Issues to consider: •
• • •
•
Risk of recurrence: only 30–40% of patients remain in remission one year after withdrawal of the drug. Most patients have a recurrence within several weeks after stopping their medication. At present, there is no good method to determine which patients will relapse following the cessation of drug therapy, although the presence of a large goiter when the medication is stopped usually predicts failure. Compliance: up to 50% of patients in the US are noncompliant. The duration of treatment is variable: 6–24 months. After a relapse, the likelihood of permanent remission with a second course of antithyroid drugs is very low, especially in adults. Therefore, definitive treatment should be considered. While rare, life-threatening side effects, such as liver failure requiring transplantation, have been described in patients being treated with antithyroid medications.
Radioactive iodine •
This is the therapy of choice among US endocrinologists for definitive therapy for Graves’ disease. Its advantages and disadvantages are outlined in Table 3. It is highly favored due to its low cost, ease of administration, and efficacy.
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Onset of response
Treatment of Graves’ disease.
Complications
Advantages
Disadvantages
Surgery
Immediate
Permanent hypothyroidism 30–100%* Recurrent hyperthyroidism 5–10% Mortality <1% Vocal cord paralysis — 1% or greater Hypoparathyroidism — 1% or greater
Effective, rapid reversal of symptoms; removal of goiter
High cost; requires general anesthesia; surgical complications, scar; lifelong T4 replacement often required
Radioiodine (I131)
Several weeks to months
Permanent hypothyroidism 50–70% Multiple treatments sometimes required (up to 30%) Recurrence 20%
Effective, simple, and costeffective
Contraindicated in pregnancy and nursing mothers; complications; effects of therapy not immediate; reduction in size of nodules is limited; lifelong T4 replacement usually required
*With total thyroidectomy. From: Costa EE, Sugg SL, Kaplan EL. Hyperthyroidism. In: Surgical Endocrinology, GM Doherty, B Skogseid (eds.). Philadelphia, PA: Lippincott Williams & Wilkins, 2001, pp. 21–36.
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Various approaches have been tried, including small repeated treatments, large ablative doses, and the use of precise dosimetry calculations. The recommended dose may vary from 55 to 200 microcuries per estimated gram of thyroid tissue, resulting in a thyroid radiation dose of 50–100 Gy. Up to 30% of patients will need two or more courses of RAI. Persistent hyperthyroidism is seen in 4–30% of patients and hypothyroidism in 10–80%. Despite the various regimens for Graves’ disease, hypothyroidism continues to occur at the rate of about 3% per year. Therefore, lifelong monitoring is necessary. Ophthalmopathy can be worsened by RAI; however, this can largely be ameliorated by pretreatment with corticosteroids.
Surgery Surgery is the recommended primary course of therapy among about 2–7% of American and European endocrinologists. Indications for surgery: • • • • •
• • • •
Nonresponse, or allergy to antithyroid medications. Severe thyrotoxicosis requiring rapid control. Patient noncompliance. A large goiter. Coexistence of a suspicious cold nodule — carcinoma of the thyroid associated with Graves’ disease was shown to be present in 1.9–9% of cases. The outcome of Graves’ associated carcinoma may be worse. Women who are pregnant or desire pregnancy in the short term. Patients wishing to avoid RAI therapy. Graves’ disease in children (relative indication). Patients with severe opthalmopathy (relative indication).
Extent of thyroidectomy: •
Determined by the desired outcome (risk of recurrence versus euthyroidism) and surgeon experience.
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Patients with coexistent thyroid cancer, those who refuse RAI therapy, have severe ophthalmopathy, or have life-threatening reactions to antithyroid medications (vasculitis, agranulocytosis, or liver failure) should undergo total or near-total thyroidectomy. With subtotal thyroidectomy, a 4–7 g remnant is recommended. The final result of surgery cannot be evaluated until at least 1–2 years postoperatively, which is the time needed for the feedback axis to compensate for and stimulate the remnant gland optimally. Even euthyroid patients require long-term followup, since different series reveal a 10–50% incidence of permanent hypothyroidism with a subtotal resection.
A prospective randomized study of 179 patients in Sweden compared the three modalities and showed that the risk of relapse was highest in medically treated patients (30–40%), followed by those treated with RAI (21%) and those treated surgically (around 5%). Most patients were satisfied with their mode of treatment, and there was no significant difference in sick leave among the three groups. All patients in the radioiodine and surgery groups developed hypothyroidism. Toxic Multinodular Goiter (Plummer’s Disease) Toxic nodular goiter occurs in the setting of a pre-existing multinodular goiter, in which nodules become autonomous and finally toxic, producing the clinical symptoms of hyperthyroidism. Treatment Unlike Graves’ disease, which may undergo spontaneous remission, toxic multinodular goiter is progressive and, therefore, antithyroid medications are generally not used for primary treatment of the disease unless there is a contraindication to ablative therapy. RAI ablation •
The dose of I131 required for radioiodine ablation of toxic multinodular goiter is considerably higher than that needed for Graves’ disease
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and ranges from 10 to 200 millicuries, depending on the size of the goiter. Multiple doses are often needed. Occasionally, exacerbation of hyperthyroidism may be caused by release of thyroid hormones after radioiodine ablation. Therefore, antithyroid medications should be given concurrently to prevent worsening of hyperthyroid symptoms or thyroid storm. With large goiters, persistence is common after RAI.
Surgery •
•
Indicated for large goiters, as it offers the opportunity to correct the cosmetic deformity and relieve local compressive symptoms, and is a highly effective means of controlling hyperthyroidism. Other indications are similar to those for Graves’ disease.
Solitary Toxic Adenoma Toxic thyroid adenoma is a solitary thyroid nodule that overproduces thyroid hormone autonomously. Most toxic nodules that result in the development of thyrotoxicosis are greater than 3 cm. Patient age is also a factor, as 57% of patients more than 60 years of age develop thyrotoxicosis, versus only 13% of younger patients. These tumors are typically follicular lesions, but may be colloid or hyperplastic nodules. The incidence of thyroid cancer in toxic adenomas is 5–10%. Treatment •
Despite the low incidence of cancer in a “hot” thyroid nodule, a fine needle aspirate with cytologic analysis should be strongly considered before initiating therapy, as the morbidity of the procedure is minimal and has the potential to alter the treatment course.
Radioactive iodine •
The results with radioactive iodine are variable. Larger nodules require higher doses, and persistence or recurrence of thyrotoxicosis
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was seen in 10% of patients and hypothyroidism in 12%. Another theoretical concern is that the normal thyroid gland is exposed to radioactivity from the toxic nodule, which may present a risk of radiation-induced tumors. Surgery •
Preferred mode of treatment, consisting of lobectomy on the side of the nodule. It is highly efficacious, with a rate of hypothyroidism for lobectomy of about 8%.
Percutaneous ethanol injection • •
Not used widely in the US; most studies have been performed in Italy, with good results. The primary disadvantage is transient dysphonia, related to recurrent laryngeal nerve damage from the procedure.
THYROID STORM Thyroid storm refers to severe hyperthyroidism triggered by a medical stressor, such as surgery, anesthesia, radioactive iodine, infection, myocardial infarction, and childbirth. It is not thought to be related to physical manipulation of the thyroid gland, although this may play a role at operation. Mortality is about 10%. Clinical Features • •
The symptoms include fever, tachycardia, abdominal pain, nausea, vomiting, heart failure, confusion, and even coma. May lead to cardiovascular collapse and/or multisystem organ failure.
Treatment •
Often needs monitored/ICU setting, cooling blanket, oxygen, and hemodynamic support as needed.
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High doses of antithyroid drugs. Iodide therapy to reduce iodine uptake and decrease hormone synthesis. Propranolol to treat hyperthyroid symptoms and block peripheral T4-to-T3 conversion. Adrenocortical steroids are also frequently utilized to prevent adrenocortical insufficiency and to reduce the conversion of T4 to T3. Definitive treatment of the cause of hyperthyroidism, typically with RAI ablation or surgery.
SELECTED REFERENCES Dickinson J, Perros P. Treatment of Graves’ hyperthyroidism: evidence-based and emerging modalities. Endocrinol Metab Clin North Am 2009;38(2):355–371. In H, Pearce EN, Wong AK, et al. Treatment options for Graves’ disease: a costeffectiveness analysis. J Am Coll Surg 2009;209(2):170–179.e1–e2. Porterfield JR Jr, Thompson GB, Farley DR, et al. Evidence-based management of toxic multinodular goiter (Plummer’s disease). World J Surg 2008;32(7):1278–1284. Torring O, Tallstedt L, Wallin G, et al. Graves’ hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine — a prospective, randomized study. Thyroid Study Group. J Clin Endocrinol Metab 1996;81:2986–2993.
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Chapter I.B.8: Management of Complications of Thyroidectomy Jason Long, MD and Peter Angelos, MD, PhD, FACS
POSTOPERATIVE HOARSENESS Overview/Presentation •
•
Hoarseness following intubation is not uncommon and may remain for several days postoperatively, mimicking or perhaps disguising a more serious injury (i.e. nerve injury or neck hematoma). Routine preoperative laryngoscopy is indicated in patients with previous thyroid surgery or existing voice disturbances.
Differential Diagnosis • •
Laryngeal irritation/edema secondary to intubation Nerve injury
Degree of injury determines extent of voice disruption — Vocal fold paresis hypomobile vocal fold ➤ Vocal fatigue ➤ Hoarseness ➤ Impairment of volume and projection ➤ Loss of upper range ➤ Breathiness — Vocal fold paralysis unilateral or bilateral muscle dysfunction ➤ Bilateral vocal fold paralysis may present acutely with airway obstruction. Commonly injured nerves — Superior laryngeal nerve (SLN) 125
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— Recurrent laryngeal nerve (RLN) — Vagus nerve Neck hematoma
Workup •
• • •
Complete head and neck physical examination, including subjective evaluation of the patient’s voice before and after surgery Assess for airway compromise Intraoperative nerve monitoring (discussed below) Intraoperative laryngoscopy if suspicious for airway compromise Otolaryngology referral Endoscopic visualization of the larynx Laryngeal electromyography (LEMG)
Management Postoperative laryngeal irritation • •
Observation Symptomatic management
Nerve injury •
Unilateral vocal fold paralysis Treatment is designed to eliminate aspiration and improve voice. Recovery of laryngeal nerve function is common if injury was not caused by transection. Voice therapy — one study found that 65% patients with unilateral RLN paralysis who had voice therapy considered their voices satisfactory and elected not to have surgery. Surgical therapy — —
Medialization — laryngeal framework surgery and injection laryngoplasty Reinnervation with ansa cervicalis, phrenic nerve, hypoglossal nerve, etc.
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Bilateral vocal fold paralysis Voice quality is significantly altered but the patient may still be able to phonate. Airway patency is jeopardized by the paramedian position of the paralyzed vocal folds. Tracheotomy may be required acutely, followed by surgery to improve the size of the glottic airway. — Lateralization of vocal folds to improve airway patency and assist with decannulation
Neck hematoma (discussed below) • •
Bedside evacuation if airway compromised Operative exploration
RECURRENT LARYNGEAL NERVE (RLN) INJURY •
•
Incidence ranges from 0.5 to 2.5%, with higher rates among patients with thyroid cancer, Graves’ disease, and undergoing reoperation. Innervates intrinsic muscles of the larynx. Unilateral denervation inability to close glottis, unilateral vocal cord paralysis, possible aspiration Bilateral denervation possible airway obstruction Anatomy
•
Right RLN — branches off the vagus and loops behind the subclavian artery and ascends superiomedially toward the tracheoesophageal groove to enter the larynx posteriorly. — 0.5% have a non-RLN on the right — branches off the vagus at the level of the cricoid cartilage and enters the larynx directly, without looping around the subclavian artery. Left RLN — branches off the vagus at the level of the aortic arch passing inferior and posterior to the arch and reverses its course superiorly in the tracheoesophageal groove to enter the larynx. Deliberate identification minimizes risk of injury
•
Anatomic landmarks —
Often found in close proximity to the inferior thyroid artery but this is not an absolute.
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Intraoperative RLN monitoring — — — —
—
An endotracheal tube is fitted with surface EMG electrodes exposed at the glottis to contact the vocal folds. Stimulation of nerves when the patient is not paralyzed results in a signal. The collective body of literature has failed to conclusively support or refute its routine use in clinical practice. Can be effective in assisting the surgeon to identify the RLN, predicting when the nerve is intact, and predicting when the nerve is not intact. Routine vagal stimulation prior to and following completion of surgery to ensure proper functioning of the monitoring system is recommended.
EXTERNAL BRANCH OF THE SLN INJURY • •
Incidence ranges from 0 to 25%. Innervates the motor portion of the cricothyroid muscles and is responsible for alterations in voice pitch.
•
Anatomy
•
Denervation results in inability to project voice. Branches off the vagus and travels inferiorly along the side of the pharynx, medial to the carotid artery, and splits at the level of the hyoid bone, entering the thyrohyoid membrane.
Intraoperative nerve monitoring
Some authors have found neuromonitoring to be useful for identifying and preserving the external branch of the superior laryngeal nerve.
SELECTED REFERENCES Angelos P. Recurrent laryngeal nerve monitoring: state of the art, ethical and legal issues. Surg Clin North Am 2009;89(5):1157–1169. Barczynski M, et al. Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy. B J Surg 2009; 96:240–246.
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Dackiw APB, Rotstein LE, Clark OH. Computer-assisted evoked electromyography with stimulating surgical instruments for recurrent/external laryngeal nerve identification and preservation in thyroid and parathyroid operation. Surgery 2002;132:1100–1106. Miller M, Spiegel J. Identification and monitoring of the recurrent laryngeal nerve during thyroidectomy. Surg Oncol Clin North Am 2008;17: 121–144. Rubin A, Sataloff R. Vocal fold paresis and paralysis: what the thyroid surgeon should know. Surg Oncol Clin North Am 2008;17:175–196.
NECK HEMATOMA Overview • •
Incidence of hematoma following thyroidectomy reported in the literature ranges from 0 to 1.6%. Best prevented by meticulous wound irrigation and hemostasis before wound closure. Simulated valsalva maneuver can help identify potential venous bleeders prior to skin closure. No clear evidence that using drains in patients undergoing thyroid operations significantly improves patient outcomes. —
Cochrane review of 11 studies comparing suction drain with no drain in patients undergoing thyroidectomy demonstrated no difference in rates of fluid collection, rates of reoperation, or rates of respiratory distress. Causative factors for neck hematoma
Slippage of ligature from major vessel Reopening of cauterized vein Postoperative coughing, retching, vomiting Valsalva maneuvers during reversal of anesthesia Postoperative hypertension Oozing from cut edge of thyroid gland in partial thyroidectomies Graves’ disease or thyroiditis associated with inflammation of tissue in proximity to thyroid Medication-related (aspirin, wafarin, ketorolac, enoxaparin, antiplatelet agents)
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Stable or slowly expanding hematomas are usually of venous origin and a major source rarely is apparent at wound exploration. Rapidly expanding hematomas, alternatively, occur most commonly from a bleeding artery. Presenting Signs and Symptoms • • •
Neck hematomas may present with respiratory distress, neck pain or pressure, and dysphagia. Respiratory distress develops due to laryngeal edema secondary to impairment of venous return from the larynx by the hematoma. Most hematomas develop within the 24 h postoperative period, with the majority occurring 4–6 h following surgery. Some authors, however, report occurrence of hematomas as late as 7 days after surgery.
Management The keys to management of a postoperative neck hematoma include close observation, early detection, airway management, and appropriate surgical intervention. Although no evidence-based recommendations can be made, many surgeons use the following general approach: •
Patients undergoing thyroid lobectomy
•
Observed for 6 h postoperatively and, if otherwise healthy, may be discharged thereafter with clear instructions regarding signs of hematoma.
Patients undergoing total thyroidectomy
Observed overnight, given the larger dissection area and the fact that both sides of the neck have been explored. A minor surgical instrument set should be readily available during the patient’s hospital stay if the need for emergent bedside evacuation of hematoma arises.
Airway Compromise? Symptoms such as breathing difficulty, neck pressure, and voice changes with an obvious collection in the wound require surgical evaluation and possibly intervention without delay.
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Airway is compromised requires emergency intervention necessitating emergent intubation and opening of the wound at bedside to evacuate clotted blood if necessary.
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Persistent airway compromise following this maneuver is likely due to laryngeal edema as a result of the hematoma and may require endotracheal intubation for some period of time after evacuation of the hematoma. All patients should undergo complete wound re-exploration in the operating room following any urgent bedside procedure.
Airway is not compromised patients without obvious airway compromise and who have a stable hematoma should undergo operative re-exploration as soon as possible.
SELECTED REFERENCES Gil Z, Patel SG. Surgery for thyroid cancer. Surg Oncol Clin North Am 2008;17:93–120. Rosenbaum MA, et al. Life-threatening neck hematoma complicating thyroid and parathyroid surgery. Am J Surg 2008;195(3):339–343. Samraj K, Gurusamy KS. Wound drains following thyroid surgery. Cochrane Database Syst Rev 2007, Oct. 17(4):CD006099.
POSTOPERATIVE HYPOCALCEMIA/ HYPOPARATHYROIDISM Overview •
Postoperative hypocalcemia is observed in up to one-third of cases and is the most common complication following thyroidectomy.
•
Due to trauma, devascularization, or inadvertent excision of one or more parathyroid glands during operation. The majority of cases are transient and resolve spontaneously, although the incidence of permanent hypoparathyroidism is reported as 1–3%.
Risk factors: Graves’ disease, malignancy, extent of thyroid resection performed, extent of lymphadenectomy performed, and hungry bones along with hemodialysis in renal failure patients.
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Evaluation and Management • • •
Check calcium levels in the perioperative period. Chvostek and Trousseau signs can be assessed at the bedside. Routine oral calcium and vitamin D supplements have been shown to be effective in reducing the incidence and severity of postoperative hypocalcemia.
Intraoperative identification of parathyroid glands is imperative. —
Preserve the blood supply to parathyroid glands by ligating all vessels distal to the glands, especially in the vicinity of the inferior thyroid artery.
—
•
•
Glands that appear compromised should be autotransplanted into the sternocleidomastoid muscle or the brachioradialis muscle. Asymptomatic hypocalcemia — calcium supplementation is not required but oral calcium may eliminate the further decline in calcium levels. Symptomatic hypocalcemia
Mild symptoms can often be treated with oral calcium and activated vitamin D. One gram IV calcium gluconate is administered over 10 min, and continue with a drip at a rate of 1–2 mg/kg/h if symptoms are severe or if symptoms continue despite initiating oral treatment.
Start oral calcium (2500–5000 mg/day calcium carbonate) and vitamin D with calcitriol (0.25–1 mcg/day).
Ensure followup with the endocrinologist for close monitoring of calcium levels and medically manage the sequelae of hypoparathyroidism.
SELECTED REFERENCE Roh J, Park C. Routine oral calcium and vitamin D supplements for prevention of hypocalcemia after total thyroidectomy. Am J Surg 2006;192:675–678.
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MANAGEMENT OF INJURY TO THE THORACIC DUCT OR CHYLE LEAKAGE •
•
Overview Chyle leakage develops as a result of injury to the thoracic duct entering the venous system at the junction of the internal jugular and subclavian veins during or after thyroidectomy and/or neck dissection. Incidence of thoracic duct injury varies in the literature. 1.4% following thyroidectomy with central neck dissection.
4.5–8.3% following thyroidectomy with lateral neck dissection.
Draining channels are highly variable and often divide into multiple vessels.
•
Most common site of injury major lymphatic duct in the lower neck lateral to the carotid sheath. May lead to chylothorax.
Leads to nutritional, metabolic, and immunologic deficiencies.
Evaluation and Management •
Physical exam Superficial fluid collection in the vicinity of the left lateral neck ± milky drainage.
Usually identified as a sudden increase in drainage volume (fluid analysis triglycerides >100 mg/dL).
•
Imaging U/S and CT scan may identify a fluid collection. Site of leak can be identified with lymphangiography or lymphoscintigraphy with technetium-99m-labeled sulfur colloid.
•
Management Conservative most leaks resolve with pressure dressings, serial aspiration, and nutritional modifications consisting of mediumchain triglycerides or total parental nutrition. —
Minimally invasive techniques, including percutaneous lymphangiography-guided cannulation and emoblization. ➤ Successful in 45–70% of cases.
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Uncontrolled chyle leakage (>300–400 mL drainage over 4–5 days) generally requires reoperation. —
Wound re-exploration with ligation of the thoracic duct. ➤ A meal rich in cream prior to operation can help to identify the leak.
—
Video-assisted thoracoscopic surgery with thoracic duct ligation.
SELECTED REFERENCES Abdel-Galil K, et al. High ouput chyle leak after neck surgery: the role of videoassisted thoracoscopic surgery. Br J Oral Maxillofac Sur 2009;47(6): 478–480. Roh JL, et al. Chyle leakage in patients undergoing thyroidectomy plus central neck dissection for differentiated papillary thyroid carcinoma. Ann Surg Oncol 2008;15(9):2576–2580. Scorza LB, et al. Modern management of chylous leak following head and neck surgery: a discussion of percutaneous lymphangiography-guided cannulation and emoblization of the thoracic duct. Otolaryngol Clin North Am 2008;41:1231–1240.
OTHER NERVES AT RISK OF INJURY DURING THYROIDECTOMY Horner’s Syndrome • •
Characterized by miosis, eyelid ptosis, enophthalmos, and anhydrosis resulting from damage to the cervical sympathetic chain. Anatomy
Fibers of the sympathetic chain innervating the ipsilateral eye leave the cord at T1 and synapse in the inferior, middle, and superior cervical ganglions postganglionic fibers pass via a plexus situated about the internal carotid artery fibers distribute along its course via the inferior thyroid artery, superior laryngeal and recurrent laryngeal nerves.
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Mechanism — injury commonly occurs to the cervical sympathetic chain, which lies posterior to the carotid sheath. Compression of the cervical sympathetic chain by large benign or malignant goiters
Following thyroidectomy: —
Postoperative hematoma compressing the cervical sympathetic chain — Ischemia-induced neural damage caused by a lateral ligature on the inferior thyroid artery trunk — Retraction injury — Damage to the communication between the cervical sympathetic chain and the recurrent laryngeal nerve during its identification 28 cases have been reported in the literature: — — —
•
35% left with a permanent syndrome. 35% had an incomplete recovery. 27% had a complete recovery.
Management is generally aimed at symptomatic relief.
Injury to the Spinal Accessory Nerve • •
•
Innervates trapezius and sternocleidomastoid muscles Anatomy Courses along the deep lateral surface of the sternocleidomastoid muscle and runs inferiorly in the lateral aspect of the posterior triangle of the neck.
Can be traced, as it gives a branch to the sternocleidomastoid muscle at this level and then passes adjacent and posterior to the digastric muscle.
At risk of injury during lateral neck dissections, including level IIB.
Evaluation
Presents with sagging shoulder, incomplete arm elevation and loss of strength, winged scapula.
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Treatment consists of operative repair at time of injury, neurolysis, or graft. Physical therapy. Reinsertion of levator scapulae and rhomboids to a more lateral point on the scapula to substitute for the paralyzed trapezius.
Other nerves at risk during lateral neck dissection include:
Greater auricular nerve ear numbness Marginal mandibular nerve lower lip weakness —
Phrenic nerve occurs in up to 8% of neck dissections — —
Usually occurs as a retraction injury. Lies under the deep cervical fascia over the anterior scalene muscles. Usually presents with unilateral elevation of the hemidiaphragm on chest x-ray.
Brachial plexus injury —
May present with ipsilateral neck pain and/or sensorimotor deficits in the ipsilateral upper extremity.
SELECTED REFERENCES Cozzaglio L, et al. Horner’s syndrome as a complication of thyroidectomy: report of a case. Surg Today 2008;38:1114–1116. Holmes JD. Neck dissection: nomenclature, classification, and technique. Oral Maxillofac Surg Clin North Am 2008;20:459–475.
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Chapter I.B.9: Thyroid Hormone Replacement/Adjustment Meei J. Yeung, MBBS, FRACS and Jonathan W. Serpell, MBBS, MD, FRACS, FACS
THYROID HORMONE REPLACEMENT/ADJUSTMENT The thyroid is responsible for producing liothyronine (tri-iodothyronine, or T3) and thyroxine (tetraiodothyronine, or T4). These thyroid hormones are available in synthetic forms, with the most commonly used one being levothyroxine.
Pharmacology T4 is variably absorbed from the gastrointestinal tract following oral administration. Approximately 50–75% is absorbed from the jejunum, ileum and duodenum. Fasting will increase the extent of absorption. Coadministration with a variety of vitamins and supplements may decrease the absorption of T4 (Table 1). T4 is primarily metabolized in the liver and kidney to tri-iodothyronine. It has a half-life of six to seven days, with the peak therapeutic effect occurring between three and four weeks. It has a long duration of action, between one and three weeks, even after discontinuation of the drug. To maximize absorption, T4 is best ingested in the fasting state, 30–60 min prior to food consumption. Because of the long half-life of T4, it is possible for once-weekly dosing in patients who are poorly compliant. A dose slightly higher than seven times the usual daily dose may be required in these cases.
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Factors affecting levothyroxine bioavailability.
Factor Increased metabolism
Decreased absorption
Drug interactions
Agent
Effect
Antiepileptics, e.g. phenytoin, carbamazepine, barbiturates Antimalarials, e.g. chloroquine, proguianil Antibacterials, e.g. rifampicin Calcium carbonate Aluminum hydroxide Magnesium hydroxide Ferrous sulfate Sucralfate Cholestyramine Soya flour Warfarin
Increased T4 requirement
SSRI (selective serotonin reuptake inhibitor) Insulin
Increased T4 requirement Increased T4 requirement Increased T4 requirement
Increased therapeutic effects of warfarin Increased T4 requirement Increased dosage of insulin required
Indications T4 replacement is commonly used in the following conditions: • • •
Primary hypothyroidism Secondary hypothyroidism Subclinical hypothyroidism
Primary hypothyroidism Primary or overt hypothyroidism occurs when there has been damage to, inhibition of or removal of the thyroid gland. It may be caused by a number of conditions, including iodine deficiency, chronic autoimmune thyroiditis (Hashimoto’s thyroiditis) and iatrogenic causes such as thyroidectomy, radioactive iodine therapy for hyperthyroidism and external beam radiation for head and neck malignancies.
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The diagnosis of primary hypothyroidism requires abnormal thyroid function test (TFT) results. A thyroid-stimulating hormone (TSH) greater than 10 mU/L (normal 4.50–5.00 mU/L) combined with a free T4 (FT4) below the reference range is diagnostic of primary hypothyroidism. There are numerous clinical signs and symptoms of hypothyroidism and these are generally proportional to the severity of thyroid hormone deficiency and its duration (Table 2). As many of these clinical features may be seen in other conditions, the diagnosis of primary hypothyroidism can be made only when they are accompanied by biochemical confirmation of thyroid hormone deficiency. Treatment with levothyroxine The aims of treatment are to make the patients feel well and to achieve a serum TSH that is within the reference range. The daily requirement of T4 is usually 100–150 µg for adults. The full replacement dose of T4 is approximately 1.6 µg/kg/day (Table 3). In the elderly or in patients with a history of cardiac disease, more cautious administration of T4 is recommended. In these cases, lower starting doses of 12.5–25 µg/day are Table 2
Signs and symptoms of hypothyroidism.
Symptoms Tiredness, weakness Dry skin Feeling cold Hair loss Difficulty in concentrating and poor memory Constipation Weight gain with poor appetite Dyspnea Hoarse voice Menorrhagia (later oligomenorrhea or amenorrhea) Paresthesia Impaired hearing
Signs Dry coarse skin; cool peripheral extremities Puffy face, hands and feet (myxedema) Diffuse alopecia Bradycardia Peripheral edema Delayed tendon reflex relaxation Carpal tunnel syndrome Serous cavity effusions
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Suggested thyroxine replacement regime.
Circumstance Adults with cardiac disease Adults <60 years; no cardiac disease Differentiated thyroid carcinoma — post–total thyroidectomy
Suggested dose (µ g/day) 50–100 100–150 150–200
suggested. In patients who may have some underlying autonomous thyroid function (for example hypothyroidism following treatment of Graves’ disease with radioactive iodine), a lower replacement dose, such as 75–125 µg/day, may suffice. Post thyroidectomy patients These include patients who have had a total thyroidectomy (removal of all thyroid tissue), thyroid lobectomy (removal of an entire thyroid lobe and isthmus) or subtotal thyroidectomy (removal of part of the thyroid gland). In patients who have no residual thyroid tissue, a dose of 100–150 µg/day is usually adequate. For patients who have some residual thyroid tissue (lobectomy or subtotal thyroidectomy patients), it may take a number of months before evident whether T4 replacement is needed. In these cases it may be practical to check the thyroid function tests at 6 to 12 weeks post surgery. The necessity for T4 replacement will be guided by these results of these and using the regime which has been suggested above. Patient who have had a total thyroidectomy for a papillary or follicular thyroid carcinoma are often given a higher dose of T4 replacement to achieve and maintain a suppressed TSH (<0.10 mU/L). The suggested commencement dose in these patients is approximately 2.2–2.5 µg/kg/day. The correct dosage of T4 is determined by the TSH levels, with the goal of treatment being to achieve a serum TSH within the normal reference range (with the exception of thyroid cancer patients, as mentioned earlier), and ideally in the lower half of the normal range. Measurement of TSH after commencement of T4 should be taken at 6–8 weeks, as it takes approximately five half-lives for a drug to equilibrate. Adjustment of T4 dosage is made in 12.5–25 µg increments. For example, patients with a rise
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in the serum TSH should have an increase in their T4 replacement with an additional 12.5–25 µg to their daily dose. Conversely, a fall in the TSH should be reflected by a decrease of 12.5–25 µg per day of the T4 dosage. Clinical effects of T4 replacement can be slow to appear and patients may not experience full relief from symptoms until 3–6 months after normal TSH levels are restored. Once patients have stabilized on the appropriate T4 dose, annual TSH measurements should be performed as followup. Treatment with tri-iodothyronine Tri-iodothyronine alone is not used as long term replacement, since it has a short half-life which requires three to four daily dosing and is associated with fluctuating T3 levels. This medication is occasionally used to bridge patients who are undergoing withdrawal from T4 therapy (such as for radioactive iodine treatment), as it may help to minimize the duration of hypothyroid symptoms. Secondary hypothyroidism Secondary or central hypothyroidism arises from pituitary or hypothalamic disorders and is rare. The biochemical diagnosis is dependent on a combination of TSH with FT4. Patients with secondary hypothyroidism usually have a low TSH concentration, although it may also be within or slightly above the reference range. However, in combination with a low T4, the diagnosis is highly suggestive of secondary hypothyroidism. Additional pituitary function tests such as PRL, FSH, LH and ACTH/cortisol may be necessary for confirming the diagnosis. Treatment Thyroid hormone accelerates the inactivation of cortisol. If given to a patient with cortisol deficiency, this may provoke an adrenal crisis. Therefore treatment with an appropriate glucocorticoid should commence prior to T4 replacement in any patient with a hypothalamic or pituitary disorder. Following this, T4 should be given in 25 µg doses and increased until FT4 concentrations are within the upper third of the reference range.
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As measurements of TSH cannot assess the response of T4 replacement in patients with secondary hypothyroidism, FT4 levels are used to monitor treatment with the aim of maintaining concentrations within the normal reference range. For long term followup, annual T4 levels should be performed once they have stabilized on the correct T4 replacement dose. Subclinical hypothyroidism Subclinical hypothyroidism is defined as elevated TSH secretion in the presence of normal concentrations of thyroid hormones. The prevalence of subclinical hypothyroidism is 8% in women, 3% in men and increases with age. Progression to overt hypothyroidism has been reported to occur in up to 30% of patients, particularly when associated with thyroid antibodies and/or goiters. Patients with subclinical hypothyroidism often have minimal or no symptoms and because of this, debate exists as to whether it should be treated or not. Subclinical hypothyroidism has been associated with an increased risk of coronary and other heart diseases, hyperlipidemia and neuropsychiatric effects. Treatment It is important to confirm that there is a sustained elevation of TSH by repeating the TFTs 3–6 months after the initial test result. The American Association of Clinical Endocrinologists (AACE) recommends treatment of subclinical hypothyroidism when TSH levels >10 µIU/mL or in patients with TSH levels between 5 and 10 µIU/mL in conjunction with a goiter and/or positive antithyroid peroxidase antibodies. These patients have the highest rate of progression to overt hypothyroidism. The aim of treatment is to restore and maintain TSH levels within the normal reference range. A starting T4 dose of 25–50 µg/day can be used and the serum TSH should be measured 6–8 weeks following initiation of treatment. Any changes to the T4 dose should be followed by TSH measurements 2–3 months later. Once a stable TSH has been achieved, it should be measured annually. Patients who do not receive T4 replacement should have followup of their TSH and FT4. For those who are thyroid
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peroxidase antibody–positive, an annual assessment would be appropriate. For patients without thyroid peroxidase antibodies, less frequent assessments are required, possibly every three years.
SELECTED REFERENCES Baskin HJ, Cobin RH, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract 2002;8(6):457–469. Clark O, et al. Textbook of Endocrine Surgery, 2nd Edn. Philadelphia: Elsevier Saunders, 2004. “UK Guidelines for the Use of Thyroid Function Tests” (2006). Col NF, Surks MI, et al. Subclinical thyroid disease: clinical applications. JAMA 2004;291(2):239–243. Daniels GH, Dayan CM, Thyroid Disorders (Fast Facts Series). Oxford: Health Press Limited, 2006. Devoren P. Modern management of thyroid replacement therapy. Aust Prescr 2008;31(6):3. Fauci AS, et al. Harrison’s Principles of Internal Medicine, 17th Edn. McGraw-Hill, 2008. Huber G, Staub JJ, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab 2002;87(7): 3221–3226. Klee GG, Hay ID. Biochemical testing of thyroid function. Endocrinol Metab Clin North Am 1997;26(4):763–775. MIMS Australia, CMP Medica Australia Pty. Ltd., 2009. Olubowale O, Chadwick DR. Optimization of thyroxine replacement therapy after total or near-total thyroidectomy for benign thyroid disease. Br J Surg 2006;93(1):57–60. Roberts GW. Taking care of thyroxine. Aust Prescr 2004;27(3):2. Ross DS. Serum thyroid-stimulating hormone measurement for assessment of thyroid function and disease. Endocrinol Metab Clin North Am 2001;30(2):245–264, vii. Vanderpump MP, Tunbridge WM. Epidemiology and prevention of clinical and subclinical hypothyroidism. Thyroid 2002;12(10):839–847.
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Chapter II.A.1: Parathyroid Laboratory Testing Denise Carneiro-Pla, MD, FACS
INTRODUCTION In this chapter, we present an overview of the biochemical workup of primary, secondary, tertiary, and familial hyperparathyroidism, as well as parathyroid cancer. In addition, genetic testing and the use of bone mineral density in patients with hyperparathyroidism are outlined. Note that all laboratory normal ranges (NRs) for tests used in the workup of parathyroid disease vary widely among institutions; therefore, the physician should use his or her institution’s published NR to evaluate patients with hyperparathyroidism.
SPORADIC PRIMARY HYPERPARATHYROIDISM (SPHPT) The classic presentation of primary hyperparathyroidism is: • • • •
Total serum calcium (NR 8.4–10.2 mg/dL or 2.2–2.6 mmol/L) or ionized calcium (NR 1.14–1.29 mmol/L or 4.5–5.6 mg/dL): elevated Intact parathyroid hormone (iPTH) (NR 14–72 or 10–65 pg/ml): elevated Renal function (creatinine and BUN): normal 24 h urinary calcium (NR 100–300 mg/24 h urine collection): normal or elevated
Selective workup: • •
Phosphorus levels (<3.0 mg/dL) are low in 50% of patients. Albumin for calcium correction in patients with poor nutrition: Corrected total serum calcium (mg/dL) = measured calcium (mg/dL) + (0.8 × [4.0 − albumin (g/dL)]). 147
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The chloride/phosphorus ratio is increased (>33) in a limited number of patients. Chloride levels are elevated in 40% of patients. Alkaline phosphatase can be elevated in patients with significant bone disease. If serum 5′-nucleotidase is elevated, alkaline phosphatase increase is associated with liver dysfunction, and not bone disease. PTH-related peptide (PTHrP): Patients with hypercalcemia and normal PTH levels should have their PTHrP measured to rule out hypercalcemia due to malignancy. Vitamin D levels: Vitamin D deficiency is defined as having 25hydroxyvitamin D [25(OH)vitamin D] below normal limits. This is often present in patients with SPHPT.
There are other biochemical presentations of hyperparathyroidism which differ from the classic presentation of SPHPT. Normocalcemic Hyperparathyroidism Patients presenting with eucalcemia and elevated PTH are often considered to have normocalcemic hyperparathyroidism. However, these patients usually have a physiologic imbalance leading to an elevated PTH level rather than a truly autonomous hyperfunction of parathyroid gland(s). They should always be evaluated for vitamin D deficiency and urinary calcium leak, because these two conditions are treated medically. Vitamin D deficiency: • • • •
Total serum calcium: low normal or normal PTH: elevated Total 25(OH)vitamin D levels (NR 30–74 ng/L): <30 ng/L confirms the diagnosis. 1,25(OH)vitamin D levels (NR 15–75 pg/ml): normal or elevated
This elevation of 1,25(OH)vitamin D occurs because the PTH increase stimulates 1α-hydroxylase, which converts 25(OH)vitamin D to 1,25(OH)vitamin D in the kidney. Patients with vitamin D deficiency should be treated with ergocalciferol 50,000 units once a week for six weeks and then be re-evaluated for 25(OH)vitamin D, PTH, total serum calcium, and ionized calcium after
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the treatment. When vitamin D replacement causes or worsens hypercalcemia without decreasing PTH levels, parathyroid function is considered to be autonomous and no longer responsive to a negative feedback. When the parathyroid glands show signs of autonomous function, parathyroidectomy should be considered. Urinary calcium leak: This is a renal abnormality resulting in chronic urinary loss of calcium, commonly associated with a long history of kidney stones. In such patients, PTH secretion increases to maintain normal serum calcium levels. • • •
Total serum calcium: normal PTH: elevated 24 h urine calcium: elevated >300 mg/L (measure creatinine levels to assure proper 24 h urine collection)
This condition is treated with hydrochlorothiazide 12.5–25 mg daily for a period of 6–8 weeks. Levels of 24 h urinary calcium, 25(OH)vitamin D, PTH, total serum, and ionized calcium should be rechecked after the treatment. Patients who developed hypercalcemia without resolution of hypercalciuria and normalization of PTH levels should be considered for parathyroidectomy, since the parathyroid glands are no longer responding to a normal feedback. If the parathyroid glands are not autonomously functioning, calcium levels should remain within normal limits, and PTH levels should return to the normal range, as should urinary calcium. Often this condition will be diagnosed after parathyroidectomy in patients with eucalcemia associated with elevated PTH levels and may lead to recurrent hyperparathyroidism if left untreated. Inappropriate Secretion of PTH Many believe that patients with hypercalcemia and nonsuppressed PTH (>30 pg/ml) should be considered for parathyroidectomy. The author urges caution in surgically treating these patients, because there is a higher incidence of operative failure and multiglandular disease in this population, possibly due to misdiagnosis. However, some patients have normal PTH levels associated with persistent hypercalcemia and enlarged parathyroid glands visualized on
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ultrasonography or Sestamibi scans. The author’s approach is to obtain PTH and calcium measurements in different laboratories which use distinct antibodies in an attempt to confirm elevated PTH levels. Often, high PTH levels are documented, confirming the classic presentation of SPHPT. Intraoperative PTH monitoring on these patients often reveals the usually elevated PTH levels, confirming that this condition is not necessarily associated with inappropriate PTH secretion, but perhaps an inability of commercially available antibodies to recognize the patient’s PTH molecule. Normal PTH levels intraoperatively decrease the accuracy of intraoperative PTH monitoring (IPM) in confirming single glandular involvement, possibly leading to multiple glandular excision and bilateral neck explorations. All of these factors should be considered before operating on a patient with normal PTH levels. In the author’s opinion, unless calcium levels are clearly and persistently elevated and an enlarged parathyroid gland can be seen on preoperative localization, these patients should not be routinely considered for parathyroidectomy.
DIFFERENTIAL DIAGNOSIS Several conditions can cause hypercalcemia, which must to be ruled out in patients with hyperparathyroidism before parathyroidectomy is considered (Table 1). Comparisons of biochemical presentations of these different etiologies with hyperparathyroidism are summarized in Table 2.
Table 1
Causes of hypercalcemia.
Hyperparathyroidism Malignancy Milk-alkali syndrome Hyperthyroidism Drugs: vitamin D, calcium, hydrochlorothiazide Lithium Sarcoidosis Immobilization
Multiple myeloma Paget’s disease Addison’s disease Hypothyroidism Pheochromocytoma VIPoma Leukemias Rhabdomyolysis
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Biochemical presentation of hyperparathyroidism and other conditions causing hypercalcemia.
N or ↑ NA N or ↑ sp transplant N or ↑ ↑ N ↑ N or ↑ ↓ N or ↑ ↑
Usually ↓ ↑ ↓ ↑ Ionized calcium ↓ 25OH vitamin D N ionized calcium
↑ PTHrP ↓ TSH
↑: above normal range. ↓: below normal range. N: normal. PTHrP: PTH-related peptide. PTH: parathyroid hormone. 25OH vitamin D: 25 hydroxyvitamin D.
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Benign Familial Hypocalciuric Hypercalcemia (BFHH) This familial condition characterized by autosomal dominant inheritance with high penetrance is diagnosed by measuring 24 h urinary calcium levels. A familial history of hypercalcemia, especially at a young age, is suspicious for BFHH. This disease is not treated surgically and can potentially lead to operative failure. • • • •
Total serum calcium: mildly elevated PTH: normal or mildly elevated 24 h urinary calcium: <100 mg/L. The 24 h urine creatinine level should be measured to confirm proper collection. Serum calcium to creatinine clearance ratio: < 0.01 (> 0.02 SPHPT)
Formula: Ca/Cr clearance ratio = (24 h urine Ca/plasma Ca) ÷ (24 h urine Cr/plasma Cr) Hypercalcemia Associated with Malignancy Renal cell carcinoma, lung squamous cell carcinoma, hepatoma and tumors of the bladder, pancreas, breast, ovary, stomach, colon, and parotid gland can cause hypercalcemia. • • •
Total serum calcium: elevated PTH: low PTH-related peptide (NR <2.0 pmol/L): elevated
Hydrochlorothiazide (HCTZ) Intake This is a common cause of hypercalcemia in patients without SPHPT, and often patients with mild disease present with higher calcium levels due to its use. Cessation of HCTZ might lower calcium levels to a normal range in mild cases of SPHPT but may not change the surgical indications in more advanced cases. Hyperthyroidism Patients with normal PTH levels and hypercalcemia should have their TSH measured to rule out hypercalcemia and hypercalciuria due to
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hyperthyroidism. Hypercalcemia should resolve when hyperthyroidism usually due to bone resorption is treated with antithyroid medications. Milk-alkali Syndrome This condition is associated with excessive use of milk products, baking soda, and antacids causing hypercalcemia; however, it is usually accompanied by low PTH levels. Sarcoidosis There are no biochemical studies that can be done to confirm sarcoidosis. Although rarely applied, the hydrocortisone suppression test (hydrocortisone 150 mg/day for 10 days) can be used to differentiate the etiology of hypercalcemia in unclear cases. Hydrocortisone reduces calcium levels in patients with sarcoidosis, vitamin D intoxication, multiple myeloma, and malignancies but rarely in SPHPT. Multiple Myeloma Hypergammaglobulinemia is observed on serum protein electrophoresis in patients with multiple myeloma.
SECONDARY HYPERPARATHYROIDISM Patients with secondary hyperparathyroidism caused by renal insufficiency present with chronic hypocalcemia, hyperphosphatemia, vitamin D deficiency, and consequently hypersecretion of parathyroid hormone as a result of the physiologic positive feedback caused by these biochemical imbalances. Intact PTH levels are usually very high in surgical patients and the standard assays will cross-react with PTH metabolites (midmolecule and C-terminal molecule), increasing even more the PTH level readings. Biointact PTH levels are more specific in measuring the true intact PTH molecule; however, this test is no longer available in the US. Baseline and stimulated aluminum levels used to be measured to rule out aluminum-induced osteodystrophy, but because phosphate binders containing aluminum are no longer used, aluminum toxicity leading to
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bone disease and hypercalcemia is rare. In suspicious cases, these measurements might be necessary along with bone biopsy.
TERTIARY HYPERPARATHYROIDISM Tertiary hyperparathyroidism is considered when patients with secondary hyperparathyroidism become hypercalcemic. This same terminology is used when patients develop hypercalcemia and elevated PTH along with normal renal function after kidney transplantation.
FAMILIAL HYPERPARATHYROIDISM Patients with familial hyperparathyroidism, i.e. multiple endocrine neoplasia (MEN) 1 and 2a, isolated familial primary hyperparathyroidism, and hereditary hyperparathyroidism–jaw tumor syndrome have the same biochemical profile as patients with primary hyperparathyroidism presenting with hypercalcemia, elevated PTH, normal renal function, and normal or high 24 h urinary calcium levels. The following description is related to the basic clinical diagnosis and commonly used genetic testing for these familial syndromes, which are thoroughly discussed individually in separate chapters. Isolated Familial Hyperparathyroidism This is considered when at least one first degree family member has primary hyperparathyroidism without any other endocrinopathies. Some, but not all, of these patients have a defect on chromosome 1 similar to that found in familial hyperparathyroidism–jaw tumor syndrome (HRPT2 gene), but they do not present with jaw tumors. Hereditary Hyperparathyroidism–Jaw Tumor Syndrome Patients with this disease present with fibro-osseous lesions of the mandible and maxilla and hyperparathyroidism, which is usually caused by a single parathyroid gland; however, there is a higher predisposition for parathyroid carcinoma. This is an autosomal dominant disease which has
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been linked to a mutation on the chromosomal region 1q21–q32 (HRPT2). Multiple Endocrine Neoplasia 1 These patients present basically with hyperparathyroidism, pituitary adenomas, and pancreatic tumors (mainly gastrinomas and insulinomas). A germline mutation in the MEN1 gene, which is a tumor suppressor gene located on chromosome 11q12–q13, has been shown. The genetic testing is available for clinical application using DNA sequencing. Multiple Endocrine Neoplasia 2a Genetic testing in patients with MEN2 is important for the diagnosis of the associated pathologies of adrenal (pheochromocytoma) and thyroid (medullary cancer) glands. Germline mutations of the RET protooncogene located on chromosome 10 are present in these patients. Individuals with mutations at codon 634 are more likely to develop HPT. All patients suspected of having MEN2 based on a personal or familial history should undergo genetic testing.
PARATHYROID CANCER Patients with parathyroid cancer have a similar clinical presentation of primary hyperparathyroidism; however, these patients usually present with very high calcium levels (>15 mg/dL) associated with high PTH values. Furthermore, patients who present with a palpable parathyroid tumor are also suspicious for parathyroid cancer. It is paramount to recognize these clinical signs for parathyroid cancer, because the ideal disease treatment is parathyroidectomy with ipsilateral thyroid lobectomy, preferably performed during the initial procedure. The genetic testing of parathyroid cancers shows uniform loss of the tumor suppressor gene RB, which is involved in cell cycle regulation. Many (60%) parathyroid cancers present with HRPT2 mutations. Also, negative parafibromin staining is associated with HRPT2 mutations, strongly predicting parathyroid malignancy.
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BONE MINERAL DENSITY IN PARATHYROID DISEASE Bone mineral density or dual-energy x-ray absorptiometry (DEXA scan) is used to evaluate bone loss in patients with SPHPT, which might be useful for defining indications for parathyroidectomy. Usually bone density is measured in the lumbar spine, femoral neck (hip) and, occasionally, forearm. The results are expressed as follows: • • • •
T-score: bone density of the patient is compared to the young adult population Z-score: bone density of the patient is compared to the gender- and age-matched population Osteoporosis: T-score ≥ −2.5 standard deviation (SD) Osteopenia: T-score > −1 and < −2.5 SD
The Z-score is used to differentiate other causes of bone loss such as menopause, since it compares patients of the same age and gender. The bone loss caused by SPHPT affects mainly cortical bone, which is the predominant bone type of the forearm. The femoral neck is a mix of cortical and trabecular bone, whereas the lumbar spine is mainly trabecular bone. When evaluating bone loss caused by SPHPT, consider evaluating the forearm bone density. If this site is not evaluated, a lower bone density in the femoral neck compared to the lumbar spine might indicate bone loss caused by parathyroid hyperfunction. In contrast, parathyroidectomy improves bone density in all sites, increasing the density by at least 1%/year after surgery mainly on the lumbar spine.
SELECTED REFERENCES Bilezikian JP, Brandi ML, Rubin M, Silverberg SJ. Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features. J Intern Med 2005;257:6–17. Carneiro-Pla DM, Irvin GL, 3rd, Chen H. Consequences of parathyroidectomy in patients with “mild” sporadic primary hyperparathyroidism. Surgery 2007; 142:795–799.
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Heath H, 3rd. Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am 1989;18:723–740. Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET protooncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 1994;6:70–74.
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Chapter II.A.2: Parathyroid Imaging Christine S. Landry, MD, Elizabeth G. Grubbs, MD, Beth S. Edeiken-Monroe, MD, Thinh Vu, MD, E. Edmund Kim, MD and Nancy D. Perrier, MD
INTRODUCTION Minimally invasive parathyroidectomy (MIP) is becoming an increasingly popular approach to the management of primary hyperparathyroidism rather than traditional four-gland exploration. Due to this technological advance, imaging of the parathyroid gland is an essential part of preoperative planning. Currently, multiple imaging modalities are available for identifying and localizing hyperfunctioning parathyroid glands. The radiological technique utilized varies across institutions. Approximately 80% of patients with primary hyperparathyroidism have an isolated parathyroid adenoma, while nearly 20% have parathyroid hyperplasia in more than one gland. Less than 1% of patients have parathyroid carcinoma, which typically involves only one gland. Preoperative determination of the exact location of the hyperfunctioning parathyroid gland in patients with a suspected parathyroid adenoma is advantageous for the patient, the surgeon, and the anesthesiologist. For instance, the surgeon can optimize head positioning and the location of the neck incision. The end result is a minimal dissection, a shorter operative time, and a decreased risk of injury to the normal parathyroid glands and the recurrent laryngeal nerves. Also, the anesthesiologist can tailor the length of anesthesia according to the operative complexity and proposed length of the surgical procedure. A nomenclature system for common locations of parathyroid glands has recently been developed at The University of Texas MD Anderson Cancer Center (MDACC) to facilitate multidisciplinary communication (Fig. 1). This system classifies gland locations according to the relationship to the 159
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Fig. 1 Parathyroid nomenclature for classifying common locations of parathyroid adenomas: knowledge of the precise location of a parathyroid adenoma preoperatively is beneficial to the surgeon, anesthesiologist, and patient, as it facilitates a focused dissection.
thyroid parenchyma and recurrent laryngeal nerves. A type A gland originates from the superior pedicle, is lateral to the recurrent laryngeal nerve, and is adherent to the thyroid gland. A type B parathyroid gland is a superior gland in the tracheoesophageal groove behind the thyroid parenchyma. A type C gland is caudal to the thyroid gland in the tracheoesophageal groove, inferior to a type B gland. A type D gland lies near the junction of the recurrent laryngeal nerve and the middle thyroid vein or inferior thyroid artery. A type E gland is located at the inferior pole of the thyroid parenchyma. A type F gland can be found in the thyrothymic ligament, and a type G gland is intrathyroidal. Defining the precise location of a parathyroid adenoma is also beneficial for collaborative efforts with other centers, and enrollment in clinical trials. This chapter describes the most common radiological techniques used to evaluate patients with primary hyperparathyroidism. Likewise, we have
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incorporated our nomenclature system into our radiological interpretations to demonstrate the ease of communication between the radiologist and the surgeon. The imaging modalities that will be discussed include: ultrasound (US), nuclear imaging, four-dimensional computed tomography scan (4D-CT), and magnetic resonance imaging (MRI).
IMAGING MODALITIES Ultrasound Depending on the center, ultrasound of the soft tissues of the neck may be performed by a radiologist, surgical endocrinologist, or medical endocrinologist, and the accuracy is operator-dependent. This technique is performed using a 7.5–12 MHz transducer with the patient in the supine position and the neck extended. Extension of the neck elevates adenomas lower in the neck, which could not otherwise be visualized. Parathyroid glands have a homogenous echogenic appearance that is hypoechoic when compared to the thyroid gland. Color Doppler ultrasound may be helpful in documenting the vascularity within the parathyroid gland (Fig. 2). In addition, a cystic component may be present. Calcifications, rarely seen in parathyroid adenomas, are more common in parathyroid hyperplasia and parathyroid carcinoma. Also, ultrasound may localize glands by side and quadrant, but this modality is not dependable in differentiating superior from inferior glands. For example, a superior parathyroid gland may have migrated inferiorly, and may be mistaken for an inferior gland. Moreover, it should be noted that ultrasound cannot definitively differentiate an adenoma from a carcinoma. Ultrasonography of the cervical region is sensitive for identifying hyperfunctioning parathyroid glands up to 92% of the time, depending on the location of the gland and on the experience of the sonographer. The specificity for this technique ranges from 60 to 80%. Ultrasound cannot image or localize parathyroid adenomas located in the mediastinum, retrotracheal, paratracheal, retroesophageal, and retrosternal areas, because sound waves are unable to penetrate through bone or the trachea. Intrathyroidal adenomas can be identified with ultrasound, but cannot be differentiated from thyroid nodules based on ultrasound characteristics alone.
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(b)
(a)
Th T
C
T –Trachea, Th –Thyroid Gland, C – Carotid Artery (c)
Fig. 2 Ultrasound of the soft tissues of the neck: (a) transverse and (b) longitudinal dimensions demonstrating a 2.9 × 1 × 0.5 cm parathyroid adenoma inferior and lateral to the thyroid gland with (c) vascular flow documented by color Doppler.
In patients with parathyroid disease, ultrasound can be used to identify concomitant thyroid pathology. This is helpful in determining whether a minimally invasive parathyroidectomy is appropriate or another procedure should be performed. In one study of 163 patients, thyroid disease such as thyroiditis or goiter was identified in 84% of patients with primary hyperparathyroidism. Among these patients, 23 of the 39 patients who underwent fine needle aspiration (FNA) for suspicious findings on ultrasound were not candidates for MIP based on abnormal FNA results. At surgical intervention, nine of these patients had a thyroid malignancy on final pathologic review. Ultrasound has also been useful at MDACC in localizing autotransplanted parathyroid tissue. In the absence of an identifying surgical clip, ultrasound-guided FNA has been used preoperatively to confirm the
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location of autotransplanted parathyroid tissue. The use of ultrasound in this way helps to minimize dissection in the reoperative patient. Nuclear Imaging Many nuclear imaging techniques have been described for evaluating patients with primary hyperparathyroidism. Initially, thallium 201technetium was used because the rich mitochondrion of parathyroid cells had a higher uptake of radio tracer when compared to adjacent thyroid parenchyma. Sestamibi trumped thallium scintigraphy when it was demonstrated that sestamibi had a higher uptake than thallium in the hyperfunctioning parathyroid cells due to its physical properties. Even though sestamibi is currently the most common isotope used, it is inaccurate in patients with multiple adenomas or parathyroid hyperplasia because it may not identify all hyperfunctioning glands. Also, sestamibi scans are limited as coexisting thyroid pathology is not visualized. There are three methods associated with technetium scans. First, single-isotope dual-phase scanning obtains cervicothoracic scans 10 min and 2–3 h after the radioisotope is injected. The delayed scan is more useful because the thyroid clears the isotope uptake faster than parathyroid glands or lesions. Second, dual-isotope subtraction scans use 99m Tc-sestamibi with another isotope specific to thyroid cells such as 99m Tc-pertechnetate or 123I sodium iodide to allow for thyroid subtraction. This technique has a sensitivity ranging from 68 to 90% for localizing parathyroid adenomas. Subtraction techniques are limited because separate studies using each isotope are required with the patient in identical positions. Patients who are mobile or uncooperative will have a higher number of artifacts as the subtraction is affected. A more modern technique is dual-phase single-tracer imaging using 99m Tc-sestamibi. This modality is now the predominant method for evaluating primary hyperparathyroidism as it has a sensitivity ranging from 89 to 95% for the localization of parathyroid adenomas (Fig. 3). More recently, it has been combined with single-photon emission computed tomography (SPECT) to provide better localization in a three-dimensional picture (Fig. 3). SPECT-CT using sestamibi, which has a higher sensitivity, can better estimate the location of an enlarged parathyroid gland. It also provides
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P
Th
E
P P: Parathyroid Gland Th: Thyroid Gland
a) (a)
(b)
E: Esophagus
Fig. 3 Sestamibi parathyroid scan with SPECT-CT: (a) 80 min delayed planar image localizing the hyperfunctioning parathyroid gland in the right thyroid bed. This anterior–posterior (A–P) view does not provide enough information for discerning if the parathyroid gland is an inferior or superior gland in origin. More information from a lateral view or a cross-sectional view is necessary in order to localize the gland as being anterior near the trachea or posterior near the spine. (b) SPECT-CT axial image displaying the parathyroid adenoma caudal to the thyroid gland in the tracheoesophageal groove consistent with a type C gland.
characterization of the lesion and additional morphological information. However, as with other sestamibi imaging, SPECT-CT is limited in patients with multiglandular disease. For instance, other centers have found that 12–18% of patients with primary hyperparathyroidism had negative sestamibi scans, and up to 30% of these patients had multiglandular disease. The early phase images of SPECT-CT is dependent on the anatomical location of the parathyroid glands as well as the uptake of tracer in both the thyroid and parathyroid glands. For instance, a parathyroid adenoma that is intrathyroidal or contiguous with the thyroid gland is apparent on early phase imaging only if the uptake is greater in the hyperfunctioning parathyroid gland, or there is asymmetry in the thyroid gland. Parathyroid adenomas often demonstrate a delayed washout pattern when compared with the thyroid gland, which may help differentiate adenomas from thyroid tissue on delayed images. However, because thyroid adenomas can also demonstrate delayed washout patterns, higher
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tracer uptake contiguous with the thyroid gland may not necessarily represent a parathyroid adenoma. Four-Dimensional CT (4D-CT) Even though sestamibi scans can be helpful in identifying hyperfunctioning parathyroid glands, the four-dimensional computed tomography scan (4DCT) is an emerging modality that provides both the anatomical location and the function of the parathyroid gland. Typically, a hyper-functioning parathyroid gland is characterized by a more rapid uptake and washout of 4D-CT when compared to normal parathyroid glands. 4D-CT helps to localize hyperfunctioning glands by incorporating 3D-CT of the neck with attention to changes in enhancement (perfusion) of the parathyroid glands over time. 4D-CT has a markedly higher sensitivity than sestamibi scans or ultrasound when used to lateralize hyperfunctioning parathyroid glands to one side of the neck, or to localize to the correct quadrant of the neck. As described previously, we have applied our nomenclature system to our preoperative imaging to identify the exact location of the hyperfunctioning gland in an effort to minimize dissection (Fig. 4). 4D-CT is especially advantageous for preoperative localization in patients who require reoperative parathyroidectomy. A prospective study at MDACC demonstrated that 4D-CT is superior to the sestamibi scan for preoperative localization in the reoperative setting, with a sensitivity of 88% for 4D-CT and 54% for sestamibi imaging, respectively. Likewise, 4D-CT is advantageous for patients with multiple endocrine neoplasia 2A (MEN 2A), since the surgical management ranges from resection of a single parathyroid adenoma to subtotal parathyroidectomy. This modality is also useful for identifying ectopic or autotransplanted parathyroid issue which may be encountered in MEN 2A patients. MRI MRI is not commonly used in the preoperative setting for localizing parathyroid adenomas because it is expensive, and patients may have claustrophobia or difficulty in remaining immobile during the procedure. However, it can be advantageous in some patients as a contrast medium is
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Th P
(a)
P
P
(b)
(c)
Fig. 4 Preoperative localization of a parathyroid adenoma with 4D-CT: patient with right type A parathyroid adenoma. Axial (a), sagittal (b), and coronal (c) reconstructed maximal intensity projection images are shown. The axial reconstructed image shows a large enhancing parathyroid adenoma lateralized to the right tracheoesophageal groove and opposed to the posterior surface of the right thyroid lobe. The sagittal and coronal reconstructed images localize the parathyroid adenoma superior to the thyroid gland, suggesting an adenomatous superior parathyroid gland. (P — parathyroid adenoma; Th — thyroid gland.)
not required, and there are no artifacts from surgically placed clips. This modality is useful for identifying ectopic glands, especially in the reoperative neck. The sensitivity of MRI for localizing parathyroid adenomas ranges from 50 to 88%. Typically, a parathyroid adenoma has a low intensity on T1 imaging and a high intensity on T2 imaging. Not all parathyroid adenomas have the same imaging characteristics. Often, thyroid nodules and enlarged lymph nodes can lead to false positive results. Likewise, false negative results can occur with parathyroid hyperplasia or when an adenoma is in close proximity to a multinodular goiter.
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Radioguided Parathyroidectomy Some centers perform minimally invasive radioguided parathyroidectomy for primary hyperparathyroidism. With this technique, patients are administered an average of 20 mCi 99Tcm-sestamibi for scanning on the morning of surgery. Delayed imaging is obtained 2 h after injection and the skin is marked over the location of the hyperfunctioning parathyroid gland. The location of the incision is then guided by the location of the highest radioactivity and the ink mark. The gamma probe is used to help identify the location of the parathyroid adenoma. Radioactive levels in vivo, ex vivo, and in the operative basin are recorded during the procedure. If the count of the excised tissue is 20% greater than the background count, this confirms that parathyroid tissue has been removed. This technique works best when the sestamibi scan is considered positive. Limitations associated with this technique include false positive results from concomitant thyroid disease and increased cost.
SPECIFIC QUESTIONS FOR THE ENDOCRINE SURGEON Which patients require preoperative imaging? Preoperative localization helps determine where to start a parathyroidectomy when single-gland disease is suspected as the source of primary hyperparathyroidism. Localization is required of a MIP is planned, and for patients who have undergone previous thyroid or parathyroid surgery. Patients who have secondary or tertiary hyperparathyroidism do not require preoperative imaging because they require four-gland exploration. Likewise, patients with concomitant thyroid disease who will receive a bilateral neck exploration of the central neck do not require preoperative imaging since both sides of the neck will be inspected intraoperatively. In addition, patients with primary hyperparathyroidism and familial disease do not require preoperative imaging since they usually have four-gland disease. Is there a role for invasive localization studies? Invasive localization studies can be helpful when the results of other imaging modalities are inconclusive, negative, or discordant. For
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instance, an ultrasound-guided FNA of a suspected nodule may be helpful in further characterizing whether a nodule is thyroid or parathyroid tissue. The aspirate can be analyzed for elevated parathyroid hormone, which may confirm parathyroid disease. Parathyroid arteriography is a difficult and expensive technique that can identify adenomas with a sensitivity ranging from 60 to 65% when subtraction techniques are used. Selective venous sampling is another option. Venous sampling lateralizes approximately 80% of adenomas, and can help identify mediastinal glands.
What studies should be ordered to evaluate patients with primary hyperparathyroidism? Imaging modalities should be selected on the basis of availability, cost, and the experience of the surgeons and radiologists. First, noninvasive imaging studies should be obtained. At MDACC, we begin our evaluation with a neck ultrasound to identify for any coexisting thyroid pathology or enlarged parathyroid glands, followed by a sestamibi SPECT-CT. If these studies are discordant, or additional anatomical information is required, we perform a 4D-CT.
What studies are required for the reoperative patient with recurrent or persistent disease? As a general rule, if re-exploration is planned for a patient with persistent or recurrent disease, two concomitant concordant images should be obtained. Operative exploration should not be performed without sufficient preoperative information from localization studies. We recommend first evaluating patients with a neck ultrasound and a sestamibi SPECTCT scan. We perform a 4D-CT to provide additional anatomical information. MRI may be beneficial if studies are discordant or 4D-CT is not available. If selective venous sampling is obtained in the patient with recurrent disease, the venous drainage may be affected from previous thyroid surgery.
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What imaging should be performed if parathyroid carcinoma is suspected? In the majority of cases, the diagnosis of parathyroid carcinoma is suspected preoperatively by older age, exceedingly high serum calcium levels, and the visualization of firm or large cystic masses on ultrasound and CT. The diagnosis is confirmed intraoperatively. 4D-CT, SPECT-CT, and ultrasound are excellent tools that can be used to evaluate suspected primary or recurrent parathyroid cancer. A CT scan of the chest and abdomen is useful for identifying mediastinal, lung, and liver metastases. Likewise, a SPECT-CT scan can be an excellent adjunctive study to identify additional parathyroid tissue. What should be done if all the parathyroid imaging is negative and the diagnosis of primary hyperparathyroidism is confirmed biochemically? Negative preoperative imaging does not mean that the patient does not have biochemical primary hyperparathyroidism. Such patients may have had a poor quality imaging study, multiglandular disease, parathyroid hyperplasia, or an adenoma contiguous with the thyroid gland. In these cases, bilateral neck exploration is necessary.
CONCLUSION Parathyroid imaging is an essential part of the preoperative workup for patients undergoing MIP, and for patients with a previous history of thyroid or parathyroid surgery. The preferred imaging techniques varies between institutions, and should be selected based on availability, cost, and experience. Incorporation of a nomenclature system to be used by the radiologist and surgeon can be an excellent tool.
SELECTED REFERENCES Adil E, Adil T, Fedok F, et al. Minimally invasive radioguided parathyroidectomy performed for primary hyperparathyroidism. Otolaryngol Head Neck Surg 2009;141(1):34–38.
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Ahuja AT. The thyroid and parathyroids. In: Practical Head and Neck Ultrasound, (ed.) A Ahuja. New York: Cambridge University Press, 2007, pp. 35–62. Bhure UN. SPECT and PET in benign thyroid and parathyroid disease. In: Molecular Anatomic Imaging: PET-CT and SPECT-CT Integrated Modality Imaging (ed.) GK von Schulthess. Philadelphia: Lippincott Williams & Wilkins, 2007. Eslamy HK, Ziessman HA. Parathyroid scintigraphy in patients with primary hyperparathyroidism: 99mTc sestamibi SPECT and SPECT/CT. Radiographics 2008;28(5):1461–1476. Kettle AG, O’Doherty MJ. Parathyroid imaging: how good is it and how should it be done? Semin Nucl Med 2006;36(3):206–211. McGreal G, Winter DC, Sookhai S, et al. Minimally invasive, radioguided surgery for primary hyperparathyroidism. Ann Surg Oncol 2001;8(10): 856–860. Monroe DP, Edeiken-Monroe BS, Lee JE, et al. Impact of preoperative thyroid ultrasonography on the surgical management of primary hyperparathyroidism. Br J Surg 2008;95(8):957–960. Mortenson MM, Evans DB, Lee JE, et al. Parathyroid exploration in the reoperative neck: improved preoperative localization with 4D-computed tomography. J Am Coll Surg 2008;206(5):888–895. Perrier ND, Edeiken B, Nunez R, et al. A novel nomenclature to classify parathyroid adenomas. World J Surg 2009;33(3):412–416. Philip M, Guerrero MA, Evans DB, et al. Efficacy of 4D-CT preoperative localization in 2 patients with MEN 2A. J Surg Educ 2008;65(3):182–185. Rodgers SE, Hunter GJ, Hamberg LM, et al. Improved preoperative planning for directed parathyroidectomy with 4-dimensional computed tomography. Surgery 2006;140(6):932–940. Rodriguez JM. Localization studies in persistent or recurrent hyperparathyroidism. In: Textbook of Endocrine Surgery, (eds.) OH Clark, Q-Y Duh. Philadelphia: Elsevier Saunders, 2005, pp. 430–438. Yip L, Pryma DA, Yim JH, et al. Sestamibi SPECT intensity scoring system in sporadic primary hyperparathyroidism. World J Surg 2009;33(3): 426–433.
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Chapter II.B.1: Clinical Management of Primary Hyperparathyroidism Joel T. Adler, MD, Rebecca S. Sippel, MD, FACS and Herbert Chen, MD, FACS
INTRODUCTION Surgical management of primary hyperparathyroidism has evolved into an operation with a greater-than-95% success rate. The complication rate is probably less than 3%, making this a successful and safe operation. This is dependent upon an accurate diagnosis, appropriate selection of patients for surgery, and good operative technique. The open, bilateral exploration of the neck has given way to a minimally invasive technique. Minimally invasive parathyroidectomy (MIP) is made possible by accurate pre- and intraoperative localization of the overactive parathyroid glands, reducing the amount of exploration necessary and resulting in a more targeted operation. It is also aided by intraoperative measurements of parathyroid hormone (ioPTH), which permits the minimally invasive approach by ruling out multigland disease. The potential benefits of MIP include improved cosmesis, reduced postoperative pain, a shorter length of stay, and a quicker return to preoperative activity level. This chapter describes the indications and operative approaches in the clinical management of primary hyperparathyroidism.
INDICATIONS There is little question that surgery is an appropriate therapeutic intervention in patients with the classic symptomatology of “bones, stones, abdominal groans, and psychiatric overtones”: osteitis fibrosa cystica, nephrolithiasis, abdominal pain, and psychiatric disturbances. However, 171
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1.0 mg/dl above upper limit of normal Reduced to <60 ml/min T score <−2.5 at any site and/or previous fracture fragility <50 years
surgical correction is associated with increased bone mineral density and improvements in quality of life, regardless of symptomatology. Surgery can ameliorate the clinical symptoms of primary hyperparathyroidism and contributes to improvements in quality of life, supporting aggressive surgical treatment of this disease. Recently, an NIH panel outlined criteria for parathyroidectomy in patients with primary hyperparathyroidism (Table 1). Many have argued that these guidelines are too restrictive, suggesting that those with “mild” disease, defined as inappropriate secretion of PTH or normocalcemic hyperparathyroidism, could also benefit from surgery in both clinical outcomes and quality-of-life measures. The benefits of parathyroidectomy are listed in Table 2. Table 2 Signs and symptoms of primary hyperparathyroidism affected by surgery. Fatigue Musculoskeletal aches and pains Back pain Weakness Polydipsia Polyuria Pruritis Memory loss Nausea Nephrolithiasis Renal failure Osteitis fibrosa cystica Recovery of bone mass (incomplete; clearer in advanced cases) Peripheral insulin resistance
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MINIMALLY INVASIVE PARATHYROIDECTOMY To effectively perform MIP, high-quality localization techniques are essential. In addition to accurate preoperative localization, successful MIP depends upon an experienced endocrine surgeon and the availability of ioPTH, which is crucial for excluding multigland disease intraoperatively. All patients with a biochemical diagnosis of primary hyperparathyroidism should undergo preoperative localization (see chapter on parathyroid localization). If imaging localizes a single parathyroid adenoma, MIP can be performed.
Local and General Anesthesia Either standard general anesthesia or local anesthesia may be used. Patient preference may dictate local anesthesia with monitored anesthesia care (MAC). If local anesthesia is chosen, it is performed via injection of 1% lidocaine with 1:100,000 epinephrine along both the anterior and posterior borders of the sternocleidomastoid muscle on the ipsilateral side of the adenoma. The injection depth is approximately 1 cm, and usually a total of 20 ml of 1% lidocaine is used. This will block the great auricular nerve, the anterior cervical nerve, and the supraclavicular nerve. Comparable operative results, clinical results, and patient satisfaction between local anesthesia with MAC and general anesthesia have been demonstrated. However, MIP is commonly still performed under general anesthesia.
Intraoperative PTH Testing A large-bore peripheral IV line is used for ioPTH levels. Prior to excision of the parathyroid adenoma, a baseline ioPTH level is obtained. ioPTH levels can be analyzed by standard machines such as the Elecsys 1010 or 2010 (Roche Diagnostics, Laval, Quebec, Canada). From the time the blood is drawn, the assay takes approximately 15 min to return a result. At the University of Wisconsin, curative resection is confirmed by measuring drop in ioPTH levels compared with the baseline at 5, 10, and 15 min postresection. A drop of 50% at any of these time points is sufficient for
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cure; a persistently elevated ioPTH indicates an inadequate resection and necessity for further exploration. Other criteria have been proposed in an effort to minimize the possibility of mutligland disease and noncurative operation. The Miami criteria are defined as an ioPTH drop of 50% or more from either the highest preoperative baseline or pre-excision level 10 min after removal. The Halle criteria are defined as an ioPTH decay into the low-normal range within 15 min of removal. The Rome criteria are an ioPTH decay greater than 50% from the highest pre-excision level, and/or ioPTH concentration within the reference range at 20 min postexcision, and/or ≤7.5 ng/L lower than the value at 10 min postexcision. The Vienna criteria are a decay 50% or greater from the preincision value within 10 min of resection. Radioguided Approach For intraoperative detection of parathyroid glands, a 10 mCi dose of 99m Tc-sestamibi is given on the day of surgery. The timing of radiotracer injection for intraoperative gamma detection is critical. The 10 mCi dose of 99mTc-sestamibi is given approximately 1–2 h before surgery to minimize incidental radiation exposure to the surgical team and may improve identification of parathyroid adenomas. Same-day protocols combining imaging and intraoperative localization have been described. A full dose of 99mTc-sestamibi is given on the day of surgery, with a dual-phase parathyroid scintigraphy for localization performed at 20 min and 2 h postinjection. While this protocol is advantageous in that it offers a sameday experience for the patient, if imaging is negative it does not allow additional imaging prior to surgery. Lower dose protocols have also been described with 5 mCi doses. Searching for the hyperactive gland is guided by preoperative parathyroid imaging. Using an 11mm collimated gamma probe (Neoprobe 2000, Ethicon Endo-Surgery Breast-Care, Cincinnati, Ohio), the background count is set on the skin overlying the thyroid isthmus, as washout from the thyroid gland is much faster than from the parathyroid glands. A1–3 cm incision is made overlying the localized parathyroid adenoma. The gamma probe is utilized to triangulate and to determine the trajectory and approach to the parathyroid gland. Following excision of the parathyroid
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adenoma, ex vivo radiotracer counts are determined by placing the parathyroid tissue on top of the gamma probe. The ex vivo rate should be at least 20%, but it is usually 50%, higher than background. No resected periglandular tissue, including fat, lymph node, or thyroid, exceeds the 20% threshold. The gamma probe is then utilized to explore the surgical bed and the rest of the neck. Surgical Technique and Other Considerations Adequate dissection of the superior parathyroid glands typically requires an incision overlying the anterior border of the sternocleidomastoid muscle, while a truncated Kocher incision is used for inferior parathyroid adenomas. The incision is made, the strap muscles are retracted, and the gamma probe is inserted directly over the presumed location of the adenoma. Meticulous intraoperative hemostasis limits postoperative complications, as intraoperative bleeding increases the risk of postoperative bleeding. Modern surgical devices have led to a lower rate of hematoma formation with an increase in the speed of surgery. The placement of neck drains is rarely required. Intraoperative frozen section analysis is not typically necessary to confirm the identity of resected glandular tissue when utilizing MIP. Most patients who undergo MIP are able to return home the same day. If necessary, due to comorbidities or physician preference, an overnight stay for observation is perfectly acceptable.
BILATERAL EXPLORATION As MIP continues to gain acceptance, the traditional bilateral exploration is becoming less frequently utilized. However, it is necessary in cases of adenomas on both sides of the neck and parathyroid hyperplasia. It also has use in situations where the ioPTH does not fall, indicating MGD. The neck is opened with a slightly larger incision that crosses the midline. Taking care not to injure the recurrent nerve, the neck is explored to discover adenomatous parathyroid glands. After resection of adenomatous glands, ioPTH levels are sent again until the levels appropriately decline. If all four glands are enlarged or abnormal, either a subtotal (3½ glands)
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parathyroidectomy or a total parathyroidectomy with reimplantation of one gland into the forearm or sternocleidomastoid muscle is appropriate.
ECTOPIC GLANDS Intrathyroidal Glands While in the majority of cases the parathyroid glands are found in the same anatomic location, parathyroid glands can also be found within the thyroid gland. This may be localized on preoperative imaging, or may become evident when parathyroid glands are not found in the expected location. Often, these glands are supernumerary as well as ectopic. As described in other chapters, preoperative ultrasound can be extremely useful for localizing these ectopic glands. Moreover, the ultrasound can be used intraoperatively to further localize an intrathyroidal or otherwise ectopic gland. If the radioguided approach is chosen, this may also prove useful for discovering glands in other locations within the neck. Video-Assisted Thoracoscopic Surgery As a consequence of the embryologic development, the parathyroid glands can be found within the thymus. These mediastinal glands can usually be removed via a cervical approach when located above the aortic arch. If they are below the aortic arch, video-assisted thoracoscopic surgery (VATS) may be used. A similar approach to MIP is employed. The first step is accurate preoperative localization. Consultation with a surgeon experienced in VATS is essential. Careful technique is utilized to avoid injury to the phrenic nerves. After the gland is localized, PTH measurements are taken as per the usual protocol to confirm successful resection of the adenomatous gland. If a radioguided approach is employed, a gamma probe can be utilized to confirm that resected tissue is parathyroid tissue within the mediastinum.
INTRAOPERATIVE NERVE MONITORING Hoarseness is a worrisome complication of parathyroidectomy, and it is due, in part, to the varied anatomy of the recurrent laryngeal nerve. To
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minimize the possibility of injury, some surgeons advocate the use of recurrent laryngeal nerve monitoring by placing an electrode-lined endotracheal tube between the vocal cords to observe electromyographic activity. A nerve stimulator is used intraoperatively to stimulate the recurrent laryngeal nerve or vagus nerve to confirm function of the nerve. A recent review noted no difference in either temporary or permanent palsy between electromyographic nerve monitoring and visual nerve identification. Transient postoperative hoarseness may also be caused by endotracheal intubation. If injury to the recurrent laryngeal nerve is permanent, a speech and swallowing specialist should be consulted.
CONCLUSIONS Surgical resection is the only cure for primary hyperparathyroidism, and it has been shown to be technically feasible, safe, and cost-effective. The potential benefits of MIP include improved cosmesis, reduced postoperative pain, a shorter length of stay, and a quicker return to preoperative activity level. The procedure depends upon a skilled surgeon with experience in parathyroid surgery, high-quality localization, and ioPTH to rule out multigland disease. With the wider introduction of this technology, MIP will continue to replace the traditional four-gland exploration as the procedure of choice at most institutions.
SELECTED REFERENCES Bénard F, Lefebvre B, et al. Rapid washout of technetium-99m-MIBI from a large parathyroid adenoma. J Nucl Med 1995;36(2):241–243. Bilezikian JP, Khan AA, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Third International Workshop. J Clin Endocrinol Metab 2009;94(2):335–339. Chen H. Radioguided parathyroid surgery. Adv Surg 2004;38:377–392. Chen H, Mack E, et al. Radioguided parathyroidectomy is equally effective for both adenomatous and hyperplastic glands. Ann Surg 2003;238(3):332–337. Chen H, Mack E, et al. A comprehensive evaluation of perioperative adjuncts during minimally invasive parathyroidectomy: which is most reliable? Ann Surg 2005;242(3):375–380.
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Chen H, Pruhs Z, et al. Intraoperative parathyroid hormone testing improves cure rates in patients undergoing minimally invasive parathyroidectomy. Surgery 2005;138(4):583–587. Chen H, Sokoll LJ, et al. Outpatient minimally invasive parathyroidectomy: a combination of sestamibi-SPECT localization, cervical block anesthesia, and intraoperative parathyroid hormone assay. Surgery 1999;126(6):1016–1021. Irvin GL, Sfakianakis G, et al. Ambulatory parathyroidectomy for primary hyperparathyroidism. Arch Surg 1996;131(10):1074–1078. Mariani G, Gulec SA, et al. Preoperative localization and radioguided parathyroid surgery. J Nucl Med 2003;44(9):1443–1458. Massaro A, Cittadin S, et al. Accurate planning of minimally invasive surgery of parathyroid adenomas by means of [(99m)Tc]MIBI SPECT. Minerva Endocrinol 2007;32(1):9–16. Nilubol N, Beyer T, et al. Mediastinal hyperfunctioning parathyroids: incidence, evolving treatment, and outcome. Am J Surg 2007;194(1):53–56. Norman J, Chheda H. Minimally invasive parathyroidectomy facilitated by intraoperative nuclear mapping. Surgery 1997;122(6):998–1003. O’Herrin JK, Weigel T, et al. Radioguided parathyroidectomy via VATS combined with intraoperative parathyroid hormone testing: the surgical approach of choice for patients with mediastinal parathyroid adenomas? J Bone Miner Res 2002;17(8):1368–1371.
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Chapter II.B.2: Secondary Hyperparathyroidism Mohamed O. Abdelgadir Adam, MD, Patrick H. Pun, MD, MHS and John A. Olson, Jr., MD, PhD
DEFINITION Secondary hyperparathyroidism (SHPT) is characterized by an elevated serum level of parathyroid hormone (PTH) due to kidney dysfunction which leads to disruptions in calcium and phosphorus homeostasis. Protracted hyperphosphatemia in combination with calcitriol deficiency and decrement in ionized calcium lead to autonomous stimulation of parathyroid growth and function, resulting in parathyroid hyperplastic proliferation and therefore exaggerated PTH secretion. Rarely, other conditions may also lead to SHPT (Table 1). Prolonged SHPT may evolve into monoclonal nodular parathyroid expansion that is characterized by insuppressible PTH and hypercalcemia, a condition known as tertiary hyperparathyroidism. Tertiary hyperparathyroidism is also the term given to patients with hypercalcemia and elevated PTH following renal transplantation.
HISTORICAL BACKGROUND Albright and colleagues are generally acknowledged as being the first to recognize the relationship between chronic kidney disease (CKD) and parathyroid enlargement, in 1934 (Albright et al., 1934). It was first thought that renal insufficiency is a consequence rather than a cause of HPT. In 1958, Stanbury and others performed the first subtotal parathyroidectomy due to uremia (Stanbury et al., 1968). However, it was not until 1975 that Wells et al. reported the first successful parathyroidectomy with parathyroid transplantation in 29 patients with concomitant SHPT and renal failure. They also introduced the concept of antecubital venous 179
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M. O. A. Adam, P. H. Pun and J. A. Olson, Jr. Table 1 • • • • • • •
Causes of secondary hyperparathyroidism.
Renal insufficiency Long-term lithium therapy Vitamin D deficiency Malabsorption Malnutrition Vitamin D–resistant rickets Hypermagnesemia
PTH sampling as a technique to assess the viability of the parathyroid autograft in the forearm (Wells et al., 1975).
EPIDEMIOLOGY HPT is a common finding in patients with end stage renal disease (ESRD). In data collected from 10 outpatient dialysis centers, 50% of the mostly African-American 612 dialysis patients were found to have PTH levels more than three times the normal limit (>165 pg/mL) (Salem, 1997). In another study of 176 predominantly Caucasian patients who were on peritoneal dialysis, 47% had a PTH level more than three times the normal range (Billa et al., 2000). Others have reported higher prevalence, as high as 78% in a population who had been on dialysis longer (Owda et al., 2003). This discrepancy in the reported prevalence rate may be a reflection of the impact of dialysis duration on the epidemiology of the disease. The length of time on dialysis in months to years (dialysis vintage) correlates well with higher prevalence of the disease as well as parathyroidectomy (Billa et al., 2000; Malberti et al., 2001; Nasri and Kheiri, 2008). Approximately 5% of patients with end stage kidney disease (ESKD) undergo parathyroidectomy as a treatment for SHPT (Johnson et al., 1988; Packman and Demeure, 1995). Factors associated with the need for parathyroidectomy in SHPT include female gender, younger age, lower hemoglobin, nondiabetic renal failure, peritoneal dialysis, and longer dialysis vintage (Decker et al., 2001; Slinin et al., 2007). A report taken from the United States Renal Database System (USRDS) registry from
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1990 to 1999 indicates that the overall incidence of parathyroidectomy among ESKD patients was 7.16 per 1000 person-years at risk (Kestenbaum et al., 2004). In Europe, according to the Lombardy Registry of Dialysis and Transplantation, the incidence rate was 5.3 per 1000 person-years (1983–1986) (Malberti et al., 2001). The Okinawa Dialysis Study (OKIDS) registry indicates a higher cumulative incidence of parathyroidectomy in Japanese nondiabetic dialysis patients: 15.2 per 1000 patient-years from 1971 to 1990 (Tokuyama et al., 1996). These large registry data suggest that there is a declining trend in the incidence of parathyroidectomy in SHPT patients (Kestenbaum et al., 2004; Tokuyama et al., 1996; Fassbinder et al., 1991), while other studies indicate that the incidence of parathyroidectomy has not changed over recent decades (Malberti et al., 2001; Decker et al., 2001).
PATHOPHYSIOLOGY In physiological conditions, the parathyroid gland maintains serum calcium and phosphorus at constant levels by either increasing or decreasing PTH secretion. A decrement in ionized calcium elicits an increase in PTH secretion by the parathyroid chief cells, which in turn increases serum calcium toward normal levels. PTH acts on the skeleton, kidney, and intestine to compensate for hypocalcemia. It mobilizes calcium from the skeletal system from areas of rapid equilibrium. In the kidney, PTH increases calcium reabsorption and phosphate excretion at the distal tubules. It also stimulates the biosynthesis of calcitriol (1,25-dihydroxycholecalciferol, activated vitamin D) in the kidney. Calcitriol increases calcium and phosphate absorption from the intestine. The mechanism by which CKD induces SHPT is incompletely understood. However, phosphate retention as a result of reduced excretion in CKD plays a central role in the genesis of SHPT. This role has been demonstrated in animal and human studies. In vitro experimentation has shown that high phosphorus increases PTH secretion in rats (Almaden et al., 1996) as well as in humans (Almaden et al., 1998). In vivo, in humans with renal failure, short-term phosphorus dietary restriction decreases serum PTH by 25%. On the other hand, increased phosphorus supplementation increases PTH by 45% (Portale et al., 1984).
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The mechanistic connection between hyperphosphatemia and the genesis of SHPT is unclear. Hyperphosphatemia causes hypocalcemia by precipitating calcium and decreasing vitamin D production. The G-protein transmembrane calcium-sensing receptor (CASR) on the surface of the parathyroid chief cell responds to this relative hypocalcemia by rapidly increasing the PTH secretion rate. Over time, this response amounts to autonomous proliferation of the parathyroid gland (hyperplasia) and exaggerated PTH secretion. Others have suggested that phosphorus-mediated calcitriol deficiency contributes to the development of SHPT, as phosphorus is known to negatively affect calcitriol synthesis by altering 1α-hydroxylase activity (Tanaka and Deluca, 1973). However, experimental evidence has shown a direct role for phosphorus in parathyroid growth and PTH secretion (Lopez-Hilker et al., 1990). A novel phosphaturic factor, FGF-23, has been proposed as a link between hyperphosphatemia and calcitriol synthesis, and may also have direct effects on parathyroid gland function (Saito et al., 2005). Decreased calcitrol production in renal failure could also independently and/or in conjunction with other factors contribute to the development of SHPT. Calcitriol acts to suppress transcription and secretion of PTH from bovine parathyroid glands (Russell et al., 1986; Brown et al., 1999) and its deficiency could result in higher PTH secretion in humans. Vitamin D deficiency is also known to decrease the intestinal calcium absorption, inducing the parathyroid to secrete more PTH.
GENETIC ETIOLOGIES The genetic mechanisms of SHPT are poorly understood. Numerous studies have demonstrated a role for downregulation of CASR and vitamin D receptor (VDR) expression in the pathogenesis of SHPT (Gogusev et al., 1997; Fukuda et al., 1993; Valimaki et al., 2001; Yano et al., 2000; Martin-Salvago et al., 2003). In addition, mounting evidence has shown VDR polymorphisms to increase parathyroid growth and to be associated with a more severe phenotype of SHPT (Tsukamoto et al., 1996; Carling et al., 1995; Fernandez et al., 1997). Others have attributed cell cycle deregulation along with VDR downregulation to the development of nodular hyperplastic growth of the parathyroid (Tokumato, 2002).
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CLINICAL MANIFESTATIONS The most common clinical picture of SHPT is nonspecific, and often masked and overlapped by the similar manifestations of advanced renal failure, including fatigability, muscle weakness, and pruritus. Other severe symptoms may also be found in cases of severe SHPT, including bone pain, bone disease, arthralgia, spontaneous tendon rupture, and soft tissue calcifications (Table 2). The bone pain usually affects the lower back, hips, and legs, and it is often described by patients as generalized and more deeply seated than in joints and muscle (Sherrard, 1986). There are different pathologic bone disorders that may be associated with SHPT. The spectrum of these osteodystrophies is classified according to the histology seen on bone biopsy. Primarily, there are three separate entities: adynamic bone disease, osteomalacia, and osteitis fibrosa. Adynamic Bone Disease (Aplastic Bone Disease) This entity represents the principal form of renal osteodystrophy observed in dialysis patients (Malluche et al., 2004; Felsenfeld et al., 1991). It is characterized by low bone turnover commonly resulting from oversuppression of PTH due to the excess clinical use of calciumbased phosphate binders and vitamin D treatment (Hercz et al., 1993; Goodman et al., 1994). There is a decrease in osteoid formation and mineralization contrasting with the increased unmineralized osteoid seen in osteomalacia, which is another low turnover disorder. The Table 2 • • • • • • •
Symptoms of secondary hyperparathyroidism.
Fatigability Muscle weakness Pruritus Neuropsychiatric impairments Bone pain Joint pain Calciphylaxis
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clinical consequences of this disorder are dominated by an asymptomatic presentation; nonetheless, there is an increased propensity toward bone fracture and hypercalcemia (Atsumi et al., 1999; Malluche and Monier-Faugere, 1992), and increased risk of vascular calcification (Goodman et al., 2000; Spasovski; 2009). The diagnosis of adynamic bone disease is established by bone biopsy or intact serum PTH less than 100 pg/mL (K/DOQI, 2003). Osteomalacia Osteomalacia is characterized by lower bone turnover, mineralization deficiency, and accumulation of unmineralized osteoid. Clinically, it is marked by skeletal deformities, fractures, and pain. The treatment focuses on maintaining normal levels of serum calcium and phosphorus, and vitamin D repletion. Osteitis Fibrosa Osteitis fibrosa is a high-turnover bone disease that is characterized by the presence of peritrabecular fibrosis on bone biopsy. The peritrabecular fibrosis is usually a result of the increased bone resorption activity. In uremic patients this disorder is mostly due to the increase in the osteoclast quantity and activity induced by the elevated PTH levels. Patients with osteitis fibrosa usually present with bone pain and an increased risk of fractures.
DIAGNOSIS Biochemical Evaluations The principal biochemical abnormality in SHPT is elevated intact PTH. CKD patients are known to have higher levels of intact PTH in comparison with whole molecule PTH, supporting the need to measure whole molecule PTH. However, intact PTH seems to provide adequate information in the surgical management of SHPT. Other abnormalities which may be observed include hypocalcemia, high alkaline phosphatase, hyperphosphatemia, and
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PTH (pg/ml)
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50 45
250
40
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20 100
15 10
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29–20
<20
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Fig. 1 Trends in calcium, phosphorus, activated vitamin D and PTH levels observed in 1,814 chronic kidney disease patients over time as GFR declines. Source: Bakris et al. ASN, 2005.
vitamin D deficiency (Fig. 1). Hypercalcemia is common among patients with ESKD and reflects the transition to tertiary HPT as it may occur in patients with severe bone turnover and in transplant patients. Radiologic Findings Radiographic studies have traditionally been used to monitor bone changes and soft tissue calcifications in dialysis patients (Owen et al., 1988). The most common radiologic feature in SHPT is subperiosteal erosions (Goodman et al., 1982). Brown tumors may also be seen in SHPT — a condition caused by intensive osteoclastic activity.
MEDICAL THERAPY The National Kidney Foundation developed practice guidelines, the Kidney Disease Outcomes Quality Initiative (K/DOQI), to improve the management outcomes of SHPT and mineral disturbances in patients with CKD. They formulated serum target levels for intact PTH, corrected total
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calcium, phosphate, and calcium-phosphate product (K/DOQI, 2003). The target levels for serum intact PTH are as follows: • • •
Patients with stage III CKD (GFR 30–59 ml/min): 35–70 pg/mL; Patients with stage IV CKD (GFR 15–29 ml/min): 70–110 pg/mL; Patients with stage V CKD (GFR <15 or dialysis): 150–300 pg/mL.
Additional guidelines restrict vitamin D treatment to avoid oversuppression of PTH and development of hypercalcemia, which are associated with adynamic bone disease. Therefore, oral vitamin D therapy is recommended in patients with CKD stage III or IV when: • • •
Serum levels of 25-OH D are less than 30 mg/mL; Serum intact PTH levels are above the range for the CKD stage; Serum corrected calcium B less than 9.5 mg/dL and serum phosphorus is less than 4.6 mg/dL.
CKD stage V dialysis patients should be treated with intravenous/oral vitamin D to reduce the PTH to a target of 150–300 pg/mL. Therapeutic Agents The hallmarks of SHPT are hypocalcemia, phosphate retention, and vitamin D deficiency. Thus, treatment regimens are based on managing these three abnormalities. The following agents are used to manage SHPT: Phosphate binders Along with dietary phosphorus restriction, oral phosphate-binding medications are indispensable agents for reducing phosphorus influx. Calcium salts are commonly used, but there is concern that calciumcontaining phosphate binders may contribute to hypercalcemia and promote accelerated vascular calcification often seen among patients with CKD, a possible pathway to premature cardiovascular mortality (Block et al., 2005). Non-calcium-containing phosphate binders include sevelamer and lanthanum carbonate, and have been shown to reduce serum phosphorus and suppress PTH without causing
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hypercalcemia, but are associated with significant expense. Overall, there is no convincing evidence that the use of one agent offers significant clinical benefits. Vitamin D analogs Vitamin D analogs have been used to control SHPT. In addition to their action to inhibit PTH secretion, they have a minimal hypercalcemic adverse effect as compared to calcitrol. Maxacalcitol is a vitamin D analog that has been shown to effectively decrease PTH secretion and bone turnover in SHPT patients (Akizawa et al., 2001). Calcimimetics Calcimimetics are therapeutic agents that suppress the secretion of PTH by increasing the sensitivity of the calcium-sensing receptors. Cinacalcet HCL (cinacalcet) has been demonstrated to effectively assist in achieving K/DOQI recommendation targets for PTH, calcium, and phosphate levels, and calcium–phosphorus product in SHPT patients (Urena et al., 2009; Moe et al., 2005).
INDICATIONS FOR PARATHYROIDECTOMY IN SHPT Approximately 1–2% of the patients with SHPT undergo parathyroidectomy each year (Triponez et al., 2008). The mainstay of treatment is medical therapy and, in general, surgical intervention can be indicated only if medical treatment fails (Table 3). Severe SHPT unresponsive to medical therapy is the most common indication for surgery. Severe presentations that require surgery include calciphylaxis, bone pain, osteodystrophy, and bone deformities. Calciphylaxis is a rare syndrome of ESKD that is characterized by vascular calcification, spontaneous ischemic soft tissue necrosis, gangrene, and sepsis. Intractable pruritus is the second-most-common indication (Olson Jr and Leight Jr, 2002). Kidney transplant patients may require surgery in specific circumstances, including persistent or symptomatic hypercalcemia and progressive osteodystrophy (Tominaga, 2000; Sancho, 1997).
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Table 3 • • • • •
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Indications for parathyroidectomy in secondary hyperparathyroidism.
Severe or symptomatic SHPT that is resistant to medical therapy Bone disease and pain Bone deformities and tendon rupture Intractable pruritus Calciphylaxis, a rare syndrome of ESRD characterized by spontaneous ischemic soft tissue necrosis gangrene and sepsis Criteria for surgery in secondary hyperparathyroidism patients with kidney transplant Persistent hypercalcemia (>2 years posttransplant) Marked hypercalcemia (>3 mmol/L) Deteriorating transplant function Progressive osteodystrophy
PREOPERATIVE ASSESSMENT Because of the higher frequency of morbidity and mortality associated with renal failure and HPT, thorough preoperative assessment is of paramount importance in identifing risk factors for perioperative complications as well as predicting treatment failure. Medical conditions associated with renal insufficiency should be identified and treated preoperatively, including cardiovascular disease, hyperkalemia, hypermagnesemia, and hypervolemia. The preoperative loading dose of vitamin D and calcium should be considered as a preventive measure to avoid hungry bone syndrome in the postoperative period. Interestingly, some have suggested that high preoperative alkaline phosphatase may be predictive of postoperative hungry bone syndrome and prolonged severe postoperative hypocalcemia (Demeure et al., 1990).
PREOPERATIVE LOCALIZATION 99
Tc-sestamibi scanning (MIBI) has been successfully used for preoperative localization of primary hyperparathyroidism (McHenry et al., 1996). However, the role of sestamibi scanning in the management of SHPT is a matter for debate. Many surgeons believe that MIBI has limited utility in
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localizing diseased secondary hyperplastic glands (Muros et al., 2007; Lomonte et al., 2006). In a retrospective study of 35 SHPT patients, MIBI detected only 42 of the 121 hyperplastic removed glands (Lomonte et al., 2006). Additionally, MIBI failed to detect all abnormal glands in a substantial proportion of SHPT patients who presented with multiple gland disease (Pons et al., 1997). Despite the lower sensitivity of MIBI, it has proven usefulness in the preoperative identification of ectopic and/or supernumerary diseased parathyroid glands (especially mediastinal), a potential cause of disease recurrence and hence reoperation (Hindie et al., 1999; Giordano et al., 2001). In light of this and the higher rate of SHPT disease recurrence (Fuster et al., 2006), we recommend selective preoperative use of MIBI in SHPT. As in other parathyroid tumors, high resolution ultrasonography (US) has been utilized to preoperatively localize hyperplastic parathyroid glands in SHPT. In a recent study of 44 SHPT patients, Kawata et al. reported that US detected abnormal glands 80% of the time (Lindqvist et al., 2005). However, 20% of 139 were found to be false positive (Kawata et al., 2009). It is crucial to understand that the utility of US is limited by the experience and skills of the operator, which may explain some of the reported higher false positive rates. Some have suggested the combined use of MIBI and US for preoperative planning in patients with SHPT. In addition to the superior sensitivity of the combined localization studies as opposed to either MIBI or US, MIBI may be useful for guiding the surgeon to the area of the potential hyperfunctioning gland(s) (Perie et al., 2005).
SURGICAL STRATEGIES Despite the advancement of medical therapy and the introduction of the calcimimetic and vitamin D in the treatment of SHPT, a constant proportion of SHPT patients still need to be treated with surgery (Grilli et al., 2009). Surgical procedures for the management of SHPT include subtotal parathyroidectomy (SPTX), total parathyroidectomy with autotransplantation (TPTX/AT), and total parathyroidectomy without immediate autotransplantation. SPTX is also practiced by a substantial number of endocrine surgeons as a standard surgical modality for SHPT (Decker et al., 2001; Demeure
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et al., 1990; Punch et al., 1995). In this procedure, all parathyroid glands are identified and exposed, and then the most normal-appearing parathyroid gland is selected for partial resection to leave a 50 mg wellvascularized remnant. It is recommended that the weight of the remnant gland should be adjusted according to the expected patient’s dialysis period. Patients projected to be on prolonged dialysis usually need a smaller remnant (20–30 mg) than those undergoing subsequent renal transplantation (50–60 mg). Although dialysis patients tolerate relative hypoparathyroidism relatively well while on dialysis, is crucial to avoid hypoparathyroidism in any patient who is a potential transplant candidate, since severe symptoms may ensue from restoration of normal renal function following transplantation. TPTX/AT is advocated by many endocrine surgeons (Wells Jr et al., 1977; Rothmund et al., 1991; Tominaga et al., 2001). Typically, this procedure includes identification and removal of all parathyroid glands, including any ectopic and/or supernumerary parathyroid gland(s). Subsequently, the most normal-appearing gland is chosen to be minced for implantation. The chosen gland is immediately chilled in iced saline (4°C) and minced into 1 × 1 × 2 mm slices. Then, about 20 of these parathyroid slices are implanted in an ectopic muscular site. Different locations have been suggested as candidate implant sites. We and others prefer the forearm brachioradialis muscle to host the implanted parathyroid gland (Wells Jr et al., 1975, 1979). However, some authors favor the sternocleidomastoid muscle (Geis et al., 1973; Diethelm et al., 1981) as an implant site. It is performed by developing a 0.7–1 cm pocket between and parallel to the muscle fibers. After making sure that there is no bleeding, 4–6 pieces of the minced parathyroid gland are placed in the pocket. Care should be taken not to traumatize the autografted area during incision or closure, to avoid bleeding into the pocket as it may impair graft revascularization and therefore engraftment (Diethelm et al., 1981). We advocate choosing the sternocledomastoid muscle only if prior dialysis access precludes safe access in the forearm. Successful forearm engraftment can be documented by examining the antecubital venous PTH gradient between the grafted and the nongrafted arm. This gradient can also be used to document the forearm graft as the source of recurrent SHPT. In most of the cases, the use of total parathyroidectomy without transplantation is discouraged due to the higher incidence of permanent
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hypothyroidism (Gasparri et al., 2001) and increased potential for adynamic bone disease as a result of this procedure. Moreover, disease recurrence cannot be excluded after TPTX (Ljutic et al., 1994), contrasting with the notion that TPTX is advantageous in reducing the rate of recurrence. Having said that, TPTX may be useful in reoperative cases and in elderly SHPT patients who are not dialysis candidates (Olson Jr and Leight Jr, 2002).
INTRAOPERATIVE PTH MONITORING Intraoperative measurement of intact PTH is an accepted approach to guiding parathyroidectomy in secondary and tertiary HPT. A ≥50% drop from the baseline intraoperative PTH is considered predictive of sufficient parathyroidectomy. Initial data reported by Clary et al. showed a significant drop in PTH levels after parathyroidectomy, with a mean of 85% reduction. PTH levels at followup were consistently below intraoperative levels (Clary et al., 1997). In a more recent study of 105 patients with SHPT and tertiary HPT, intraoperative PTH fell by >50% in 95% of the patients, and the PTH level reliably predicted postoperative cure (Pitt et al., 2010). Due to concern about delayed renal clearance of PTH, longer intraoperative PTH monitoring may be indicated in some patients. In theory, intraoperative PTH monitoring could help to avoid persistent HPT secondary to missed glands. However, the true ability of this technique to detect unresected glands in SHPT is unclear (Olson Jr and Leight Jr, 2002).
SURGICAL OUTCOMES Generally, surgery is very effective in improving the biochemical abnormalities, symptoms, and quality of life inherent in SHPT. In a large retrospective series of more than 1000 SHPT patients, there was an improvement in the biochemical indices, neuromuscular and psychiatric symptoms, and radiological signs of osteitis fibrosa cystica (Tominaga et al., 2001). In other studies, parathyroidectomy was successful in ameliorating the symptoms of SHPT 80–95% of the time (Demeure et al., 1990; Punch et al., 1995). Abdelhadi and Nordenstrom reported a bone
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mass index increase of 7–23% after surgery in hemodialysis SHPT patients (Abdelhadi and Nordenstrom, 1998). Transient postoperative hypocalcemia is more prevalent in SHPT than in primary HPT. In a series of 30 uremic patients, transient hypocalcemia developed in 97% (29/30) of the patients. Symptoms including perioral numbness and paresthesia occurred in 45% and the Chvostek sign (spasm of facial muscles upon tapping on the facial nerve trunk) was positive 7% of the time (Mittendorf et al., 2004). Others have reported a similar high incidence of symptomatic hypocalcemia (95%) (McHenry et al., 2001). Thus, thorough postoperative evaluation should be considered to screen for postoperative hypocalcemia, followed by intravenous calcium and/or vitamin D administration if necessary. Hungry bone syndrome is a common complication following parathyroidectomy (Jofre et al., 2003). It is characterized by severe symptomatic hypocalcemia and hypophatemia due to extensive remineralization of the skeleton. These symptoms may become protracted and often require aggressive calcium and vitamin D supplementation.
DISEASE PERSISTENCE/RECURRENCE Persistent SHPT is defined as hypercalcemia within six months of parathyroidectomy. The reported frequency of disease persistence is up to 8% (Demeure et al., 1990). SHPT recurrence is defined as recurrence of hypercalcemia after six months after surgery. The frequency of SHPT recurrence increases over time. In a large series of 1000 SHPT patients, Tominaga and others reported a gradual increase in the recurrence incidence from 10% at three years and 20% at five years to 30% at seven years (Tominaga et al., 2001). This gradual increase in the recurrence rate may reflect the continued growth of either a parathyroid gland remnant or an autograft.
TYPE OF PARATHYROIDECTOMY Comparative studies show no difference in the outcomes of patients treated by either TPTX/AT or SPTX (Takagi et al., 1984; Welsh et al., 1984; Malmaeus et al., 1982; Gagne et al., 1992). It seems that the two
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Table 4 Subtotal parathyroidectomy (SPTX) versus total parathyroidectomy with autotransplantation (TPTX/AT). SPTX Pros
• Technically easier • No need for cryopreservation
Cons
• Risky to reoperate in case of recurrence • Tenuous blood supply to remnant gland
TPTX/AT • Ability to check graft integrity by PTH gradient • Easily accessible for recurrence treatment • Technically complicated • Requires cryopreservation
surgical modalities are equivalent and the selection of either is less important than the surgeon’s preference and experience (Table 4).
PERCUTANEOUS ETHANOL INJECTION Real time ultrasound-guided ethanol injection of the enlarged parathyroid has been proposed to treat refractory SHPT. The technique includes destruction of the dominant parathyroid gland with 90–100% ethanol injection and then controlling the other enlarged gland(s) with vitamin D treatment. Usually, the PTH is measured immediately after the procedure and weeks later to determine if a further round of injections is needed to keep the PTH to the K/DOQI target levels. Successful destruction of the diseased gland can be confirmed by absence of blood flow on the color Doppler flow mapping (Tanaka et al., 2003). Ethanol injection combined with vitamin D treatment is widely used in Japan as an alternative treatment for severe SHPT (Tanaka et al., 2003, 2005; Koiwa et al., 2003, 2007; Kakuta et al., 1999, 2000; Nakamura et al., 2003) with standard practice guidelines (Fukagawa et al., 2003). In a multicenter study from Japan, ethanol injection was effective in treating 63% of the 321 SHPT patients (Koiwa et al., 2007). When ethanol injection was compared to parathyroidectomy in ESRD, the K/DOQI target PTH level was achieved in 67% (14/21) and 18% (2/11) of the patients at one-year followup, respectively (Tanaka et al., 2005).
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Despite the minimaly invasive nature and the reported efficacy of this technique to control refractory SHPT, we believe that there is uncertainty in terms of the safety of the procedure. Given the anatomic complexity of the neck and the inability to monitor for the recurrent laryngeal nerve integrity, potential serious complications may well be associated with this procedure, including recurrent laryngeal nerve paralysis and injury to nearby structures. Moreover, the effectiveness of this procedure appears to be limited in patients with multiple-gland disease (three or four glands) (Tanaka et al., 2003, 2006). Thus, we recommend reserving ethanol injection therapy for inoperable SHPT patients with single-gland disease.
SUMMARY Secondary hyperparathyroidism is very prevalent in CKD patients. It represents an unregulated compensatory response to the continuous hyperphosphatemia and vitamin D deficiency associated with CKD. Parathyroidectomy is still the treatment of choice in patients with severe unresponsive SHPT. It is very effective in correcting biochemical disturbances and alleviating symptoms of SHPT patients. Both subtotal parathyroidectomy and total parathyroidectomy with autotransplantation are acceptable surgical approaches, with similar postoperative outcomes in treating SHPT.
SELECTED REFERENCES Abdelhadi M, Nordenstrom J. Bone mineral recovery after parathyroidectomy in patients with primary and renal hyperparathyroidism. J Clin Endocrinol Metab 1998;83(11):3845–3851. Akizawa T, et al. Clinical effects of maxacalcitol on secondary hyperparathyroidism of uremic patients. Am J Kidney Dis 2001;38(4 Suppl 1): S147–S151. Albright F, Cope O, Bloomberg E. Studies on the physiology of the parathyroid glands IV. Renal complications of hyperparathyroidism. Am J Med Sci 1934;187:49–65. Almaden Y, et al. Direct effect of phosphorus on PTH secretion from whole rat parathyroid glands in vitro. J Bone Miner Res 1996;11(7):970–976.
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Almaden Y, et al. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol 1998;9(10):1845–1852. Atsumi K, et al. Risk factors for vertebral fractures in renal osteodystrophy. Am J Kidney Dis 1999;33(2):287–293. Billa V, et al. High prevalence of hyperparathyroidism among peritoneal dialysis patients: a review of 176 patients. Perit Dial Int 2000;20(3):315–321. Block GA, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 2005;68(4): 1815–1824. Brown AJ, et al. 1alpha,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of 1alpha,25-dihydroxyvitamin D3, is a potent suppressor of parathyroid hormone secretion. J Cell Biochem 1999;73(1):106–113. Carling T, et al. Vitamin D receptor genotypes in primary hyperparathyroidism. Nat Med 1995;1(12):1309–1311. Clary BM, Garner SC, Leight GS Jr. Intraoperative parathyroid hormone monitoring during parathyroidectomy for secondary hyperparathyroidism. Surgery 1997;122(6):1034–1038; discussion 1038–1139. Decker PA, et al. Subtotal parathyroidectomy in renal failure: still needed after all these years. World J Surg 2001;25(6):708–712. Demeure MJ, et al. Results of surgical treatment for hyperparathyroidism associated with renal disease. Am J Surg 1990;160(4):337–340. Diethelm AG, et al. Treatment of secondary hyperparathyroidism in patients with chronic renal failure by total parathyroidectomy and parathyroid autograft. Ann Surg 1981;193(6):777–793. Fassbinder W, et al. Combined report on regular dialysis and transplantation in Europe, XX, 1989. Nephrol Dial Transplant 1991;6(Suppl 1):5–35. Felsenfeld AJ, et al. A comparison of parathyroid-gland function in haemodialysis patients with different forms of renal osteodystrophy. Nephrol Dial Transplant 1991;6(4):244–251. Fernandez E, et al. Association between vitamin D receptor gene polymorphism and relative hypoparathyroidism in patients with chronic renal failure. J Am Soc Nephrol 1997;8(10):1546–1552. Fukagawa M, et al. Guidelines for percutaneous ethanol injection therapy of the parathyroid glands in chronic dialysis patients. Nephrol Dial Transplant 2003;18(Suppl 3):iii31– iii33.
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Fukuda N, et al. Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 1993;92(3):1436–1443. Fuster D, et al. Role of pre-operative imaging using 99mTc-MIBI and neck ultrasound in patients with secondary hyperparathyroidism who are candidates for subtotal parathyroidectomy. Eur J Nucl Med Mol Imaging 2006;33(4): 467–473. Gagne ER, et al. Short- and long-term efficacy of total parathyroidectomy with immediate autografting compared with subtotal parathyroidectomy in hemodialysis patients. J Am Soc Nephrol 1992;3(4):1008–1017. Gasparri G, et al. Secondary and tertiary hyperparathyroidism: causes of recurrent disease after 446 parathyroidectomies. Ann Surg 2001;233(1):65–69. Geis WP, et al. The diagnosis and treatment of hyperparathyroidism after renal homotransplantation. Surg Gynecol Obstet 1973;137(6):997–1010. Giordano A, Rubello D, Casara D. New trends in parathyroid scintigraphy. Eur J Nucl Med 2001;28(9):1409–1420. Gogusev J, et al. Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 1997;51(1):328–336. Goodman WG, Slatopolsky E, Salusky IB. Renal osteodystrophy in adult and pediatric patients. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism (ed.) MJ Favus. New York: Raven, 1982, pp. 341–360. Goodman WG, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000;342(20): 1478–1483. Goodman WG, et al. Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy. Kidney Int 1994;46(4):1160–1166. Grilli M, et al. Salvinorin A exerts opposite presynaptic controls on neurotransmitter exocytosis from mouse brain nerve terminals. Neuropharmacology 2009;57(5–6):523–530. Hercz G, et al. Aplastic osteodystrophy without aluminum: the role of “suppressed” parathyroid function. Kidney Int 1993;44(4):860–866. Hindie E, et al. Preoperative imaging of parathyroid glands with technetium99m-labelled sestamibi and iodine-123 subtraction scanning in secondary hyperparathyroidism. Lancet 1999;353(9171):2200–2204.
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Jofre R, et al. Parathyroidectomy: whom and when? Kidney Int Suppl 2003(85):S97–S100. Johnson WJ, et al. Results of subtotal parathyroidectomy in hemodialysis patients. Am J Med 1988;84(1):23–32. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003;42(Suppl 3):S1. Kakuta T, et al. Long-term prognosis of parathyroid function after successful percutaneous ethanol injection therapy (PEIT) guided by color Doppler flow mapping in chronic dialysis patients. Biomed Pharmacother 2000;54(Suppl 1):60s–65s. Kakuta T, et al. Prognosis of parathyroid function after successful percutaneous ethanol injection therapy guided by color Doppler flow mapping in chronic dialysis patients. Am J Kidney Dis 1999;33(6):1091–1099. Kawata R, et al. Ultrasonography for preoperative localization of enlarged parathyroid glands in secondary hyperparathyroidism. Auris Nasus Larynx 2009;36(4):461–465. Kestenbaum B, et al. Parathyroidectomy rates among United States dialysis patients: 1990–1999. Kidney Int 2004;65(1):282–288. Koiwa F, et al. Efficacy of percutaneous ethanol injection therapy (PEIT) is related to the number of parathyroid glands in haemodialysis patients with secondary hyperparathyroidism. Nephrol Dial Transplant 2007;22(2): 522–528. Koiwa F, et al. Time course of change in calcium x phosphorus product after percutaneous ethanol injection therapy. Nephrol Dial Transplant 2003; 18(Suppl 3):iii53–iii57. Lindqvist E, et al. Prognostic laboratory markers of joint damage in rheumatoid arthritis. Ann Rheum Dis 2005;64(2):196–201. Ljutic D, et al. Long-term follow-up after total parathyroidectomy without parathyroid reimplantation in chronic renal failure. QJM 1994;87(11): 685–692. Lomonte C, et al. Sestamibi scintigraphy, topography, and histopathology of parathyroid glands in secondary hyperparathyroidism. Am J Kidney Dis 2006;48(4):638–644. Lopez-Hilker S, et al. Phosphorus restriction reverses hyperparathyroidism in uremia independent of changes in calcium and calcitriol. Am J Physiol 1990;259(3 Pt 2):F432–F437.
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Malberti F, et al. Parathyroidectomy in patients on renal replacement therapy: an epidemiologic study. J Am Soc Nephrol 2001;12(6):1242–1248. Malluche HH, Monier-Faugere MC. Risk of adynamic bone disease in dialyzed patients. Kidney Int Suppl 1992;38:S62–S67. Malluche HH, Mawad H, Monier-Faugere MC. The importance of bone health in end-stage renal disease: out of the frying pan, into the fire? Nephrol Dial Transplant 2004;19(Suppl 1):i9–i13. Malmaeus J, et al. Parathyroid surgery in chronic renal insufficiency: subtotal parathyroidectomy versus total parathyroidectomy with autotransplantation to the forearm. Acta Chir Scand 1982;148(3):229–238. Martin-Salvago M, et al. Decreased expression of calcium receptor in parathyroid tissue in patients with hyperparathyroidism secondary to chronic renal failure. Endocr Pathol 2003;14(1):61–70. McHenry CR, et al. Parathyroid localization with technetium-99m-sestamibi: a prospective evaluation. J Am Coll Surg 1996;183(1):25–30. McHenry CR, Wilhelm SM, Ricanati E. Refractory renal hyperparathyroidism: clinical features and outcome of surgical therapy. Am Surg 2001;67(4): 310–316; discussion 316–317. Mittendorf EA, Merlino JI, McHenry CR. Post-parathyroidectomy hypocalcemia: incidence, risk factors, and management. Am Surg 2004;70(2):114–119; discussion 119–120. Moe SM, et al. Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl. Kidney Int 2005;67(2):760–771. Muros MA, et al. Two-phase scintigraphy with technetium 99m-sestamibi in patients with hyperparathyroidism due to chronic renal failure. Am J Surg 2007;193(4):438–442. Nakamura M, Fuchinoue S, Teraoka S. Clinical experience with percutaneous ethanol injection therapy in hemodialysis patients with renal hyperparathyroidism. Am J Kidney Dis 2003;42(4):739–745. Nasri H, Kheiri S. Effects of diabetes mellitus, age, and duration of dialysis on parathormone in chronic hemodialysis patients. Saudi J Kidney Dis Transpl 2008;19(4):608–613. Olson JA Jr, Leight GS Jr. Surgical management of secondary hyperparathyroidism. Adv Ren Replace Ther 2002;9(3):209–218. Owda A, et al. Secondary hyperparathyroidism in chronic hemodialysis patients: prevalence and race. Ren Fail 2003;25(4):595–602.
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Owen JP, et al. Critical analysis of the use of skeletal surveys in patients with chronic renal failure. Clin Radiol 1988;39(6):578–582. Packman KS, Demeure MJ. Indications for parathyroidectomy and extent of treatment for patients with secondary hyperparathyroidism. Surg Clin North Am 1995;75(3):465–482. Perie S, et al. Usefulness of combination of high-resolution ultrasonography and dual-phase dual-isotope iodine 123/technetium Tc 99m sestamibi scintigraphy for the preoperative localization of hyperplastic parathyroid glands in renal hyperparathyroidism. Am J Kidney Dis 2005;45(2): 344–352. Pitt SC, et al. Secondary and tertiary hyperparathyroidism: the utility of ioPTH monitoring. World J Surg 2010;34(6):1343–1349. Pons F, et al. Preoperative parathyroid gland localization with technetium-99m sestamibi in secondary hyperparathyroidism. Eur J Nucl Med 1997;24(12): 1494–1498. Portale AA, et al. Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 1984; 73(6):1580–1589. Punch JD, Thompson NW, Merion RM. Subtotal parathyroidectomy in dialysisdependent and post-renal transplant patients: a 25-year single-center experience. Arch Surg 1995;130(5):538–542; discussion 542–543. Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy versus total parathyroidectomy and autotransplantation in secondary hyperparathyroidism: a randomized trial. World J Surg 1991;15(6):745–750. Russell J, Lettieri D, Sherwood LM. Suppression by 1,25(OH)2D3 of transcription of the pre-proparathyroid hormone gene. Endocrinology 1986;119(6): 2864–2866. Saito H. et al. Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 2005;280(4):2543–2549. Salem MM. Hyperparathyroidism in the hemodialysis population: a survey of 612 patients. Am J Kidney Dis 1997;29(6):862–865. Sancho JJ, et al. Surgical approach to secondary hyperparathyroidism. In: Textbook of Endocrine Surgery (eds.) OH Clark, QW Duh. Philadelphia: WB Saunders, 1997. Sherrard DJ. Renal osteodystrophy. Semin Nephrol 1986;6(1):56–67.
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Slinin Y, Foley RN, Collins AJ. Clinical epidemiology of parathyroidectomy in hemodialysis patients: the USRDS waves 1, 3, and 4 study. Hemodial Int 2007;11(1):62–71. Spasovski G. Strategies to manage low-bone turnover. Nefrologia 2009;29(4): 295–297. Stanbury SW, Lumb GA, Nicholson WF. Elective subtotal parathyroidectomy for renal hyperparathyroidism. Lancet 1960;1(7128):793–799. Takagi H, et al. Subtotal versus total parathyroidectomy with forearm autograft for secondary hyperparathyroidism in chronic renal failure. Ann Surg 1984;200(1):18–23. Tanaka M, et al. Combination therapy of intravenous maxacalcitol and percutaneous ethanol injection therapy lowers serum parathyroid hormone level and calcium x phosphorus product in secondary hyperparathyroidism. Nephron Clin Pract 2006;102(1):c1–c7. Tanaka M, et al. Efficacy of percutaneous ethanol injection therapy for secondary hyperparathyroidism in patients on hemodialysis as evaluated by parathyroid hormone levels according to K/DOQI guidelines. Ther Apher Dial 2005;9(1):48–52. Tanaka R, et al. Long-term (3 years) prognosis of parathyroid function in chronic dialysis patients after percutaneous ethanol injection therapy guided by colour Doppler ultrasonography. Nephrol Dial Transplant 2003;18(Suppl 3): iii58–iii61. Tanaka Y, Deluca HF. The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus. Arch Biochem Biophys 1973;154(2):566–574. Tokumoto M, et al. Reduced p21, p27 and vitamin D receptor in the nodular hyperplasia in patients with advanced secondary hyperparathyroidism. Kidney Int 2002;62(4):1196–1207. Tokuyama K, et al. An epidemiologic analysis of parathyroidectomy in chronic dialysis patients. The Okinawa Dialysis Study Group. Nippon Jinzo Gakkai Shi 1996;38(7):309–313. Tominaga Y, et al. More than 1,000 cases of total parathyroidectomy with forearm autograft for renal hyperparathyroidism. Am J Kidney Dis 2001; 38(4 Suppl 1): S168–S171. Tominaga Y. Management of renal hyperparathyroidism. Biomed Pharmacother 2000;54(Suppl 1):25s–31s.
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Triponez F, et al. Surgical treatment of persistent hyperparathyroidism after renal transplantation. Ann Surg 2008;248(1):18–30. Tsukamoto Y, et al. More on hyperparathyroidism and the vitamin D receptor. Nat Med 1996;2(11):1162. Urena P, et al. Cinacalcet and achievement of the NKF/K-DOQI recommended target values for bone and mineral metabolism in real-world clinical practice — the ECHO observational study. Nephrol Dial Transplant 2009;24(9):2852–2859. Valimaki S, et al. Heterogeneous expression of receptor mRNAs in parathyroid glands of secondary hyperparathyroidism. Kidney Int 2001;60(5): 1666–1675. Wells SA Jr, et al. Transplantation of the parathyroid glands in man. Transplant Proc 1977;9(1):241–243. Wells SA Jr, et al. Transplantation of the parathyroid glands: current status. Surg Clin North Am 1979;59(1):167–177. Wells SA Jr, et al. Transplantation of the parathyroid glands in man: clinical indications and results. Surgery 1975;78(1):34–44. Welsh CL, et al. Parathyroid surgery in chronic renal failure: subtotal parathyroidectomy or autotransplantation? Br J Surg 1984;71(8):591–592. Yano S, et al. Association of decreased calcium-sensing receptor expression with proliferation of parathyroid cells in secondary hyperparathyroidism. Kidney Int 2000;58(5):1980–1986.
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Chapter II.B.3: Tertiary Hyperparathyroidism Steven E. Rodgers, MD, PhD, John I. Lew, MD and Carmen C. Solórzano, MD
INTRODUCTION In response to hyperphosphatemia and impaired production of 1,25-hydroxyvitamin D, patients with chronic renal failure often develop derangements of calcium homeostasis leading to hyperplasia and hypersecretion of the parathyroid glands, a process known as secondary hyperparathyroidism (HPT). Following correction of the underlying etiology by kidney transplantation, one or more of these hyperplastic parathyroid glands may fail to involute, resulting in autonomous hyperfunctioning of the glands. This is generally referred to as tertiary HPT. It may manifest itself as hypercalcemia; however, many patients will remain eucalcemic in the face of elevated parathyroid hormone levels. In addition to hypercalcemia, patients with tertiary HPT may present with hypercalciuria, nephrolithiasis, nephrocalcinosis, osteoporosis, bone pain, pathologic fractures, pruritus, and muscle weakness.
DIAGNOSIS The laboratory diagnosis of tertiary HPT should include measurement of serum calcium, phosphorus, intact parathyroid hormone (PTH), creatinine, and 25-hydroxyvitamin D, as well as a 24 h urine calcium level. Following kidney transplant, patients will have varying degrees of renal insufficiency. It is important to note that PTH levels will vary depending on the glomerular filtration rate (GFR). As the GFR drops below 60 (mL/min/1.73 m2), the expected range of intact PTH increases. When 203
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the GFR is between 15 and 30, the expected PTH level is 70–110 pg/mL. When it drops below 15, the PTH level may range from 150 pg/mL to as high as 300 pg/mL (Eknoyan et al., 2003). Bone densitometry is useful for detecting evidence of decreased bone mineral density. A detailed history and physical examination may reveal signs and symptoms of hypercalcemia, including kidney stones, bone pain, prior fractures, muscle weakness, and pruritus. Role of Imaging Whereas the majority of patients with primary HPT are found at operation to have single gland disease, tertiary HPT may be due to one or multiple hyperplastic parathyroid glands. For this reason, an initial four-gland exploration is typically performed in the operating room, and preoperative imaging with sestamibi scanning and cervical ultrasonography (US) is felt by many to be unnecessary. However, the incidence of ectopic parathyroid glands is reported to be between 4 and 22% based on autopsy studies and preoperative imaging (Pitayakorn and McHenry, 2006; Sofferman and Nathan, 1998; Vail and Coller, 1967; Wang, 1976). Furthermore, up to 13% of patients have supernumerary glands at the time of autopsy (Akerstrom et al., 1984). Preoperative imaging with sestamibi scanning has been advocated prior to surgery for tertiary HPT in order to identify ectopic and supernumerary glands; however, this remains controversial. Sestamibi scans are often unable to identify all affected glands. Cervical US frequently allows identification of one or more enlarged parathyroid glands prior to surgical intervention (Fig. 1) and may help visualize glands not seen on sestamibi. In experienced hands, US can localize ectopic parathyroid glands (e.g. undescended glands or superior glands low in the tracheoesophageal groove). Additionally, it can be used to readily identify the presence of concomitant thyroid pathology.
SURGICAL TREATMENT Most patients with end-stage renal disease will have elevated PTH levels. Following kidney transplant, PTH levels slowly return to normal as the hyperplastic parathyroid glands involute. Up to one-third of these patients
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Fig. 1 Cervical ultrasound of a 33-year-old male with tertiary HPT showing (a) a right superior parathyroid gland (1.1 × 0.7 cm), (b) a right inferior parathyroid gland (0.9 cm), and (c) a left inferior parathyroid gland (0.9 × 0.8 cm). The left superior parathyroid gland was not identified on ultrasound. The parathyroid glands are indicated by white arrows. CA — common carotid artery; Tr — trachea.
develop hypercalcemia, but the majority of cases will resolve spontaneously within one year. Although indications for surgery in patients with tertiary HPT are controversial, parathyroidectomy should be considered in patients with hypercalcemia persisting greater than one year after transplant and in any patient with symptoms of hypercalcemia (Table 1). The symptoms include nephrolithiasis or nephrocalcinosis of the renal graft, pruritus, and bone or muscle pain. Additionally, patients with hypercalciuria are at risk of developing stones and should be considered for surgery. There are data to suggest deleterious effects of elevated PTH levels on bone mineralization and on the renal graft in eucalcemic patients (Dumoulin et al., 1997; Traindl et al., 1993). However, the use of parathyroidectomy in patients with elevated PTH levels in the absence of hypercalcemia following kidney transplant has not been properly studied. Extent of Surgical Resection The standard surgical approaches to the treatment of tertiary hyperparathyroidism include subtotal parathyroidectomy and total parathyroidectomy with autotransplantation. Following parathyroidectomy, impaired renal function and increased renal graft rejection have been documented
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Indications for parathyroidectomy in patients with tertiary HPT.
Hypercalcemia (>1 year after transplant) Hypercalciuria Nephrolithiasis or nephrocalcinosis Osteoporosis Bone pain Muscle pain or weakness Pruritus
(Schmid et al., 1997; Schwarz et al., 2007). The exact mechanism of this is not understood. However, the same phenomenon has been noted after thyroid surgery and is likely related to an acute drop in serum PTH levels. Following subtotal parathyroidectomy, the drop in serum PTH levels and the decrease in renal function (estimated by the glomerular filtration rate) may be less acute than following total parathyroidectomy with autotransplantation (Schlosser et al., 2007). These data have been employed to support the use of subtotal parathyroidectomy as the procedure of choice for tertiary HPT. More recently, limited parathyroidectomy with removal of only enlarged glands has been advocated for patients found to have one or more normal-appearing glands at the time of surgery. In several studies, long-term followup data of tertiary HPT patients who underwent limited parathyroidectomy showed equivalent or lower rates of recurrent disease when compared to patients who underwent subtotal parathyroidectomy or total parathyroidectomy with autotransplantation. Additionally, patients who underwent limited parathyroidectomy had a lower incidence of postoperative hypocalcemia than patients who underwent the more extensive procedures (Nichol et al., 2002). Based on the high incidence of supernumerary parathyroid glands (commonly located within the thymus gland), some surgeons routinely perform bilateral superior horn thymectomy at the time of parathyroidectomy for patients with tertiary HPT. Others advocate the selective use of thymectomy when all four parathyroid glands cannot be identified intraoperatively. However, the long-term benefit of these strategies has not been demonstrated.
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Intraoperative PTH Monitoring The benefit of intraoperative PTH monitoring (IPM) has been well established in the treatment of primary HPT. IPM has been used in a similar fashion for the treatment of tertiary HPT, in which during subtotal parathyroidectomy a 50% drop in the PTH level signals removal of an adequate amount of parathyroid tissue (Triponez et al., 2006). IPM has also been used during total parathyroidectomy with autotransplantation to signal the complete removal of all parathyroid tissue (Kaczirek et al., 2005). It should be noted that criteria for IPM to determine cure in tertiary HPT have not been clearly established. The use of IPM in patients with tertiary HPT is further complicated by evidence that modern two-site PTH immunoassays crossreact with some truncated fragments of the PTH molecule and that these truncated fragments accumulate to higher levels in patients with renal insufficiency (Brossard et al., 2000; Lepage et al., 1998). IPM may serve to confirm the adequate resection of parathyroid tissue in patients with single or multiple enlarged glands undergoing less-than-subtotal parathyroidectomy. Alternatively, it may help to signal the presence of supernumerary glands in patients undergoing subtotal or total parathyroidectomy.
MANAGEMENT OF RECURRENT DISEASE Recurrence of tertiary HPT following parathyroidectomy is most often related to a decline in renal function and loss of the transplanted kidney. It may also be due to overgrowth of the parathyroid remnant(s) or to the presence of a missed or supernumerary gland. As is the case with primary HPT, many tertiary HPT patients develop elevated PTH levels following parathyroidectomy but remain eucalcemic. The significance of this is unclear, and re-exploration of the neck is generally not recommended. In patients with recurrent tertiary HPT, careful planning is required prior to re-exploration. Imaging with both sestamibi scanning and cervical US should be performed. If no parathyroid tissue is identified, fourdimensional computed tomography (CT), or CT angiography, of the neck may be considered (Harari et al., 2008; Rodgers et al., 2006). An additional technique available for parathyroid localization is differential jugular venous sampling performed either preoperatively or intraoperatively.
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Vocal cord assessment using indirect or fiber-optic laryngoscopy should be considered prior to reoperation for recurrent disease. Subjective evaluation of the voice is an unreliable measure of vocal cord function. Finally, operative reports and pathology results from prior operations in the neck should be carefully reviewed.
SUMMARY Tertiary HPT is characterized by hypercalcemia and elevated PTH after renal transplantation. It usually presents with symptoms of hypercalcemia and/or low bone mineral density. At our institution, patients with tertiary HPT are routinely evaluated using cervical US. A four-gland exploration with subtotal parathyroidectomy (3½ gland excision) is performed in the majority of cases, leaving a portion of the most normal-appearing gland. In cases where one of the inferior parathyroid glands is not found intraoperatively, cervical thymectomy is performed. In the event that one or more glands appear normal, excision of only the enlarged glands is considered; however, the long-term results of this approach are unknown. In all cases, we use IPM to confirm an adequate drop in the PTH level and to rule out the presence of supernumerary glands.
SELECTED REFERENCES Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95(1):14–21. Brossard JH, Lepage R, Cardinal H, et al. Influence of glomerular filtration rate on non-(1-84) parathyroid hormone (PTH) detected by intact PTH assays. Clin Chem 2000;46(5):697–703. Chen H, Pruhs Z, Starling JR, Mack E. Intraoperative parathyroid hormone testing improves cure rates in patients undergoing minimally invasive parathyroidectomy. Surgery 2005;138(4):583–587; discussion 7–90. Dumoulin G, Hory B, Nguyen NU, et al. No trend toward a spontaneous improvement of hyperparathyroidism and high bone turnover in normocalcemic long-term renal transplant recipients. Am J Kidney Dis 1997;29(5):746–753. Eknoyan G, Levin A, Levin NW. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42(4 Suppl 3):S1–S201.
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Harari A, Zarnegar R, Lee J, et al. Computed tomography can guide focused exploration in select patients with primary hyperparathyroidism and negative sestamibi scanning. Surgery 2008;144(6):970–976; discussion 6–9. Irvin GL, 3rd, Solorzano CC, Carneiro DM. Quick intraoperative parathyroid hormone assay: surgical adjunct to allow limited parathyroidectomy, improve success rate, and predict outcome. World J Surg 2004;28(12): 1287–1292. Kaczirek K, Riss P, Wunderer G, et al. Quick PTH assay cannot predict incomplete parathyroidectomy in patients with renal hyperparathyroidism. Surgery 2005;137(4):431–435. Lepage R, Roy L, Brossard JH, et al. A non-(1-84) circulating parathyroid hormone (PTH) fragment interferes significantly with intact PTH commercial assay measurements in uremic samples. Clin Chem 1998;44(4):805–809. Nichol PF, Starling JR, Mack E, et al. Long-term follow-up of patients with tertiary hyperparathyroidism treated by resection of a single or double adenoma. Ann Surg 2002;235(5):673–678; discussion 8–80. Phitayakorn R, McHenry CR. Incidence and location of ectopic abnormal parathyroid glands. Am J Surg 2006;191(3):418–423. Rodgers SE, Hunter GJ, Hamberg LM, et al. Improved preoperative planning for directed parathyroidectomy with 4-dimensional computed tomography. Surgery 2006;140(6):932–940; discussion 40–41. Schlosser K, Endres N, Celik I, et al. Surgical treatment of tertiary hyperparathyroidism: the choice of procedure matters! World J Surg 2007; 31(10): 1947–1953. Schmid T, Muller P, Spelsberg F. Parathyroidectomy after renal transplantation: a retrospective analysis of long-term outcome. Nephrol Dial Transplant 1997; 12(11):2393–2396. Schwarz A, Rustien G, Merkel S, et al. Decreased renal transplant function after parathyroidectomy. Nephrol Dial Transplant 2007;22(2):584–591. Sofferman RA, Nathan MH. The ectopic parathyroid adenoma: a cost justification for routine preoperative localization with technetium Tc 99m sestamibi scan. Arch Otolaryngol Head Neck Surg 1998;124(6):649–654. Traindl O, Langle F, Reading S, et al. Secondary hyperparathyroidism and acute tubular necrosis following renal transplantation. Nephrol Dial Transplant 1993;8(2):173–176. Triponez F, Dosseh D, Hazzan M, et al. Accuracy of intra-operative PTH measurement during subtotal parathyroidectomy for tertiary hyperparathyroidism after renal transplantation. Langenbecks Arch Surg 2006;391(6):561–565.
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Vail AD, Coller FC. The parathyroid glands: clinicopathologic correlation of parathyroid disease as found in 200 unselected autopsies. Mo Med 1967; 64(3):234–238. Wang C. The anatomic basis of parathyroid surgery. Ann Surg 1976;183(3): 271–275.
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Chapter II.B.4: Parathyroid Carcinoma Elliot J. Mitmaker MD, MSc, FRCSC and Wen T. Shen, MD, MA
The most reliable clue to the presence of malignancy in our experience is a fibrous inflammatory-like reaction, which surrounds the tumor and binds it firmly to adjacent structures. The fibrosis involves the capsule and is found also inside the tumor in thick stromal bands. Such a fibrous reaction is not seen either around or inside the benign adenomas or the hyperplastic glands. — Oliver Cope, Carcinoma of the parathyroid glands: 4 cases among 148 patients with hyperparathyroidism. Ann Surg 1953;138(4):661–671.
INTRODUCTION Parathyroid carcinoma is a rare endocrine neoplasm, accounting for approximately 1% of all cases of primary hyperparathyroidism. As opposed to the more commonly encountered benign parathyroid adenoma, patients afflicted with parathyroid cancer usually are more symptomatic and have higher calcium and parathormone (PTH) levels. This chapter summarizes the demographic data, clinical presentation, diagnostic studies, and surgical approach, as well as the role of adjuvant and medical therapies in the management of both primary and recurrent or metastatic parathyroid cancer.
DEMOGRAPHIC DATA Worldwide, there have been approximately 700 cases of parathyroid carcinoma reported in the medical literature. Parathyroid cancer accounts 211
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Demographic data for parathyroid cancer.
Gender (M:F) Age of diagnosis Incidence (of 1° HPT) Prevalence (in the US)
1:1 5th decade ~1% 0.005%
for 0.005% of all cancers and is the cause of 1% of cases of hyperparathyroidism, with some centers reporting incidences of up to 5% of cases (Table 1). In 1999, the National Cancer Database (NCDB) published their report of 286 prospectively accrued patients who were diagnosed with parathyroid cancer between 1985 and 1996. They found no differences with respect to gender, ethnicity, income, and geographic location. More recently, analysis of the Surveillance, Epidemiology and End Results (SEER) cancer registry revealed a significant increase of 60% in the incidence of parathyroid cancer from the years 1988–1991 to 2000–2003. This dramatic increase may be due to the fact that more cases of asymptomatic hyperparathyroidism are being discovered by biochemical screening for calcium and immunoassays of PTH levels. As a result, more parathyroidectomies are being performed with subsequent detection of parathyroid carcinoma on final pathology.
ETIOLOGY The etiology of parathyroid cancer is largely idiopathic. There are some reports of parathyroid carcinomas that are associated with multiple endocrine neoplasia type I (an autosomal dominant form of familial hyperparathyroidism), hereditary hyperparathyroid–jaw tumor syndrome (HPT-JT, a condition associated with tumors of the parathyroid glands and fibro-osseous tumors of the jaw), and external radiation exposure.
CLINICAL PRESENTATION The majority of cases diagnosed as parathyroid carcinoma are of the hyperfunctioning variety with markedly elevated levels of both PTH and calcium. A few anecdotal cases have been reported as nonfunctional with
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normal levels of PTH and calcium; however, they are only a minority. The classic signs and symptoms associated with parathyroid cancer are similar to primary hyperparathyroidism. The following is a list of the signs and symptoms commonly seen in these patients. 1. 2. 3. 4. 5. 6. 7.
Fatigue Weakness Polyuria Polydipsia Depression Nausea Kidney stones
8. 9. 10. 11. 12. 13. 14.
Pathologic bone fractures Subcortical bone resorption Bone pain Peptic ulcers Recurrent pancreatitis Anorexia Dehydration
Parathyroid cancer should be suspected in patients presenting with severe “classic” signs and symptoms of hyperparathyroidism. On the other hand, patients with benign primary hyperparathyroidism rarely have severe symptoms, and are usually diagnosed earlier when they are asymptomatic or minimally symptomatic, by screening blood tests demonstrating elevated calcium levels and PTH. Parathyroid cancers are hormonally active and secrete markedly elevated levels of PTH. In the long term, the effects of prolonged secretion of PTH on the skeleton and of calcium on the kidneys are the ultimate debilitating morbidities that characterize this disease. Generally speaking, patients with parathyroid cancer tend to have much higher levels of calcium and PTH as compared to patients who have benign primary hyperparathyroidism. One should suspect parathyroid cancer in a patient with the following biochemical profile: • • • • •
Calcium levels greater than 14 mg/dL, or 2–4 mg/dL above the normal calcium level High PTH levels (3–10 times normal) Renal and skeletal abnormalities in conjunction with an elevated PTH level Palpable cervical mass Compression or local invasion (evidence of the recurrent laryngeal nerve paralysis)
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The last two findings are occasionally noted on physical exam, but in the majority of cases the clinician establishes a high index of suspicion based upon clinical and biochemical findings. The next step in establishing the diagnosis is to perform localization studies prior to surgery. Fine needle aspiration biopsy is to be avoided, due to the risk of tumor seeding along the needle tract.
LOCALIZATION STUDIES Several imaging modalities are available for preoperative planning, including neck ultrasound, computed axial tomography (CT), magnetic resonance imaging (MRI), and sestamibi scan. If four-gland exploration is the operative procedure of choice, then preoperative localization studies are considered to be superfluous. However, as unilateral gland exploration and minimally invasive parathyroidectomy (MIP) are becoming more popular, the need for preoperative imaging is growing stronger. Unfortunately, there is little radiographic information to help distinguish benign from malignant parathyroid tumors. Ultrasound provides information with respect to the number of parathyroid glands, their location with respect to adjacent structures, and the visualization of the thyroid gland in order to rule out any coexisting thyroid nodules. It also has the advantage of being used intraoperatively to help guide surgical management. The sestamibi scan is a nuclear medicine study in which a very mild dose of a radioactive material (technetium Tc 99m sestamibi radiopharmaceutical) is injected intravenously. Its main goal is to help localize the hyperfunctioning parathyroid gland, as opposed to making the diagnosis of primary hyperparathyroidism. In addition, it can help distinguish between unigland and multigland disease, and also help detect metastatic disease. When ultrasound and sestamibi scans are equivocal, second-line imaging should consist of CT scanning or MRI. Although imaging studies for the initial operation for hyperparathyroidism are useful for guiding the surgeon’s operative strategy, they are of critical importance in the reoperative setting. In the case of parathyroid carcinoma, these tumors are associated with high local recurrence rates and distant metastasis. Ultrasound is generally accurate in identifying the location of the recurrence and its relationship to any surrounding
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structures. On the other hand, sestamibi scanning maintains its role in being able to identify hyperfunctioning parathyroid lesions and distant metastases. If the aforementioned methods fail, then the patient is sent for a contrast CT to look for recurrence. MRI with gadolinium represents the ideal method for detecting recurrence of parathyroid cancer, as it is not limited by clip artifacts from previous operations (in contrast to CT scans). If all noninvasive studies are equivocal in locating the recurrence of parathyroid cancer, then an invasive approach using selective venous catheterization is the procedure of choice.
PATHOLOGY The distinguishing histologic features of parathyroid cancer are difficult to define. There are a variety of gross and microscopic features that aid in establishing the diagnosis of a parathyroid carcinoma as opposed to the more common parathyroid adenoma (Table 2). Unfortunately, none of these features is pathognomonic of parathyroid cancer and some can be found in parathyroid adenomas as well. Due to the lack of defining histopathologic features, attention has turned to molecular and genetic studies to help distinguish between adenoma and carcinoma. Several studies using flow cytometry and mean nuclear DNA Table 2 Macroscopic and microscopic pathologic features of parathyroid carcinoma. Macroscopic features • • • • • •
Typically large (>3 cm) (see Figs. 1 and 2) Grayish-white Often adherent to adjacent tissues More common in inferior glands Irregular and firm Occasionally found in ectopic location
Microscopic features •
Fibrous trabeculae (thick fibrous bands) • Mitotic figures • Vascular or capsular invasion • •
Chief cell — predominant cell type Cellular atypia
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Fig. 1 Parathyroid carcinoma — left inferior gland (courtesy of M. R. Vriens, MD, PhD, Utrecht, The Netherlands).
Fig. 2 4.8 cm parathyroid cancer (courtesy of M. R. Vriens, MD, PhD, Utrecht, The Netherlands).
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have shown a difference between benign and malignant parathyroid tissue. Immunohistochemical analysis has demonstrated the lack of staining of the retinoblastoma (Rb) protein, which is usually present in benign parathyroid tissue. In addition, molecular studies have shown increased expression of the PRAD1 oncogene (which codes for cyclin D1) and mutations in the tumor suppressor gene HRPT2.
OPERATIVE MANAGEMENT The only successful long-term treatment of parathyroid cancer is surgical. En bloc removal of the entire parathyroid tumor along with the ipsilateral thyroid lobe, isthmus, and ipsilateral central lymph node compartment (starting inferiorly at the level of the upper mediastinum to the larynx superiorly) should routinely be performed when parathyroid cancer is suspected preoperatively either from a needle biopsy or based on the biochemical results. The reason for the thyroid lobectomy is to obtain clear resection margins (not necessarily for the possibility of a lesion arising from within the thyroid gland itself). If there is evidence of local invasion, then all tumor tissue should be removed with careful attention to avoid disruption of the capsule of the parathyroid gland so as to prevent tumor seeding (parathyromatosis). If the tumor is clearly invading the recurrent laryngeal nerve, then the nerve needs to be sacrificed. On the other hand, if it appears as though the lesion could be shaved off the nerve, then every attempt should be made to preserve the function of the recurrent laryngeal nerve. Although more aggressive surgical approaches to the treatment of parathyroid carcinoma have been described in the literature, most studies have shown no benefit when it comes to performing wide local excision with free margins and prophylactic neck dissection. It is not always possible to make the diagnosis of parathyroid cancer preoperatively or even intraoperatively. Approximately 20% of the time, the diagnosis is confirmed only by the final pathologic report. In such cases, if the patient continues to be symptomatic with biochemical evidence of hypercalcemia or evidence of vascular or capsular invasion on pathology, then reoperation is indicated. The patient should then undergo ipsilateral thyroidectomy along with ipsilateral central node compartment dissection,
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ensuring that all nodal tissue in the ipsilateral tracheoesophageal groove is removed. If the patient is normocalcemic and there is only microscopic evidence of disease, then the consensus is to follow the patient with serial laboratory determinations of calcium and PTH, along with serial neck ultrasounds to detect local recurrence. Unfortunately, disease recurrence is common (up to 50%) in patients diagnosed with parathyroid carcinoma. Parathyroid cancer is a slowgrowing disease that can present with local invasion, lymph node metastases, or with distant metastases most commonly to the liver, lungs, or bones. Most recurrent disease occurs within the first 2–3 years after initial treatment (the median time to recurrence is 33 months and can range from 1 to 228 months). Patients with recurrence usually present with an elevated calcium and/or elevated PTH level. These patients are rarely symptomatic, thus stressing the need for lifelong followup with their surgeon and endocrinologist. As with other forms of malignancy, a short disease-free interval is associated with a poor prognosis. The decision for further surgery on these patients should be discussed with the patient, their family, as well as the endocrinologist or primary care physician in order to clarify the goals and potential outcomes of the operation. Reoperative neck surgery is associated with a high morbidity and cures are rarely achieved. The goal for the majority of these patients is symptomatic palliation by reducing tumor load and normalizing calcium levels in an attempt to minimize the devastating effects of this cancer on the kidneys and bones. Even in the presence of locoregional recurrence and concomitant distant metastases, every attempt should be made to resect both the recurrent and distant metastases in order to induce periods of normocalcemia. An additional advantage of removing metastatic tumor deposits is to allow the patient being treated medically to achieve better control of their symptoms. A question often discussed in the literature is whether there is a limit to the number of times the surgeon should re-explore a reoperative neck for recurrence. Some studies have shown that the best results achieved for controlling calcium and PTH levels are achieved within the first two reoperations. Subsequent re-exploration has been associated with higher morbidities and less-than-satisfactory control of the patient’s symptoms and biochemistry. However, resectable lesions that are found outside of the neck should be excised for the purpose of palliation.
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MEDICAL MANAGEMENT AND ADJUVANT THERAPIES Just as operative management is of central importance in the initial treatment of parathyroid cancer, so is the medical management of its associated hypercalcemia. Patients presenting with hyperfunctioning malignant parathyroid tissue require prompt attention to prevent irreversible end organ effects of hypercalcemia on the cardiovascular, renal, and musculoskeletal systems. The first step in the medical management of severe hypercalcemia is the administration of intravenous fluids (normal saline) to restore the intravascular volume of the patient and increase the glomerular filtration rate. Once intravascular volume is restored, loop diuretics are given (such as furosemide, starting at 40 mg IV) if renal function is adequate. Loop diuretics aid in excreting excess calcium by blocking calcium resorption at the level of the ascending loop of Henle. Other drugs that decrease serum calcium include calcitonin, plicamycin, and the bisphosphonates. Calcitonin is a short-acting osteoclast inhibitor and acts by decreasing serum calcium levels through inhibition of bone resorption. Plicamycin, another short-acting osteoclast inhibitor, acts in a similar fashion but can be a problem due to its gastrointestinal side effects. There are three commercially available bisphosphonates: pamidronate, etidronate, and clodronate. These agents tend to be more potent osteoclast inhibitors and are long-acting, with a reduced side effect profile. A new agent for the treatment of patients with unresectable parathyroid cancer and/or refractory hypercalcemia is Cinacalcet (Sensipar). Cinacalcet is a calcimimetic drug that binds to the calcium-sensing receptors via allosteric activation. It reduces the synthesis of PTH, thereby lowering the serum calcium levels. Its ability to reduce serum calcium levels and maintain those levels (up to three years) in patients with metastatic parathyroid cancer has made this drug an effective treatment. Many case studies and reports have looked at the efficacy of chemotherapeutic regimens in the treatment of parathyroid cancer. These studies were based on a small number of patients and looked at a variety of different chemotherapeutic regimens (alone or in combination) using 5-fluoruracil, cyclophosphamide, dacarbazine, adriamycin, vincristine, actinomycin D, and lomustine. To date, there has been little evidence that chemotherapy is effective for metastatic parathyroid cancer, nor in its
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ability to control PTH and calcium levels. Radiotherapy, in the past, has generally been considered ineffective for local control of this disease. However, recent studies published by the Mayo Clinic and MD Anderson Cancer Center have suggested that radiotherapy may have a role in improving the disease-free survival of these patients. Further studies are needed to define the exact role of chemotherapy and radiotherapy in the treatment of metastatic parathyroid cancer.
PROGNOSIS AND OUTCOMES The prognosis of parathyroid carcinoma is variable, as reported in the literature. Five-year survival rates range from 46% to 90%, with the National Cancer Database (NCDB) reporting 5-year and 10-year survival rates of 85.5% and 49.1%, respectively, over a 10-year period (1985–1995). The Swedish Cancer Registry database reported a 10-year overall survival rate of 70%. Although survival has been shown to be favorable, the rate of recurrence still remains elevated at about 50%. Once recurrence occurs, the potential for local invasion, as well as lymphatic and hematogenous spread to distant sites, often leads to a significant burden of disease with no hope of achieving cure. The cause of mortality from parathyroid cancer is directly related to the physiologic and metabolic consequences of hypercalcemia, as opposed to the tumor burden itself. The SEER database (1988–2003) reported an all-cause 5-year mortality rate of 16% and a 10-year mortality rate of 33%. Overall, patients whose tumors are discovered early have a favorable prognosis, while those patients who develop recurrence may require multiple reoperations and will likely succumb to the metabolic complications associated with severe hypercalcemia.
SELECTED REFERENCES Amos KD, Habra MA, Perrier ND. Carcinoma of the thyroid and parathyroid glands. In: The MD Anderson Surgical Oncology Handbook, 4th Edn. BW Feig (ed.). Philadelphia: Lippincott Williams & Wilkins, 2006, pp. 441–463. Bilezikian JP. Management of acute hypercalcemia. N Engl J Med 1992;326:1196–1203.
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Bukowski RM, Sheeler L, Cunningham J, Esselstyn C. Successful combination chemotherapy for metastatic parathyroid carcinoma. Arch Intern Med 1984;144:399–400. Calandra DB, Chejfec G, Foy BK, et al. Parathyroid carcinoma: biochemical and pathologic response to DTIC. Surgery 1984;96:1132–1137. Chahinian AP, Holland JF, Nieburgs HE, et al. Metastatic nonfunctioning parathyroid carcinoma: ultrastructural evidence of secretory granules and response to chemotherapy. Am J Med Sci 1981;282:80–84. Cope O, Nardi GL, Castleman B. Carcinoma of the parathyroid glands: 4 cases among 148 patients with hyperparathyroidism. Ann Surg 1953;138(4): 661–671. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. Two hundred eighty-six cases of parathyroid carcinoma treated in the U.S. between 1985–1995: A National Cancer Data Base Report. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1999;86:538–544. Kebebew E, Arici C, Duh QY, Clark OH. Localization and reoperation results for persistent and recurrent parathyroid carcinoma. Arch Surg 2001;136:878–885. Lee PK, Jarosek SL, Virnig BA, et al. Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer 2007;109:1736–1741. Marcocci C, Cetani F, Rubin MR, et al. Parathyroid carcinoma: is there a role for adjuvant radiation therapy? Cancer 2003;98:2378–2384. Marcocci C, Cetani F, Rubin MR, et al. Parathyroid carcinoma. J Bone Miner Res 2008;23(12):1869–1880. Rawat N, Khetan N, Williams DW, Baxter JN. Parathyroid carcinoma. Br J Surg 2005;92(11):1345–1353. Sandelin K. Parathyroid carcinoma. In: Textbook of Endocrine Surgery, 2nd Edn. OH Clark (ed.) Philadelphia: Elsevier Saunders, 2005, pp. 549–554. Shane E. Clinical review 122: parathyroid carcinoma. J Clin Endocrinol Metab 2001;86:485–493. Silverberg SJ, Rubin MR, Faiman C, et al. Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma. J Clin Endocrinol Metab 2007;92:3803–3808.
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Chapter II.B.5: Hyperparathyroidism in Familial Disease Charles Tuggle, BS, Julie Ann Sosa, MD, MA and Robert Udelsman, MD, MBA
OVERVIEW Primary hyperparathyroidism (HPT) occurs at all ages, with a predominance in elderly, white women; sporadic disease represents >95% of incident cases. Inherited syndromes are rare but must be considered during evaluation. Detection necessitates a thorough history and physical examination, with an emphasis on family history and a complete review of systems (Fig. 1).
MULTIPLE ENDOCRINE NEOPLASIA 1 (MEN1) (Online Mendelian Inheritance in Man [OMIM] 131100, gene locus 11q13) This accounts for the majority of familial HPT. Epidemiology and Presentation •
• • •
Evaluate for recurrent HPT, gastrointestinal ulcers, pancreatic neuroendocrine tumors, pituitary tumors, lipomas, truncal collagenomas, and facial angiofibromas Incidence: 0.015 per 1000 Autosomal dominant inheritance HPT
First clinical manifestation in 90% of carriers Typical presentation at age 20–25 223
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Fig. 1 Algorithm for detection and management of familial HPT (fHPT) in adult patients.
•
90% of carriers present by age 50 Pathology: multigland hyperplasia (often asymmetric), increased incidence of supernumerary glands
Penetrance of at least one associated clinical feature is >50% by age 20, and >95% by age 40
Diagnosis •
Clinical criteria: ≥2 MEN1-associated endocrine tumors [parathyroid, anterior pituitary, or gastroenteropancreatic (GEP) neuroendocrine tumors]
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Familial criteria: family with at least one index case of MEN1 and a first-degree relative with ≥1 MEN1-associated endocrine tumors
Genetic Testing (Table 1) •
Candidates are:
• •
10% of incident cases result from a de novo mutation and lack a family history Commercially available sequence analysis of coding regions (exons 2–10)
•
Patients with ≥2 MEN1-associated tumors Family members at risk of inheritance of a known mutation
80–90% sensitivity
Subsequent deletion/duplication analysis if sequence analysis fails to detect a mutation
Offered by select laboratories; will detect an additional 1–3% of cases
Parathyroid Imaging • •
Unnecessary before primary surgery; only utility is to exclude ectopic glands Required before remedial surgery (see Chapter II.A.2)
Surgery Primary surgery Parathyroidectomy should be thought of as a “debulking” procedure, as the risk of recurrence is high. Early parathyroidectomy reduces exposure to chronic hypercalcemia, but predisposes to earlier recurrence and need for remedial surgery. Delayed surgery allows the glands to enlarge so as to facilitate identification. In patients with Zollinger–Ellison syndrome, parathyroidectomy should be performed prior to, or at the time of, pancreatic surgery.
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Initial surgery is either subtotal parathyroidectomy or total parathyroidectomy with heterotopic autotransplantation and transcervical thymectomy. Cryopreservation should be considered (see Chapter II.B.8). The risk of remedial cervical exploration is greater with the former strategy, while the risk of hypoparathyroidism is greater with the latter. A thorough search for supernumerary and ectopic glands should be performed; thymectomy removes occult parathyroid glands and helps prevent development of thymic carcinoid tumors. A minimally invasive approach should not be used.
Remedial surgery Recurrent HPT arises from remnant tissue in the neck following sub-total resection, ectopic and/or supernumerary tissue in the neck or mediastinum missed at the primary procedure, autotransplantation graft, or a combination. Remedial surgery comes at increased risk of complications. •
Preoperative evaluation
•
Confirm diagnosis Review all previous operative and pathology reports Perform laryngoscopy to assess recurrent laryngeal nerve function Image to localize recurrence site; this can include ultrasound, sestamibi with SPECT (to include graft site if present), 4D-CT, MRI, ultrasound-guided parathyroid aspiration, and angiography with venous sampling (see Chapter II.A.2)
Surgery
Minimally invasive approach can be employed if recurrence is in forearm or well-localized in neck
Surveillance • •
Low genotype-to-phenotype correlation Carriers should be checked periodically for common expressions of MEN1
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•
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Biochemical testing annually; abdominal and pituitary imaging every 3–5 years Cost-effective panel — serum calcium corrected for albumin or ionized calcium (henceforth referred to as serum calcium), iPTH, gastrin, prolactin (from age 5) Complete biochemical panel — serum calcium, iPTH, gastrin, prolactin; consider glucagon, fasting glucose, insulin, proinsulin, insulin-like growth factor 1, chromogranin-A Imaging — abdominal CT or MRI (from age 20) and head MRI, pituitary protocol When genetic testing fails to identify a mutation in a patient with clinical MEN1 syndrome, children should undergo cost-effective biochemical testing every three years. If testing remains negative through age 30, the risk of being a carrier falls to 10%, and testing intervals can be lengthened.
MULTIPLE ENDOCRINE NEOPLASIA 2A (MEN2A) (OMIM 171400, gene locus 10q11.2) Initial presentation and management of carriers is dominated by medullary thyroid cancer (MTC) (see Chapter I.B.4). Epidemiology and Presentation • • • •
•
Evaluate for MTC, uni/bilateral pheochromocytoma, hypertensive sudden death, cutaneous lichen amyloidosis, Hirschprung’s disease Prevalence: estimated at 1 in 30,000 Autosomal dominant inheritance with incomplete penetrance, variable disease pattern HPT Mild and often asymptomatic Pathology: typically single-gland enlargement; multigland disease does occur Strong genotype–phenotype correlation The specific REarranged during Transfection proto-oncogene (RET ) mutation and the familial pattern of disease predict the likelihood and age of onset of associated tumors
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HPT is most commonly associated with codon 634 mutations, which account for ∼85% of families with MEN2A
Diagnosis •
Clinical criteria: ≥2 MEN2A-associated endocrine tumors [MTC (>95% in carriers), pheochromocytoma (∼50%), or parathyroid tumor(s) (20–30%)]
Genetic Testing (Table 2) • • • •
• • •
Follows biochemical testing for MTC if thyroid is in situ in the proband and MEN2 is suspected Appropriate for all cases of MTC; likelihood of mutation is 1–7% in patients with apparently sporadic MTC Not indicated in cases of HPT without other suggestive features of MEN2 In a patient with MTC, no evidence of C-cell hyperplasia in thyroidectomy specimen, and a negative family history, the probability of hereditary disease is <10% <5% of cases result from de novo mutation Most laboratories sequence exons 10–11, sometimes 13–16 95% sensitivity in patients with clinical MEN2A Extended sequencing can be performed for the remaining coding regions if no mutation is identified during initial testing
Parathyroid Imaging •
Approached in the same manner as for sporadic HPT (see Chapter II.A.2)
Surgery •
Preoperatively, pheochromocytoma must be excluded with biochemical evaluation.
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Indications for parathyroidectomy are similar to those for sporadic HPT. The intraoperative rapid PTH assay can be helpful in guiding resection. MTC is the dominant feature, and generally HPT is diagnosed synchronously or following thyroidectomy. Enlarged parathyroid glands encountered during thyroidectomy for MTC in a eucalcemic patient should be resected, sparing normal-appearing glands.
Surveillance Periodic screening of MEN2 carriers should consider the MEN2 variant, which is characterized by the specific RET codon mutation and by the pattern of tumors within the family. However, the data are too few and the overlap too great to recommend exclusion of families from adrenal or parathyroid screening based on mutation data. •
•
Annual biochemical testing until age 35: plasma or 24-h urine metanephrine, catecholamine, and VMA (see Chapter III.A.3), and serum calcitonin and CEA (see Chapter I.B.4) Serum iPTH and calcium every 2–3 years
Annual testing if there is a 634 mutation, or a family history of HPT
FAMILIAL ISOLATED HPT (FIHPT) This is associated with a known genetic mutation in a minority of cases. Epidemiology and Presentation • •
Overall, higher prevalence of multigland hyperplasia (∼60%) and supernumerary glands (∼10%) Clinically and genetically heterogeneous disorder (<20% associated with one of three genes)
MEN1-associated FIHPT presents with mild hypercalcemia and multigland hyperplasia, similar to MEN1-HPT HRPT2-associated FIHPT is more severe, with parathyroid tumor(s) that often have atypical or cystic features, or parathyroid carcinoma
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CASR-associated FIHPT can be distinguished from familial benign hypocalciuric hypercalcemia (FHH) as a result of HPTrelated sequelae (nephrolithiasis and hypercalciuria)
Diagnosis • •
Symptomatic HPT (i.e. with nephrolithiasis) Family history
• •
HPT or its sequelae, without associated syndromic lesions or endocrinopathies Persistent/recurrent HPT following surgery, multigland disease
Young age at diagnosis (<40 years) Diagnosis of exclusion
Genetic Testing (Tables 1, 3, 4) •
A genetic cause cannot be identified in a majority of cases
Parathyroid Imaging • •
Decreased utility before primary surgery because of the prevalence of multigland disease Required before remedial surgery (see Chapter II.A.2)
Surgery •
Without a pre-operative genetic diagnosis:
•
Due to a high recurrence rate, bilateral neck exploration and subtotal parathyroidectomy is recommended. The intraoperative rapid PTH assay can be helpful in determining adequacy of resection.
With a preoperative genetic diagnosis:
MEN1-associated FIHPT: surgical approach for MEN1 HRPT2-associated FIHPT: all grossly enlarged glands should be removed; if all four glands are enlarged, consider subtotal parathyroidectomy
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CASR-associated FIHPT: multigland disease treated with subtotal parathyroidectomy
Surveillance •
Should resemble that for the related syndrome
MEN1-associated FIHPT: serum calcium, iPTH, gastrin, and prolactin annually HRPT2-associated FIHPT: serum calcium and iPTH every six months CASR-associated FIHPT: serum calcium and iPTH annually
HPT– JAW TUMOR SYNDROME (HPT-JT) (OMIM 145001, gene locus 1q25–q31) This is an exceedingly rare disorder, with approximately 30 families reported. Epidemiology and Presentation •
• •
Evaluate for jaw tumors, parathyroid cancer, kidney cysts or tumors, severe hypercalcemia, and palpable cervical mass (parathyroid carcinoma) Autosomal dominant inheritance HPT
•
Fibromas of the maxilla or mandible occur in 30–40% of cases
•
80–90% penetrance Manifests in late adolescence, early adulthood Pathology: typically single parathyroid tumor; multigland disease does occur 10–15% due to carcinoma Present prior to age 30 Occur in molar, premolar areas Do not regress after parathyroidectomy
Renal lesions (including cysts, and rarely hamartomas, Wilms’ tumor) occur in 20% of affected individuals
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Increased incidence of uterine tumors 20–29% of apparently sporadic cases of parathyroid carcinoma are carriers
Diagnosis •
Clinical criteria: HPT with concomitant ossifying fibromas of the maxilla and/or mandible, or presence of HPT or maxillary/mandibular fibromas and a close relative with documented HPT-JT syndrome
Genetic Testing (Table 3) •
Most laboratories offer sequence analysis of the HRPT2 gene in two tiers
•
83% of detected mutations have been identified in exons 1–7 (tier 1) Exons 8–17 (tier 2) should be sequenced if no mutation is identified in first tier
58–70% sensitivity
Parathyroid Imaging •
Approached in the same manner as for sporadic HPT (see Chapter II.A.2)
Surgery The surgeon should anticipate the need to perform an aggressive en bloc resection because of the high probability of parathyroid cancer. This generally would include resection of the culprit parathyroid, ipsilateral thyroid lobe, contiguous soft tissues, and lymph nodes. A minimally invasive approach may be considered as long as one can verify adequacy of resection in the operating room. In addition, these patients will require lifelong diligent surveillance of serum calcium and iPTH because of the high probability of recurrent disease with malignant potential.
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Surveillance There are no well-established guidelines for HPT-JT. The youngest reported incident case was at age 10, so surveillance should begin then. Dental providers should be informed, and monitoring for gnathic lesions conducted. Concomitant follow-up of renal and uterine abnormalities is advised. • • •
Serum calcium and iPTH every 6–12 months Annual neck ultrasound to evaluate for nonfunctioning parathyroid carcinoma Immunohistochemical staining for loss of parafibromin expression associated with more aggressive disease; need for closer follow-up
NEONATAL SEVERE HPT (NSHPT) AND AUTOSOMAL DOMINANT MILD HPT (ADMH) (OMIM 239200, gene locus 3q13.3–q21) These are both extremely rare and result from mutations in the same gene. Epidemiology and Presentation Infants with NSHPT present with severe hypercalcemia, hypotonia, lethargy, failure to thrive, and bone undermineralization, sometimes resulting in skeletal deformation. There are reports of milder, transient cases treated successfully with medical management. One underlying pathology is parathyroid hyperplasia. Severe forms are caused by homozygous/compound heterozygous or dominant-negative heterozygous inactivating CASR mutations. ADMH is caused by a mutation in the cytoplasmic tail of the CASR gene (codon 881 of exon 7). Sequelae of hypercalcemia, such as nephrolithiasis, have been observed in carriers. The underlying pathology is parathyroid hyperplasia. Diagnosis •
NSHPT: severe hypercalcemia, dehydration, skeletal demineralization (if untreated)
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ADMH: hypercalcemia, inappropriately high serum iPTH, hypermagnesemia, relative hypercalciuria, hyperphosphaturia
Genetic Testing (Table 4) •
•
NSHPT results from homozygosity in a consanguineous FHH union, compound heterozygosity arising from two distinct mutations in FHH parents, or de novo mutation(s) Sequencing of the CASR gene is available commercially
Parathyroid Imaging •
Not indicated, as multigland disease necessitates bilateral neck exploration
Surgery •
Severe NSHPT requires total parathyroidectomy with heterotopic autotransplantation within the first months of life, and consideration of cryopreservation Treatment should not be delayed for genetic testing results
Information for tables obtained from http://www.genetests.org: Table 1
Laboratories offering sequencing for MEN1.
MEN1 testing laboratories
Website
Athena Diagnostics Inc. Reference Lab Worcester, MA Emory University School of Medicine Emory Molecular Genetics Laboratory Atlanta, GA GeneDx Gaithersburg, MD Yale University School of Medicine DNA Diagnostics Laboratory New Haven, CT
http://www.athenadiagnostics.com/content/index.jsp
http://genetics.emory.edu/egl
http://www.genedx.com http://dnalab.sites.yale.edu
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Laboratories offering sequencing for MEN2.
MEN2A testing laboratories ARUP Laboratories Molecular Genetics Laboratory Salt Lake City, UT Athena Diagnostics Inc. Reference Lab Worcester, MA Children’s Hospital of Philadelphia Molecular Genetics Laboratory Philadelphia, PA Comprehensive Genetic Services Molecular Diagnostic Laboratory Milwaukee, WI Emory University School of Medicine Emory Molecular Genetics Laboratory Atlanta, GA GeneDx Gaithersburg, MD Henry Ford Hospital DNA Diagnostic Laboratory Detroit, MI Huntington Medical Research Institutes Cancer Genetics Laboratory Pasadena, CA Mayo Clinic–Minnesota Molecular Genetics Laboratory Rochester, MN Quest Diagnostics Nichols Institute Molecular Genetics Laboratory San Juan Capistrano, CA
Website http://www.aruplab.com
http://www.athenadiagnostics.com/content/ index.jsp
Requisition available upon request
http://www.compgene.com
http://genetics.emory.edu/egl
http://www.genedx.com Requisition available upon request
http://home.pacbell.net/genedoc/ Eggspage.html
http://www.mayomedicallaboratories.com/ test-info/molecular/index.html http://www.questdiagnostics.com/hcp/ qtim/testMenuSearch.do
(Continued)
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Table 2
(Continued ).
MEN2A testing laboratories The Ohio State University Molecular Pathology Laboratory Columbus, OH University of Pittsburgh Medical Center Division of Molecular Diagnostics Pittsburgh, PA Washington University Molecular Diagnostic Laboratory St. Louis, MO Yale University School of Medicine DNA Diagnostics Laboratory New Haven, CT
Table 3
Website http://www.pathology.med.ohio-state. edu/ext/Divisions/Clinical/molpath http://path.upmc.edu/divisions/mdx/ diagnostics.html
http://www.pathology.wustl.edu/patientcare/ moldiagnostic.php http://dnalab.sites.yale.edu
Laboratories offering sequencing for HRPT2.
HRPT2-related disorders testing laboratories
Website
GeneDx Gaithersburg, MD
Table 4 CASR-related disorders testing laboratories Athena Diagnostics Inc. Reference Lab Worcester, MA GeneDx Gaithersburg, MD Mayo Clinic–Minnesota Endocrine Laboratory Rochester, MN
http://www.genedx.com
Laboratories offering sequencing for CASR.
Website http://www.athenadiagnostics.com/content/index.jsp
http://www.genedx.com http://www.mayomedicallaboratories.com/index.html
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ADMH requires aggressive subtotal parathyroidectomy or total parathyroidectomy with heterotopic autotransplantation, and consideration of cryopreservation
Surveillance •
Serum iPTH and calcium should be checked periodically
NEUROFIBROMATOSIS TYPE 1 (NF1) (OMIM 162200; gene locus 17q11.2) It can be associated with HPT, but this is rare.
Epidemiology and Presentation • • • •
NF1 patients with severe skeletal deformities, osteoporosis, and loss of motor activity should be evaluated for concurrent HPT Incidence: 1 in 3000 Autosomal dominant inheritance 100% penetrance, variable expressivity
Diagnosis •
≥2 of the following: ≥6 café au lait macules, ≥2 neurofibromas, freckling in axillary or inguinal regions, optic glioma, ≥2 Lisch nodules, osseous lesions, first-degree relative with NF1
Genetic Testing • • •
∼50% result from de novo mutation Sequence analysis of mRNA and genomic DNA (sensitivity ∼90%) Subsequent deletion/duplication analysis if sequence analysis fails to detect a mutation (sensitivity ∼5%)
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Parathyroid Imaging •
Approached in the same manner as for sporadic HPT (see Chapter II.A.2)
Surgery Preoperatively, pheochromocytoma must be excluded with biochemical evaluation. Disease is typically uniglandular and can be approached in the same manner as for sporadic HPT (see Chapter II.B.1). Surveillance •
Same as for sporadic HPT
FAMILY SCREENING AND GENETIC TESTING The benefits of detection of familial HPT include confirmation of a clinical diagnosis, enhanced knowledge of a patient’s risk of persistent/ recurrent disease, directed surgery, screening for associated conditions with improved surveillance, and screening of family members. •
•
•
• •
A negative genetic test cannot fully exclude the possibility of a positive carrier status. Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Genetic testing for the purpose of diagnosis should be performed on a sample that is representative of the patient’s germline DNA, typically derived from a peripheral blood sample, not from resected tumor. A previous bone marrow transplant will interfere with testing. If a specific familial mutation is identified in the index case, targeted sequencing of that gene segment or restriction fragment analysis is recommended for initial genetic testing in at-risk family members. In the absence of a documented mutation, initial screening of at-risk family members should include serum calcium and iPTH levels. If the patient belongs to a family with a previously documented mutation, genetic testing should be limited to the culprit gene segment.
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•
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Members of a family in which the causative mutation has been identified who demonstrate an absence of the mutation on targeted genetic analysis do not require periodic screening. An isolated or apparently sporadic case of any clinically diagnosed syndrome does not necessarily signify that it is nonhereditary; incomplete penetrance and variable expressivity should be considered.
GENETIC TESTING AND COUNSELING Professional genetic counseling is essential, as there are significant ethical, legal, and medical implications. These implications should be discussed prior to blood or tissue collection. Formal counseling should include discussion of genetic transmission, probability of inheritance, privacy issues, potential for errors in testing, and implications of a positive/negative test result with regard to future treatment and surveillance. Psychological and spiritual support should be available. Written consent should be obtained from the patient or legal guardian if the patient is a minor. Posttest counseling should be arranged when the genetic testing results can be given in person. Genetic testing in a child should be reserved for instances in which identification of a genetic condition will provide a clear benefit (e.g. MEN1, MEN2). Referral to a genetic counselor is recommended. The Genetic Information Nondiscrimination Act (GINA) was signed into law in May 2008. It prohibits health insurance companies and employers from discriminating on the basis of genetic information.
SELECTED REFERENCES Carling T, Udelsman R. Parathyroid surgery in familial hyperparathyroid disorders. J Intern Med 2005;257(1):27–37. Scriver CR, et al. Metabolic and Molecular Bases of Inherited Disease, 8th Edn. www.ommbid.com. New York: McGraw-Hill, 2004. Simonds WF, et al. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) 2002;81(1):1–26. http://www.genetests.org. Accessed July 2009.
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Chapter II.B.6: Management of Hypercalcemic Crisis Carrie C. Lubitz, MD and Antonia E. Stephen, MD
ETIOLOGY There are many possible causes of hypercalcemia. Over 90% of the time, however, it is due to hyperparathyroidism or malignancy (i.e. multiple myeloma, breast cancer, lung cancer). Other rare causes, such as granulomatous disorders, should not be considered until these two entities are ruled out. In hyperparathyroidism, PTH-induced conversion to calcitriol leads to increased small bowel absorption of calcium as well as resorption of filtered calcium at the distal tubule. This is in contradistinction to malignancy, where hypercalcemia is primarily caused by osteoclastic activity or, in a minority of cases, PTH-related peptide (PTHrP). Excess exogenous 1,25-dihydroxyvitamin D (calcitriol) and/or calcium can contribute to hypercalcemia. Hypercalcemic crisis is a rare but severe manifestation of primary hyperparathyroidism, termed “acute hyperparathyroidism” or “parathyrotoxic crisis,” and is considered a medical emergency. Precipitating events, such as pregnancy or use of thiazide diuretics, in patients with undiagnosed hyperparathyroidism are common. Patients with parathyroid carcinoma are particularly prone to developing severe hypercalcemia, although primary hyperparathyroidism due to benign parathyroid overgrowth can cause it as well. It is hypothesized that degeneration within parathyroid adenomas, including necrosis or hemorrhage, precipitates acute hypercalcemic crisis.
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DEFINITION • •
•
Serum calcium of 14 mg/dL or 3.5 mmol/L (normal 8.5–10.2 mg/dL or 2–2.5 mmol/L) along with signs and symptoms of hypercalcemia. Corrected total calcium (mg/dL) = measured total calcium mg/dL + 0.8(4.4—measured albumin g/dL), although this is frequently inaccurate. Ionized calcium levels, representing 50% of total body calcium, are a more accurate measurement in the acute setting. An ionized calcium level greater than 10 mg/dL or 2.5 mmol/L is considered dangerous (normal 4.5–5 mg/dL or 1.0–1.4 mmol/L). When interpreting levels, one should correct for serum pH (low pH, elevated ionized Ca2+).
Other Common Laboratory Abnormalities • • • • •
Serum intact PTH (normal or ↑ in hyperparathyroidism, ↓ in malignancy) Alkaline phosphatase (elevated) Phosphate (normal to low) Chloride (elevated) PTHrP (elevated in certain malignancies)
CLINICAL MANIFESTATIONS Clinical signs and symptoms of hypercalcemia may be more severe depending on the etiology and the rapidity of onset: •
• • • •
Cardiovascular: hypertension, bradycardia EKG changes: QT interval shortening, PR and QRS prolongation, T wave inversion, heart block Gastrointestinal: nausea, vomiting, anorexia, abdominal pain, constipation, gastroesophageal reflux disease, peptic ulcer disease Neurological and psychiatric: mental status changes, confusion, depression, lethargy, hyperreflexia, fasciculation, coma Musculoskeletal: proximal muscle weakness and pain, joint pain Renal: severe dehydration, polyuria, nephrolithiasis
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Hypercalcemic crisis can present with hypotension, heart failure, arrhythmias, soft tissue calcifications, pancreatitis, and acute renal failure leading to death. Signs and symptoms of hypercalcemia are reversible with correction of serum calcium. Moreover, the risk of lethal cardiac arrhythmias mandates medical treatment of hypercalcemia prior to parathyroidectomy.
ACUTE TREATMENT OPTIONS Goals of Therapy for Targeted Reduction of Calcium • • • • • • •
Discontinuation of offending and contraindicated pharmacologic agents (i.e. thiazide diuretics which inhibit urinary calcium excretion) Dilution and increased excretion with adequate hydration Dialysis in patients with renal failure (low calcium dialysate) Decreased absorption of calcium Increased urinary excretion of calcium Inhibition of osteoclast activity on the bone Treatment of the underlying cause
Once severe hypercalcemia is diagnosed, cessation of any causal or contraindicating medications (i.e. calcium supplements, vitamin D supplements, thiazide diuretics, digitalis) and administration of normal saline should be initiated. In volume-depleted patients, a net fluid balance of 2 L with hourly urine output of 100 cc (2–2.5 L/d) should be attained in the first day (Fig. 1). Volume repletion alone can reduce serum calcium up to 2.4 mg/dL and augment renal excretion. Patients should be carefully monitored for signs of fluid overload (i.e. edema). Calciuresis with a loop diuretic (furosemide) can be used cautiously following adequate extracellular fluid volume repletion and can be a useful adjunct in patients with borderline cardiovascular tolerance or in those who develop signs of fluid overload. Antiresorptive therapy should be initiated promptly. Bisphosphonates, commonly pamidronate or zolendronic acid (ZA), are effective in upward of 80% of patients in normalizing hypercalcemia secondary to bone resorption. ZA has the advantages of greater potency and shorter infusion time,
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Fig. 1 Algorithm for initial treatment of hypercalcemic crisis. For patients with severe renal insufficiency, congestive heart failure, or severe symptoms of hypercalcemia, hemodialysis in a calcium-free bath should be considered. A list of primary and secondary therapies is given in Table 1. Although as effective as pamidronate, gallium nitrate requires a continuous drip and is nephrotoxic. Plicamycin and IV phosphates are rarely used secondary to toxicity and should be considered only when other therapies have failed. Glucocorticoids are primarily used in cases of vitamin D toxicity. Cinacalcet, a calcimimetic, may be helpful in rare cases of parathyroid carcinoma.
but with a higher risk of nephrotoxicity. Serum calcium levels improve starting at 24 h following treatment and effects continue for greater than a week, at which time additional doses may be considered. Bisphosphonate use is contraindicated in severe renal failure (GFR <30 mL/min;
Drug
Medical therapies for hypercalcemic crisis, listed in order of therapy.
Dose & route
Mechanism of action
4–8 IU/kg IM or SQ every 6–12 h for 24 h
Inhibits bone resorption, enhances renal excretion
4 h, 1–2 days
Pamidronate (Aredia)
Moderate ↑Ca2+ 60 mgIV, severe 90 mg IV in 1 L NS or D5W over 2–4 h 4 mg IV in 100 cc of NS or D5W over 15 min 20–40 mg IV q6–12 h, increase to effect (max 500 mg/d)
Inhibits bone resorption
24–48 h, 1–4 weeks
Inhibits bone resorption
24–48 h, 1–4 weeks
Inhibits renal resorption
Immediate, 6 h
Furosemide (Lasix)
$$
$$$
$$$
$
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Calcitonin (Calcimar, Cibacalcin, Miacalcin)
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Immediate, during therapy
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Enhances renal excretion
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Congestive heart failure, renal failure, ↓K+, ↓Mg3+ Vomiting, flushing, tachyphylaxis, hypersensitivity to salmon or prior calcitonin Nephrotoxicity, ↓Ca2+, ↓PO4, ↓Mg3+, febrile reaction, class D in pregnancy Nephrotoxicity, GI side effects, class D in pregnancy ↓K+, ↓Mg3+
200–400 cc/h IV; 4 L/24 h
Cost per dose
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Cautions & Indications
Management of Hypercalcemic Crisis
Onset & duration of action
Normal saline
Zoledronic acid (Zometa)
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Drug
Dose & route
Mechanism of action
Onset & duration of action
Inhibits bone resorption, blocks PTH
6–12 h, 48–72 h
Gallium nitrate (Ganite)
100–200 mg per m2 IV over 24 h in 1 L NS or D5W for 5 days 8–15 mmol IV over 6 h
Inhibits bone resorption
24–72 h, 2 weeks
Calcium phosphate precipitation
Hours
30 mg PO qd
↓PTH, ↑sensitivity of calcium-sensing receptor
2–3 days, during therapy
Potassium phosphate
Cinacalcet (Sensipar)
*No longer manufactured in the U.S.
Antacids act as phosphate binders; use only in ↓PO4 state/normal GFR Nausea and vomiting common; parathyroid carcinoma
$
N/A
$
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25 g/kg IV over 6 h qd for 3–5 doses
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*Plicamycin (Mithramycin)
Used for vitamin D intoxication, hematologic malignancies, granulomatous disorders Hepatotoxic, nephrotoxic; thrombocytopenia, bone marrow toxicity, local soft tissue reaction Nephrotoxic, ↓PO4
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2–5 days, 5–14 days
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Inhibits conversion to calcitriol, inhibits gut absorption, enhances renal excretion
Cost per dose
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200–300 mg IV qd for 3 days or 20–50 mg PO BID
Cautions & Indications
C. C. Lubitz and A. E. Stephen
Hydrocortisone (Cortef) or prednisone
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Table 1 (Continued).
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creatinine >4.5 mg/dL) and halving the dosage and/or infusion rates is recommended for patients with moderate renal insufficiency (i.e. ZA 4 mg IV over 30 min and pamidronate 45 mg IV over 4 h). Calcitonin, while less potent (<2 mg/dL drop in Ca2+), can be added regardless of renal function for rapid control in hypercalcemic crisis in conjunction with hydration. Given the short onset of action (hours), this is an option for rapid control in anticipation of the sustained effects of a bisphosphonate. However, the limited duration of effect and side effect profile make this solely a temporizing measure. With all treatments for severe hypercalcemia, serial electrolytes including potassium, phosphate, magnesium, and calcium as well as serum creatinine should be monitored and treated. Patients should be monitored for signs of fluid overload and/or EKG abnormalities. Moreover, immobilization must be avoided as it redirects inflow of calcium into the skeletal tissue to the serum. Once patients with parathyrotoxicosis are stabilized and optimized for surgery, preoperative localization studies should be done expeditiously. Preoperative sestamibi imaging is recommended given the higher incidence of ectopic glands in this population. Furthermore, patients with hypercalcemic crisis are at increased risk of symptomatic hypocalcemia following parathyroidectomy and should be monitored closely. Patients with hypercalcemia secondary to malignancy ultimately need treatment of the primary disease.
SELECTED REFERENCES Ariyan CE, Sosa JA. Assessment and management of patients with abnormal calcium. Crit Care Med 2004;32:S146–S154. Bilezikian JP. Management of acute hypercalcemia. N Engl J Med 1992;326: 1196–1203. Bilezikian JP. Clinical review 51: management of hypercalcemia. J Clin Endocrinol Metab 1993;77:1445–1449. Cameron JL. Current Surgical Therapy. Philadelphia: Mosby Elsevier, 2008. Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician 2003;67:1959–1966.
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Kronenberg HM (ed.). In: Williams Textbook of Endocrinology, 11th Edn. Philadelphia: Saunders Elsevier, 2008. Phitayakorn R, McHenry CR. Hyperparathyroid crisis: use of bisphosphonates as a bridge to parathyroidectomy. J Am Coll Surg 2008;206:1106–1115. Slomp J, van der Voort PH, Gerritsen RT, et al. Albumin-adjusted calcium is not suitable for diagnosis of hyper- and hypocalcemia in the critically ill. Crit Care Med 2003;31:1389–1393. Ziegler R. Hypercalcemic crisis. J Am Soc Nephrol 2001;12(Suppl 17):S3–S9.
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Chapter II.B.7: Postoperative Hypocalcemia Daniel Levin, MD and Jacob Moalem, MD
INTRODUCTION Postoperative hypocalcemia (PH) is one of the most frequent complications of thyroid and parathyroid surgery, and may be an asymptomatic laboratory finding or a life-threatening biochemical disturbance. The frequency of this complication varies widely in the literature, and depends on the indication and extent of surgery, as well as the experience of the operating surgeon (Tomusch et al., 2003; Zarnegar et al., 2003; Shoback, 2008). Although most cases of PH are transient with normalization of serum calcium levels within six months of operation, up to 4% of all patients who undergo cervical operations may be permanently hypocalcemic (Steen et al., 2009). Since the mechanism for and thus strategies to predict and prevent PH depend on the operation performed, thyroid and parathyroid operations will be discussed separately.
THYROID SURGERY PH after thyroidectomy occurs as a direct result of inadvertent resection or devascularization of the parathyroid glands. Because a single functioning parathyroid gland is sufficient to maintain eucalcemia, this complication should not be seen after thyroid lobectomy in a patient who has not had previous neck surgery. Conversely, PH is more frequent when central compartment lymph node dissection is added to thyroidectomy, since the lower parathyroid glands are at risk for injury during this operation (Henry et al., 1998). PH is best prevented by ligating all of the attachments to the thyroid in the plane of its capsule, and by meticulously reducing parathyroid 249
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glands that are tightly adherent to the thyroid capsule whenever possible. Because parathyroid glands may be confused with lymph nodes or brown fat, fragments of all suspicious tissues that have been devascularized or removed should be evaluated by frozen section, and if verified to be parathyroidal, the remaining tissues should be autotransplanted into the sternocleidomastoid or brachioradialis muscle. Positive identification and preservation of more than two parathyroid glands was recently demonstrated to be associated with a lower frequency of PH (Del Rio et al., 2009) and, conversely, identification of fewer than three glands is associated with a higher likelihood of PH (Pattou et al., 1998). Additional factors that are associated with a higher likelihood of PH are a high preoperative free thyroxine level (Abboud et al., 2002; McHenry et al., 1994), substernal goiters, and the need for parathyroid autotransplantation (Abboud et al., 2002). Current evidence has also demonstrated the utility of postoperative parathyroid hormone (PTH) measurements in predicting PH. A recent meta-analysis concluded that a 65% decrease in the PTH level checked 6 h after completing thyroidectomy was highly accurate (sensitivity of 96.4% and specificity of 91.4%) in predicting PH (Noordzij et al., 2007).
PARATHYROID SURGERY Beyond operative trauma, there are also pathophysiologic mechanisms for PH in patients who undergo parathyroidectomy. Patients with primary hyperparathyroidism may exhibit suppression of normal parathyroid tissue by adenomatous PTH secretion. An intraoperative PTH drop of >80% (as measured from preincision PTH to 10 min postexcision PTH) has been identified as a strong predictor of PH ( p = 0.02) (Steen et al., 2009). Such a drop predicted the need for postoperative calcium and vitamin D supplementation in 46% and 71% of patients undergoing surgery for single and multigland disease, respectively (Steen et al., 2009). Another common cause of PH in patients with primary hyperparathyroidism is hungry bone syndrome (HBS) — a derangement in calcium, phosphate, and magnesium turnover. Prior to surgery, patients with hyperparathyroidism have an exaggerated rate of bone remodeling with a net efflux of calcium from bone. Postoperatively, the sudden decrease in PTH
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results in an imbalance between osteoblast and osteoclast activity and widespread bone remineralization. This sudden increase in bone uptake of calcium, phosphate, and magnesium leads to an abrupt decrease in the serum levels of these elements. Authors have defined HBS by the presence of low serum calcium and phosphorus levels (<8.5 mg/dL and <3.0 mg/dL) three days after parathyroidectomy. Using these criteria, the overall incidence of HBS was found to be 12.6% among patients treated for primary hyperparathyroidism (Brasier and Nussbaum, 1988). Another study, using a stricter definition, found the incidence of HBS to be 20% in patients treated for secondary hyperparathyroidism (Jofre et al., 2003). Although the literature lacks a unifying biochemical definition for HBS, when it presents clinically it must be recognized and managed appropriately. To date, four risk factors that lead to the development of HBS have been identified. Patients who developed HBS had larger glands resected [4.49 +/− 1.9 cm3 (4.44 +/− 1.0 g) vs. 1.33 +/− 0.22 cm3 (1.78 +/− 0.21 g)], had higher preoperative blood urea nitrogen concentrations (BUN; 20.5 +/− 2.4 vs. 14.2 +/− 0.4) and a higher preoperative alkaline phosphatase concentrations (68.2 +/− 15.0 vs. 38.2 +/− 1.5 IU/L). Moreover, individuals who developed HBS were approximately 10 years older than those who did not (Brasier and Nussbaum, 1988). Additional predictors of PH after parathyroidectomy are actively being sought. An osteocalcin level of > 6.0 micrograms was associated with an odds ratio of + 4.4 with regard to the development of symptomatic hypocalcemia by postoperative day 4 (Westerdahl et al., 2000). Preoperative eucalcemia or only minimally elevated calcium levels were also reported to be an independent risk factor for postoperative hypocalcemia (Steen et al., 2009). There are conflicting reports as to the impact of the type of neck exploration (unilateral vs. bilateral): one study found bilateral neck exploration to be associated with an odds ratio of +3.8 for the development of symptomatic hypocalcemia (Westerdahl et al., 2000), and other authors agreed (Mittendorf et al., 2004; Westerdahl and Bergenfelz, 2007). Other studies, however, found this factor to be statistically insignificant (Steen et al., 2009). A similar debate exists concerning the relationship between parathyroid adenoma weight and the likelihood of postoperative hypocalcemia (Steen et al., 2009; Brasier and Nussbaum, 1988; Mittendorf et al., 2004).
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Finally, patients with refractory secondary or tertiary hyperparathyroidism are at the highest risk of developing PH, with a broad published frequency of 20–85% (Sancho and Sitges-Serra, 1997). In one series 97% of all patients with renal hyperparathyroidism, all of whom were treated with subtotal parathyroidectomy, developed PH (Mittendorf et al., 2004).
REOPERATIVE NECK SURGERY In cervical reoperations, the safest approach is to presume that any parathyroid glands that were in the previous dissection field have been removed or devascularized. Frozen section and autotransplantation should be liberally used. Patients with hyperparathyroidism who have undergone previous total thyroidectomy or bilateral parathyroid exploration are a particularly challenging group, and when a parathyroid adenoma is found it should be presumed to be the last functioning gland, and a portion should be either cryopreserved or autotransplanted.
PATHOPHYSIOLOGY Although bone turnover is a major factor in calcium metabolism in hyperparathyroidism, it is less related to the pathophysiology of hypoparathyroidism, which is caused mainly by two other mechanisms: First, the loss of PTH prevents renal production of 1,25-dihydroxyvitamin D [1,25 (OH)2D]. The loss of this active form of vitamin D dramatically decreases absorption of dietary calcium. In addition, PTH has potent anticalciuric activity in the distal convoluted tubule; the loss of this activity results in high losses of calcium in the urine (Horwitz and Stewart, 2008). Serum magnesium levels should also be checked and corrected, as alterations in these can have profound effects on calcium metabolism. Magnesium is essential for PTH secretion and activation of the PTH receptor, and therefore hypomagnesemia induces a state of functional hypoparathyroidism (Shoback, 2008). High levels of magnesium, on the other hand, can cross-activate extracellular calcium receptors, and suppress PTH release (Shoback, 2008).
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POSTOPERATIVE MONITORING Since the frequency of PH is as high as 44% in patients who undergo parathyroidectomy (Mittendorf et al., 2004) and 30–50% in patients who undergo thyroidectomy (Noordzij et al., 2007; Reeve and Thompson, 2000), all patients should be carefully monitored for signs and symptoms of hypocalcemia after these operations. Moreover, patients have varying thresholds for development of symptoms, and serum calcium levels (reference range = 8.5–10.2 mg/dL; to convert to mmol/L, divide by 4) should be checked postoperatively, as well. Patients with a serum calcium level less than 8.5 mg/dL should be diagnosed with PH, and treated accordingly (see below). The measured calcium concentrations must be corrected for the albumin level, because 30–55% of circulating serum calcium is protein-bound (corrected calcium = [0.8 * (normal albumin — Pt’s albumin)] + serum calcium) (Calvi and Bushinsky, 2008). Ionized calcium measurement (reference range = 4.5–5 mg/dL) is more reflective of patients’ true circulating calcium levels, but is more costly and technically challenging (Calvi and Bushinsky, 2008). A recent study reported that ionized calcium levels correlated more accurately with patients’ symptoms, and better predicted patients at risk for symptomatic hypocalcemia than serum calcium measurements (Bentrem et al., 2001). The signs and symptoms of hypocalcemia typically follow a predictable progression and relate to neuromuscular excitability. Mild hypocalcemia (serum calcium < 8.5 mg/dL) most commonly manifests with complaints of perioral numbness and tingling and carpopedal spasm. In asymptomatic patients, signs of hypocalcemia may be provoked by tapping over the facial nerve to induce facial muscle spasm (Chvostek’s sign) or by creating mild tissue hypoxemia inflating a blood pressure cuff for 3 min to precipitate carpopedal spasms (Trusseau’s sign). Trusseau’s sign is better diagnostic maneuver, and is positive in 94% of hypocalcemic patients, as compared to Chvostek’s sign, which was positive in only 71% in one series (Cooper and Gittoes, 2008). However, this test is fairly uncomfortable for the patient, and hence is rarely used clinically. Severe hypocalcemia (serum calcium <7.5 mg/dL) may manifest with laryngospasm, stridor, seizures, or tetany, and on EKG, QT prolongation may be seen. It should be noted that the development of symptoms of
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hypocalcemia depends both on the absolute concentration and on the rate of decline in serum calcium levels. Unlike chronic hypocalcemia, rapid changes in serum calcium levels, as seen in postsurgical patients, are often accompanied by symptoms (Cooper and Gittoes, 2008). It should be noted that in a prospective study symptoms of hypocalcemia were observed to most commonly manifest between 24 and 48 h after thyroidectomy (Mowshenson and Hodin, 1995). When compared with primary hyperparathyroidism, patients with treated secondary or tertiary hyperparathyroidism were recently found to have more profound PH, but rarely developed symptoms (Mittendorf et al., 2004).
TREATMENT OF POSTOPERATIVE HYPOCALCEMIA The mainstay of treatment for PH is enteric supplementation with large quantities of calcium and vitamin D, with the desired effect of augmenting intestinal absorption of calcium sufficiently to overwhelm the higher renal clearance of calcium, causing serum levels to rise (Horwitz and Stewart, 2008). A variety of calcium salt formulations are commercially available; they are compared in Table 1. Additional agents, designed to augment enteric absorption and minimize renal excretion, are available, and are summarized in Table 2. The treatment of hypocalcemia requires careful observation and follow-up, because chronic overtreatment results in nephrolithiasis, nephrocalcinosis, and renal failure (Horwitz and Stewart, 2008; Winer et al., 1998). Even with a stable pharmacologic treatment regimen, patients’ calcium levels vary with changes in hydration and dietary calcium intake. A recent series of studies highlighted the frequency of complications from chronic overtreatment of hypoparathyroidism: cumulatively, 80% of patients had a reduced glomerular filtration rate and 40% had nephrocalcinosis (Winer et al., 1996, 1998, 2008). A contributing factor to the high rate of complications related to overtreatment of hypoparathyroidism is the erroneous notion that the therapeutic goal should be eucalcemia, with serum calcium levels in the 9.0–10.5 mg/dL range. Instead, the goal should be to supplement the patient with just enough calcium to avoid hypocalcemic symptoms, but without causing hypercalcuria (Horwitz and Stewart, 2008).
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Table 1
Calcium and vitamin D content of commercially available calcium supplements. elemental Ca content Vitamin D content
12 12 12 10 10 10 12 4 6 8 2 3.3 2.6 12 3.8 10
240 240 240 200 200 200 240 80 120 160 42 66 53 240 76 200
6 6 6 5 5 5 6 2 3 4 1 1.3 1.3 6 1.9 5
None 200 IU 400 IU None 200 IU 400 IU 200 IU None None None 200 IU 200 IU 200 IU 200 IU None 200 IU
Modified from www.uptodate.com (“Elemental calcium content per pill of different calcium supplements, 2009”).
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Available drugs for the treatment of postoperative hypocalcemia.
IV Ca++ bolus IV Ca++ drip PO calcium Calcitriol D3 HCTZ PTH
10–20 ml 10% Ca gluconate (1–2 ampoules) diluted in 50–100 ml of D5W; infuse over 10 min, may repeat until symptoms resolve 100 ml 10% Ca gluconate (10 ampoules) diluted in 1000 ml D5W or 0.9% saline; infuse at a starting rate of 50 mL/h See Table 1 0.25–0.5 µg PO QD or BID 50,000 IU Q week * 8–12 weeks 25 mg PO QD, may increase, follow urinary Ca levels 20 µg subcutaneously QD; not FDA-approved for hypocalcemia
Abbreviations: Ca++ = calcium; D5W = 5% dextrose in water; D3 = cholecalciferol; HCTZ = hydrochlorothiazide; PTH = teriparatide.
Calcium Salts Oral calcium salts represent the basis of therapy for PH. The most widely available formulations are calcium carbonate and calcium citrate. Calcium carbonate is the most cost-effective form and should be taken with food to optimize absorption. Calcium citrate can be taken without food and is the supplement of choice for patients who are taking histamine-2 blockers or protein pump inhibitors, which interfere with calcium carbonate absorption (Straub, 2007). In general, calcium carbonate preparations contain 40% elemental calcium, whereas calcium citrate supplements contain 21% elemental calcium. From a practical standpoint, the only difference is that in order to achieve dose equivalence, more tablets of calcium citrate are required, which might negatively affect patient compliance, particularly given the higher price of calcium citrate (Straub, 2007). A few studies have compared the absorption and bioavailability of these two calcium salt formulations. While one study demonstrated superior bioavailability for calcium citrate compared to calcium carbonate (Heller et al., 1999), others have demonstrated no difference (Heaney, 2001; Heaney et al., 1999, 2001). One study demonstrated that ingestion of 500 mg of either calcium preparation produced an average increase in total serum calcium of 0.6 mg/dL that was measurable at 5 h, with a subsequent trend back toward the baseline by 24 h (Heaney et al., 2001). A potential source of confusion is that calcium can be dosed based on the amount of elemental calcium (mg), the amount of calcium salt (mg),
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milliequivalents (mEq) or millimoles (mmol). Table 1 outlines the equivalent doses of the various commercially available preparations. IV Calcium Patients with severely symptomatic hypocalcemia (seizures, laryngospasm, cardiac failure, altered mental status) require rapid correction of serum calcium levels and should be treated with intravenous infusion of calcium regardless of their serum calcium level (Shoback, 2008). Moreover, because the rate of severe hypocalcemia after parathyroidectomy for secondary or tertiary hypoparathyroidism is so high, authors recommend starting all such patients on IV calcium postoperatively, and transitioning them to oral calcium salts when feasible (Mittendorf et al., 2004). Calcium gluconate is the preferred form of intravenous calcium, because it is not associated with local irritation and skin necrosis, effects attributed to calcium chloride (Cooper and Gittoes, 2008). For rapid correction of severe hypocalcemia, one or two 10 ml ampules of 10% calcium gluconate should be diluted in 50–100 ml of 5% dextrose and infused over 10 min, and repeated until the symptoms have cleared. Electrocardiographic monitoring is recommended during this treatment to monitor for dysrhythmias, which may develop if correction is too rapid (Cooper and Gittoes, 2008). Since IV correction of acute, severe hypocalcemia is often only transient, it should be followed by continuous administration of a dilute calcium gluconate solution to prevent recurrence of symptoms (Shoback, 2008; Cooper and Gittoes, 2008). Ten 10 ml ampules of calcium gluconate should be diluted in 1L of 5% dextrose or 0.9% saline and infused at a starting rate of 50 mL/h. Infusion of 10 mL/kg of this solution (over 4–6 h) results in an increase of serum calcium by 1.2–2.0 mg/dL. This infusion should be tapered over 24–48 h, and oral calcium and vitamin D should be given in conjunction with this treatment (Cooper and Gittoes, 2008). Vitamin D Formulations Vitamin D supplements, either vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol), are widely available and are commonly used in the
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treatment of vitamin D deficiency. These are biologically equivalent, and two highly effective short-term therapies for vitamin D deficiency are oral administration of 50,000 IU weekly for eight weeks or intramuscular injection of 300,000 IU every three months (Malabanan et al., 1998). Because these formulations require PTH for conversion to their active form (1,25-dihydroxyvitamin D), they have limited activity in cases of PH and hypoparathyroidism (Cooper and Gittoes, 2008). Calcitriol Calcitriol (Rocaltrol®, Roche) is a synthetic 1,25-dihydroxyvitamin D3 and is widely used in the treatment of patients with PH and hypoparathyroidism. This drug is recommended by the Australian Endocrine Surgeons’ Guidelines for the patients with undetectable PTH levels (Australian Endocrine Surgeon’s Guidelines, 2007). To the best of our knowledge, the only study evaluating its effect on PH compared calcitriol to placebo in 14 patients with end-stage renal disease who underwent parathyroidectomy for secondary hyperparathyroidism. The seven patients who received calcitriol enjoyed a lesser decrease in serum calcium levels, and required substantially less calcium replacement. In four of the seven patients receiving placebo, treatment was interrupted because of severe hypocalcemia (Clair et al., 1987). A recent survey showed that German endocrine surgeons preferred dihydrothachsterol to calcitriol for the treatment of hypoparathyroidism in adults (Schilling and Ziegler, 1997). Although calcitriol has been demonstrated to prevent PH (Tartaglia et al., 2005; Testa et al., 2006), there are some theoretic concerns regarding its use in hypoparathyroid patients. 1,25-dihydroxyvitamin D and ionized calcium are the principal inhibitors of PTH secretion by decreasing pre-pro-PTH mRNA transcription and by inhibiting proliferation of parathyroid cells (Schmitt et al., 1998). Nevertheless, calcitriol has been demonstrated to increase serum calcium levels in a variety of clinical scenarios (Clair et al., 1987; Tartaglia et al., 2005; Testa et al., 2006; Brandi et al., 2005), and should be considered as part of the treatment of severe PH. The typical treatment dose is 0.25–0.5 µg once or twice daily.
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Thiazide Diuretics Because patients with hypoparathyroidism often have marked hypercalcuria, thiazide diuretics are often added to their treatment (Porter et al., 1978; Kurzal and Hagen, 1990). These drugs exert their anticalciuric effect by stimulating calcium reabsorption at the distal convoluted tubule of the nephron (Horwitz and Stewart, 2008), and can be considered in patients with PH whose 24 h urinary calcium is higher than 250 mg (Shoback, 2008).
Recombinant PTH Teriparatide (Forteo®, Eli Lilly) is synthetic human PTH (1–34) that was approved for the treatment of osteoporosis in the US in 2002 (Brixen et al., 2004). Administered by subcutaneous injection, it is available as a preloaded pen with 28 doses, and appears to have few adverse side effects (Gold et al., 2006; Saag et al., 2007). A recent large randomized trial demonstrated greater increases in bone mineral density in patient treated with this drug as compared with alendronate (Saag et al., 2007). Evidence is accumulating to suggest that Teriparatide may also be effective in the treatment of hypoparathyroidism. A group of randomized trials (Winer et al., 1996, 1998, 2008) and a single case report (PuigDomingo et al., 2008) have shown promising results in this regard. It more effectively normalized serum calcium levels and decreased the mean urinary calcium content. In patients with PH, twice-daily dosing appeared to reduce the tendency toward nighttime hypocalcemia, and maintained serum calcium levels within a more narrow range (Winer et al., 1998, 2008). Although early results are encouraging, long-term studies of this drug are yet unavailable, and it is not approved by the FDA for the treatment of hypoparathyroidism.
Prophylactic Treatment To date, there have only been a small number of studies on the efficacy of empiric or prophylactic calcium supplementation in patients who undergo thyroidectomy or parathyroidectomy. Two prospective studies
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have demonstrated reductions in symptomatic PH with routine supplementation of oral calcium and vitamin D after thyroidectomy (Bellantone et al., 2002; Roh and Park, 2006). Another retrospective study (Uruno et al., 2006) also suggested that prophylactic IV infusion of calcium is effective in prevention of symptomatic hypocalcemia. Finally, two recent prospective randomized studies demonstrated that empiric calcitriol can decrease PH. One of them demonstrated that the addition of calcitriol (0.5 µg or 1 µg twice daily) to a daily supplement of 1500 mg of oral calcium salts reduced the frequency of postoperative tetany and paresthesias (Tartaglia et al., 2005). The other study demonstrated that calcitriol and hydrochlorothiazide were more effective than placebo in preventing postthroidectomy hypocalcemia and reducing the length of stay (Testa et al., 2006). Other authors contend that because postoperative tetany is relatively infrequent, treatment of all postthyroidectomy patients with calcium is unnecessary. They prefer a selective approach and emphasize the importance of patient education regarding the signs and symptoms of PH (Schwartz et al., 1998; Lo Gerfo et al., 1991).
SUMMARY Postoperative hypocalcemia is the most common complication of thyroid and parathyroid operations, occurring in up to 50% and 44% of patients, respectively (Mittendorf et al., 2004; Reeve and Thompson, 2000). A high index of suspicion should be maintained for this diagnosis, and serum calcium levels should be monitored in all patients who are at risk for PH. Empiric calcium and vitamin D may be effective in preventing PH.
SELECTED REFERENCES Abboud B, Sargi Z, Akkam M, Sleilaty F. Risk factors for postthyroidectomy hypocalcemia. J Am Coll Surg 2002;195(4):456–461. Australian Endocrine Surgeon’s Guidelines AES06/01. Postoperative parathyroid hormone measurement and early discharge after total thyroidectomy: analysis of Australian data and management recommendations. ANZ J Surg 2007; 77(4):199–202.
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Bellantone R, Lombardi CP, Raffaelli M, et al. Is routine supplementation therapy (calcium and vitamin D) useful after total thyroidectomy? Surgery 2002;132(6):1109–1113. Bentrem DJ, Rademaker A, Angelos P. Evaluation of serum calcium levels in predicting hypoparathyroidism after total/near-total thyroidectomy or parathyroidectomy. Am Surg 2001;67(3):249–251; discussion 251–252. Brandi L, Egfjord M, Olgaard K. Comparison between 1 alpha(OH)D3 and 1,25(OH)2D3 on the suppression of plasma PTH levels in uremic patients, evaluated by the “whole” and ‘intact” PTH assays. Nephron Clin Pract 2005;99(4):c128–137. Brasier AR, Nussbaum SR. Hungry bone syndrome: clinical and biochemical predictors of its occurrence after parathyroid surgery. Am J Med 1988; 84(4):654–660. Brixen KT, Christensen PM, Ejersted C, Langdahl BL. Teriparatide (biosynthetic human parathyroid hormone 1–34): a new paradigm in the treatment of osteoporosis. Basic Clin Pharmacol Toxicol 2004;94(6):260–270. Calvi LM, Bushinsky DA. When is it appropriate to order an ionized calcium? J Am Soc Nephrol 2008;19(7):1257–1260. Clair F, Leenhardt L, Bourdeau A, et al. Effect of calcitriol in the control of plasma calcium after parathyroidectomy: a placebo-controlled, double-blind study in chronic hemodialysis patients. Nephron 1987;46(1):18–22. Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008;336(7656):1298–1302. Del Rio G, Arcuri MF, Sara T, Sianesi M. Is the number of parathyroid glands identified during total thyroidectomy a real predictive factor of postoperative hypocalcemia? Endocrinologist 2009;19(2):60–61 Gold DT, Pantos BS, Masica DN, et al. Initial experience with teriparatide in the United States. Curr Med Res Opin 2006;22(4):703–708. Heaney RP, Dowell MS, Barger-Lux MJ. Absorption of calcium as the carbonate and citrate salts, with some observations on method. Osteoporos Int 1999;9(1):19–23. Heaney RP, Dowell MS, Bierman J, et al. Absorbability and cost-effectiveness in calcium supplementation. J Am Coll Nutr 2001;20(3):239–246. Heaney RP. Meta-analysis of calcium bioavailability. Am J Ther 2001;8(1):73–74. Heller HJ, Stewart A, Haynes S, Pak CY. Pharmacokinetics of calcium absorption from two commercial calcium supplements. J Clin Pharmacol 1999;39(11): 1151–1154.
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Henry JF, Gramatica L, Denizot A, et al. Morbidity of prophylactic lymph node dissection in the central neck area in patients with papillary thyroid carcinoma. Langenbecks Arch Surg 1998;383(2):167–169. Horwitz MJ, Stewart AF. Hypoparathyroidism: is it time for replacement therapy? J Clin Endocrinol Metab 2008;93(9):3307–3309. Jofre R, Lopez Gomez JM, Menarguez J, et al. Parathyroidectomy: whom and when? Kidney Int Suppl 2003(85):S97–S100. Kurzel RB, Hagen GA. Use of thiazide diuretics to reduce the hypercalciuria of hypoparathyroidism during pregnancy. Am J Perinatol 1990;7(4):333–336. Lo Gerfo P, Gates R, Gazetas P. Outpatient and short-stay thyroid surgery. Head Neck 1991;13(2):97–101. Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet 1998;351(9105):805–806. McHenry CR, Speroff T, Wentworth D, Murphy T. Risk factors for postthyroidectomy hypocalcemia. Surgery 1994;116(4):641–647; discussion 647–648. Mittendorf EA, Merlino JI, McHenry CR. Post-parathyroidectomy hypocalcemia: incidence, risk factors, and management. Am Surg 2004;70(2): 114–119; discussion 119–120. Mowschenson PM, Hodin RA. Outpatient thyroid and parathyroid surgery: a prospective study of feasibility, safety, and costs. Surgery 1995;118(6):1051–1053; discussion 1053–1054. Noordzij JP, Stephanie LL, Victor JB, et al. Early prediction of hypocalcemia after thyroidectomy using parathyroid hormone: an analysis of pooled individual patient data from nine observational studies. J Am Coll Surg 2007;205(6):748–754. Pattou F, Combemale F, Fabre S, et al. Hypocalcemia following thyroid surgery: incidence and prediction of outcome. World J Surg 1998;22(7):718–724. Porter RH, Cox BG, Heaney D, et al. Treatment of hypoparathyroid patients with chlorthalidone. N Engl J Med 1978;298(11):577–581. Puig-Domingo M, Diaz G, Nicolau J, et al. Successful treatment of vitamin D unresponsive hypoparathyroidism with multipulse subcutaneous infusion of teriparatide. Eur J Endocrinol 2008;159(5):653–657. Reeve T, Thompson NW. Complications of thyroid surgery: how to avoid them, how to manage them, and observations on their possible effect on the whole patient. World J Surg 2000;24(8):971–975.
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Roh J-L, Park CI. Routine oral calcium and vitamin D supplements for prevention of hypocalcemia after total thyroidectomy. Am J Surg 2006;192(5):675–678. Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoidinduced osteoporosis. N Engl J Med 2007;357(20):2028–2039. Sancho J, Sitges-Serra, A. Surgical approach to secondary hyperparathyroidism. In: Textbook of Endocrine Surgery (eds.) OH Clark, Q-Y Duh. Philadelphia, PA: Saunders, 1997, pp. 403–409. Schilling T, Ziegler R. Current therapy of hypoparathyroidism — a survey of German endocrinology centers. Exp Clin Endocrinol Diabetes 1997;105(4):237–241. Schmitt CP, Schaefer F, Huber D, et al. 1,25(OH)2-vitamin D3 reduces spontaneous and hypocalcemia-stimulated pulsatile component of parathyroid hormone secretion. J Am Soc Nephrol 1998;9(1):54–62. Schwartz AE, Clark OH, Ituarte P, Lo Gerfo P. Therapeutic controversy: thyroid surgery — the choice. J Clin Endocrinol Metab 1998;83(4):1097–1105. Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med 2008;359(4): 391–403. Steen S, Rabeler B, Fisher T, Arnold D. Predictive factors for early postoperative hypocalcemia after surgery for primary hyperparathyroidism. Proc (Bayl Univ Med Cent) 2009;22(2):124–127. Straub DA. Calcium supplementation in clinical practice: a review of forms, doses, and indications. Nutr Clin Pract 2007;22(3):286–296. Tartaglia F, Giuliani A, Sgueglia M, et al. Randomized study on oral administration of calcitriol to prevent symptomatic hypocalcemia after total thyroidectomy. Am J Surg 2005;190(3):424–429. Testa A, Fant V, De Rosa A, et al. Calcitriol plus hydrochlorothiazide prevents transient post-thyroidectomy hypocalcemia. Horm Metab Res 2006;38(12): 821–826. Tomusch O, 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(2):180–185. Uruno T, Miyauchi A, Shimizu K, et al. A prophylactic infusion of calcium solution reduces the risk of symptomatic hypocalcemia in patients after total thyroidectomy. World J Surg 2006;30(3):304–308. Westerdahl J, Bergenfelz A. Unilateral versus bilateral neck exploration for primary hyperparathyroidism: five-year follow-up of a randomized controlled trial. Ann Surg 2007;246(6):976–981.
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Westerdahl J, Lindblom P, Valdemarsson S, et al. Risk factors for postoperative hypocalcemia after surgery for primary hyperparathyroidism. Arch Surg 2000;135(2):142–147. Winer KK, Sinaii N, Peterson D, et al. Effects of once versus twice-daily parathyroid hormone 1–34 therapy in children with hypoparathyroidism. J Clin Endocrinol Metab 2008;93(9):3389–3395. Winer KK, Yanovski JA, Cutler GB, Jr. Synthetic human parathyroid hormone 1–34 vs calcitriol and calcium in the treatment of hypoparathyroidism. JAMA 1996;276(8):631–636. Winer KK, Yanovski JA, Sarani B, Cutler GB, Jr. A randomized, cross-over trial of once-daily versus twice-daily parathyroid hormone 1–34 in treatment of hypoparathyroidism. J Clin Endocrinol Metab 1998;83(10):3480–3486. Zarnegar R, Brunaud L, Clark OH. Prevention, evaluation, and management of complications following thyroidectomy for thyroid carcinoma. Endocrinol Metab Clin North Am 2003;32(2):483–502.
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Chapter II.B.8: Cryopreservation and Autotransplantation of Parathyroid Tissue Jennifer McAllaster, MD and Mark S. Cohen, MD, FACS
INTRODUCTION Parathyroid hormone (PTH) is essential for calcium homeostasis and, under normal physiologic conditions, is secreted in response to low serum calcium. It acts to increase serum calcium via stimulating bone resorption, limiting renal excretion of calcium, and enhancing intestinal calcium absorption. The loss of all functional parathyroid glands during surgery on the thyroid or parathyroid places a patient at risk for permanent hypoparathyroidism and subsequent lifelong calcium and vitamin D replacement therapy. Loss of parathyroid gland function may result from intentional resection of all four parathyroid glands during parathyroid surgery for multiglandular disease or from inadvertent resection or devascularization of nonresected glands with subsequent loss of function. Autotransplantation of parathyroid gland tissue has been successfully described and implemented for greater than 35 years. Immediate or delayed parathyroid transplantation is useful for preserving parathyroid function in patients undergoing total thyroidectomy or in patients undergoing parathyroidectomy, especially for multiglandular disease. Typically, parathyroid gland tissue resected from its normal anatomic location may be sectioned into smaller pieces and reimplanted into either the sternocleidomastoid muscle in the neck or the brachioradialis muscle in the forearm. This transplanted tissue will begin to function anywhere from 2–3 weeks to 2–3 months postoperatively to produce PTH, thus avoiding permanent hypoparathyroidism and obviating the need for chronic replacement therapy. Autotransplantation 265
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may be undertaken at the time of the initial operation, termed “immediate autotransplantation,” or the tissue may be frozen in a selected medium and be available for future use, termed “cryopreserved heterotopic parathyroid autotransplantation” (CHPA).
INDICATIONS FOR PARATHYROID AUTOTRANSPLANTATION AND CRYOPRESERVATION The goal of parathyroid cryopreservation is to have viable parathyroid tissue available to treat the uncommon occurrence of postoperative permanent hypoparathyroidism after thyroid or parathyroid surgery. Hypoparathyroidism from initial surgery for primary hyperparathyroidism (HPT) is uncommon but can be seen in up to 10% of patients after initial surgery for multiglandular hyperplasia and in up to 30% of patients undergoing reoperation for persistent or recurrent HPT. Cryopreservation of parathyroid tissue has been advocated for patients having subtotal or total parathyroidectomy for primary, secondary, or tertiary HPT or for reoperation for persistent or recurrent HPT. Total thyroidectomy also may result in inadvertent resection of the parathyroid glands or sufficient devascularization of the glands, leading to inactivity. Immediate autografting of parathyroid tissue is reported to have an 80–99% success rate and should be performed in these various settings, as listed in Table 1. Cryopreservation of parathyroid tissue for delayed autotransplantation should also be considered for selected indications. The success rates of cryopreservation are more variable, ranging from 17 to 83%, but can be optimized if proper technique is used. The potential benefit of cryopreservation in this setting is to provide a secondary opportunity to regain parathyroid function in a patient who has become permanently hypoparathyroid either due to failure of an immediate autograft or lack of adequate hormone production to maintain calcium homeostasis.
METHODS FOR CRYOPRESERVATION OF PARATHYROID TISSUE For patients undergoing parathyroid cryopreservation for subsequent autotransplantation, the institution should have an IRB-approved protocol
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Indications for autotransplantation and cryopreservation.
Immediate autotransplantation Four-gland resection for multiglandular HPT (primary, secondary, or tertiary) Observed devascularization or inadvertent resection of parathyroid gland during thyroid or parathyroid surgery Reoperation for persistent or recurrent HPT, especially after previous 3½-gland resection Familial HPT (i.e. MEN 1 or MEN 2)
Cryopreservation Consider Consider whether multiple glands affected or last remaining gland Consider
Consider Patients with thyroid or head and neck cancer undergoing functional neck dissection where postoperative external beam radiation is being considered
for tissue storage and handling, as this should ideally be performed in a sterile facility or laboratory which handles human tissues for later use (i.e. a central specimen facility or laboratory where tissues such as bone marrow transplantation specimens are stored). For parathyroid cryopreservation, the following materials and solutions should be available: 1. 2. 3. 4.
5. 6. 7. 8.
Cold sterile saline 10–15 mL sample of the patient’s blood RPMI 1640 solution Freezing mixture (60% RPMI 1640, 30% autologous serum, and 10% dimethyl sulfoxide (DMSO) mixed together and filtered using a 0.2-micron syringe filter Sterile pipettes and biological hood 2 mL Sarstedt screw-cap vials for cryofreezing (or similar vials) Nalgene Cryo 1°C Freezing Container (Nalgene Corporation, Lima, OH) or similar container Both a −70°C freezer and a liquid nitrogen freezer.
The parathyroid is removed from the neck at the time of parathyroidectomy and morcellated on a cutting block using a #10 or #20 blade
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scalpel into fragments approximately 1–3 mm in size. These fragments are then placed in a sterile cup filled with cold saline and then put on ice. In addition to the parathyroid tissue, 10–15 mL of the patient’s blood is drawn and placed in a clot tube to prepare autologous serum. The saline in which the parathyroid tissue is placed is then removed with a pipette and replaced with RPMI 1640 solution. Next, 12 mL of a freezing mixture consisting of 60% RPMI 1640, 30% autologous serum, and 10% dimethyl sulfoxide (DMSO) is prepared and filtered using a 0.2-micron syringe filter. The RPMI surrounding the tissue is removed with a pipette, and replaced with 6 mL of the filtered freezing mixture. The cup containing the tissue and freezing mixture is then swirled every minute for 10 min. The freezing mixture is removed from the tissue with a pipette, and the remainder of the fresh sterile freezing mixture is added to the tissue. The tissue is pipetted with a large bore pipette into 2 mL Sarstedt screw-cap vials for cryofreezing. Each vial contains 15–20 tissue fragments in 1.5 mL of freezing solution. Controlled rate freezing (at a rate of 1°C per minute) is then performed in a Nalgene Cryo 1°C Freezing Container (Nalgene Corporation, Lima, OH), which is placed into a −70°C freezer overnight. The tissue vials are then transferred to permanent storage in a liquid nitrogen freezer at −170°C.
LONG TERM STORAGE, VIABILITY, AND THAWING OF CRYOPRESERVED GLANDS Since the goal of delayed autotransplantation from cryopreserved tissue is to restore parathyroid functionality to a patient who has poor or no parathyroid function following thyroid or parathyroid surgery with immediate autografting, it is important that the cryopreserved tissue is stored and thawed in an appropriate manner to maximize tissue viability. Unfortunately, there are no foolproof methods to predict whether a patient will have postoperative hypoparathyroidism and require cryopreserved autotransplantation. Because of this unpredictability, only a minority of patients having parathyroid tissue cryopreserved will actually require delayed implantation of this tissue. Although there is a tangible institutional cost of maintaining the viability of cryopreserved tissue, all immediate parathyroid autograft procedures carry a small but tangible risk
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of failure. Having cryopreserved tissue available to patients as an alternative to lifelong calcium, vitamin D, or PTH supplementation remains a viable option that many patients prefer and request. After the tissue is placed in a liquid nitrogen freezer, it should be reimplanted as soon as it becomes medically necessary, which may be dependent on both physician and patient factors. The most ideal time frame for reimplanting tissue with maximal viability is the first 3–6 months after cryopreservation. While some reports have demonstrated cryopreserved parathyroid viability as far out as 106 months after initial preservation with full functionality as far out as 22 months, the recommended “ideal” period of storage for reimplantation is 3–6 months or less. Additionally, secondary procedures can be performed for reimplantation of cryopreserved tissue after a failed CHPA procedure; however, the likelihood of success in this setting is significantly decreased compared to the 25–60% success rate observed with initial CHPA.
Method for Thawing of Cryopreserved Parathyroid Tissue For thawing of cryopreserved tissue, it is important to have the following materials ready: 1. 2. 3. 4. 5. 6. 7. 8.
RPMI 1640 medium Patient blood sample (10 mL) 37°C water bath Sterile biologic hood and processing room Pipettes 70% ethanol spray bottle 0.2-micron syringe filter 50 mL conical centrifuge tube.
At the time samples are removed for thawing, 10 mL of rinse medium consisting of 70–90% RPMI 1640 and 10–30% autologous serum is prepared and sterilely filtered with a 0.2-micron syringe filter. One or more vials of cryopreserved parathyroid tissue are removed from the liquid nitrogen storage and thawed rapidly in a 37°C water bath (usually 2–5 min). The vials are removed from the water bath and then
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sprayed on the outside with 70% ethanol solution to sterilize the outer surface. Next, the caps are removed and the contents poured into a sterile disposable 50 mL conical centrifuge tube. The existing freezing mixture is removed with a pipette. An aliquot of 3 mL of rinse medium is then added to the tissue fragments and the contents are swirled for approximately 30 s, and the rinse medium is then removed with a pipette. This rinse process is repeated twice, and a final 4 mL of rinse medium is then added to the tissue, and the container is then placed on ice and transferred to the operating room for immediate grafting.
AUTOTRANSPLANTATION OF PARATHYROID TISSUE For both immediate and delayed autotransplantation, the brachioradialis muscle of the nondominant forearm (or arm without a fistula or AV graft in patients with secondary or tertiary HPT) has been a welldescribed location for graft implantation. In patients undergoing immediate autografting, another equally viable site is the sternocleidomastoid muscle of the neck, which avoids prepping out a separate area and can be performed through the same incision of the neck operation. For illustrative purposes, a forearm implantation will be outlined below; however, this same procedure is easily applicable to the SCM in the neck.
Procedure for immediate or delayed (CHPA) autotransplantation For immediate autografting, the parathyroid tissue must be cut into fragments for improved viability (optimal imbibition during the early postoperative period) •
•
The parathyroid specimen is initially placed in a sterile cup filled halfway with saline and is then put on ice until the specimen is ready to be autotransplanted. The parathyroid tissue is subsequently transferred to a cutting block and sectioned with a #10 or #20 blade scalpel into 1–2 mm fragments, and the pieces are then replaced in the cold saline.
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For both immediate and delayed autotransplantation procedures, the method is as outlined: •
A small pocket is created in the muscle belly by gently spreading the fibers with a fine mosquito clamp, and 3–5 pieces of parathyroid tissue are transferred with fine forceps into the muscle pocket. The pocket is carefully pinched at the surface as the forceps are withdrawn, to avoid extrusion of the parathyroid fragments.
In the forearm, this pocket can also be made by creating a 1 cm incision lengthwise in the brachioradialis fascia and dissecting a small pocket by spreading the muscle fibers apart with a clamp and then placing the parathyroid fragments in the pocket (see Fig. 1). •
The pocket is closed with a prolene or other permanent monofilament suture. Additionally, a small titanium surgical clip can be placed next to the pocket for later identification. Typically, 6–10 pockets are created to ensure adequate parathyroid graft functionality.
POST-OPERATIVE MANAGEMENT FOLLOWING PARATHYROID AUTOTRANSPLANTATION It is important to have close followup with biochemical analysis in patients having autotransplantation, as they are likely to be moderately to severely symptomatic from hypocalcemia in the immediate postoperative period (which can last from two weeks to up to three months postoperatively), until the parathyroid autografts demonstrate adequate hormone secretion. Typically, these patients should be placed on both elemental calcium and vitamin D (calcitriol; to assist with GI absorption of the calcium supplements). The amount of calcium needed for supplementation is patient-dependent and should be determined in the first 24–48 h postoperatively. Occasionally, patients may require intravenous calcium supplementation in addition to oral supplements if they are still symptomatic on their oral regimens. This can be given either as calcium gluconate or calcium chloride injections (notably, a standard ampule of calcium chloride typically has 2–3 times the bioavailable calcium as an ampule of
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Fig. 1 Technique of heterotopic parathyroid autotransplantation to the forearm. A longitudinal incision is made over the skin, subcutaneous tissue and fascia overlying the brachioradialis muscle of the nondominant forearm, and 20–25 pieces of parathyroid tissue (approximately 50–75 mg) are placed into 5–10 pockets in the muscle and the brachioradialis muscle of the forearm. The muscle pockets are closed with 4-0 or 5-0 permanent sutures. (Copied with permission from Palayan E, Lawrence AM. Endocrine Surgery: A Handbook of Operative Surgery. Chicago: Year Book, 1976.)
calcium gluconate) or as a calcium drip (typically made as 3 ampules of calcium gluconate mixed in 500 mL of D5W solution and delivered at a rate of 60 mL/h). The timing of measuring total or ionized calcium postoperatively is somewhat surgeon-dependent, but often it is measured q 6 or q 8 h after surgery. Outcome Evaluation Following Autografting Outcomes of parathyroid cryopreservation have been extremely variable, with success rates ranging from 17 to 83%, compared to the
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80–99% success rate reported for immediate autotransplantation. A recent prospective study of CHPA demonstrated a fully functional graft rate of 40% and with some degree of parathyroid function preserved in 60% of patients. The factors accounting for the discrepancy of success rates between immediate autotransplantation and cryopreservation are unknown, but may be a result of decreased cell viability secondary to cryopreservation. A longer duration (typically greater than 6–12 months) of cryopreservation is, however, a significant predictor of graft failure. The outcome of parathyroid autotransplantation and CHPA is based on biochemical profiles of total serum calcium, PTH level, and PTH gradients. Autograft function is subsequently designated as fully functional, partially functional, or nonfunctional based on the results of this biochemical testing (see Table 2). PTH gradients have been used in the past as a gold standard measurement for assessment of forearm autograft function as the antecubital veins are easily accessible for simultaneous sampling. However, a recent prospective study demonstrated no correlation between PTH gradient and autograft function, suggesting that factors other than the absolute PTH value or the ability of grafts to produce a hormone level contribute to maintaining normocalcemia.
Table 2
Autograft functionality assessment.
PTH level
Calcium level
Calcium supplementation None Calcium and vitamin D supplementation utilized but usually not high doses or severely symptomatic with a missed dose Dependent on calcium/ vitamin D supplementation
Fully functional Partially functional
Normal Normal
Normal Mild hypocalcemia
Nonfunctional
Low or absent
Hypocalcemia
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REOPERATION FOR HYPERFUNCTIONAL AUTOGRAFTS In patients with HPT from multiglandular disease, especially those with MEN 1, autotransplanted parathyroid tissue is still hyperfunctional tissue and has the potential to develop into recurrent HPT. If a 3½-gland resection was initially performed, the surgeon has the option of debulking the remaining gland (in some cases using intraoperative PTH monitoring as a guide for residual functionality). Alternatively, the entire gland can be resected and a portion autotransplanted into either the SCM or the brachioradialis muscle. If an autograft becomes hyperfunctional, it requires operative debulking, which can involve resection of a portion of the surrounding muscle in which it was implanted. In this situation, measurement of intraoperative PTH using the rapid assay may be helpful in determining the extent of debulking required. The goal is to retain just enough tissue to keep the PTH level in the normal range and maintain normocalcemia. In the setting of a debulking reoperation, it is reasonable to consider cryopreserving some of the resected parathyroid tissue to treat the complication of permanent hypoparathyroidism (as high as 10–30% of cases), which can occur either from the residual parathyroid left in situ not producing enough hormone to maintain normocalcemia or becoming devascularized or nonfunctional postoperatively.
SELECTED REFERENCES Brennan MF, Norton JA. Reoperation for persistent and recurrent hyperparathyroidism. Ann Surg 1985;201:40–44. Cameron JL (ed.), Current Surgical Therapy, 9th Edn. Elsevier, 2008, pp. 605–614. Cohen MS, Dilley WG, Wells SA Jr, et al. Long-term functionality of cryopreserved parathyroid autografts: a 13-year prospective analysis. Surgery. 2005; 138(6):1033–1041. De Menezes Montenegro FL, Custodio MR, Arap SS, et al. Successful implant of long-term cryopreserved parathyroid glands after total parathyroidectomy. Head Neck 2007;29(3):296–300.
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Grant CS, van Heerden JA, Charboneau JW, et al. Clinical management of persistent and/or recurrent primary hyperparathyroidism. World J Surg 1986;10: 555–565. Herrera M, Grant C, van Heerden JA, et al. Parathyroid autotransplantation. Arch Surg 1992;127:825–830. Saxe AW. Parathyroid transplantation: a review. Surgery 1984;95:507–526.
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ADRENAL
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Chapter III.A.1: Adrenal Incidentaloma Rashmi Roy, MD and James A. Lee, MD
OVERVIEW Adrenal incidentaloma is the term used to refer to an adrenal mass discovered in a radiological study that was performed for an unrelated reason. Adrenal masses thought to be metastatic in a patient with a known primary are not considered to be adrenal incidentalomas. The prevalence of adrenal incidentalomas is estimated to be 1–4% in abdominal imaging studies and increases with the patient’s age. One study estimates that there is a 7% chance of having an incidentaloma by the age of 70. Due to the much more widespread use of abdominal imaging, incidentally discovered adrenal masses have become a more frequent clinical finding. The two main questions that must be addressed when dealing with an adrenal incidentaloma are: (1) Is the tumor functional? (2) What is the risk of malignancy (based primarily on size and imaging characteristics)? Malignant tumors and functional tumors should be resected. Approximately 15–20% of incidentalomas are functional, with 10% having subclinical Cushing’s, 5% being pheochromocytomas, and 1.5% being aldosterone-producing adenomas. Depending on the series, 4 to 12% of incidentalomas are carcinomas. However, the majority of incidentalomas are nonfunctional and benign and require only close followup.
LABORATORY EVALUATION Ruling out Functional Tumors Patients with an adrenal incidentaloma should be evaluated for Cushing’s syndrome, an aldosterone-producing adenoma, and a 279
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pheochromocytoma. Sex-hormone-producing tumors are so rare that screening is not indicated. The National Institutes of Health (NIH) released a State of the Science Statement in 2002, suggesting the following biochemical workup for all patients with an adrenal incidentaloma: • • •
Cushing’s: 1 mg dexamethasone suppression test Pheochromocytoma: plasma-free metanephrines Aldosterone-producing adenoma: plasma aldosterone concentration/ plasma renin activity (to determine the ratio) as well as serum potassium levels for patients with hypertension
Cushing’s syndrome — cortisol overproduction Abnormalities in cortisol secretion without obvious clinical signs of Cushing’s syndrome, the so-called subclinical Cushing’s syndrome (SCS), have been reported in as high as 20% of adrenal incidentalomas. There are five biochemical abnormalities that can occur in SCS: (1) (2) (3) (4) (5)
Failure to suppress cortisol with dexamethasone Loss of diurnal variation in cortisol secretion Low or suppressed plasma ACTH Lack of ACTH response to CRH Elevated 24 h urine-free cortisol (late finding associated with clinical signs)
The first screening test that should be performed is the low dose dexamethasone suppression test. In patients with a normal pituitary–adrenal axis, the administration of exogenous steroid should suppress the production of cortisol. Dexamethasone is a glucocorticoid that does not interfere with the measurement of cortisol. • • •
1 mg of dexamethasone is given at 11 pm; An 8 am plasma cortisol level is collected; If the cortisol level is greater than 3–5 mcg/dL, then it is not suppressed and the patient may have Cushing’s syndrome;
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Once the diagnosis is confirmed, the patient should undergo further testing with plasma ACTH and urine-free cortisol levels or salivary cortisol.
Cortisol Cortisol is a glucocorticoid released from the adrenal cortex in response to ACTH, which is produced by the pituitary gland. Cortisol levels are measured to evaluate the pituitary–adrenal axis. • •
Normal values at 8 am are 6–23 mcg/dL. Higher-than-normal levels may indicate: Adrenal tumor Cushing’s disease (pituitary tumor) Ectopic ACTH-producing tumors
•
Drugs that can increase cortisol measurements include: Estrogen Synthetic glucocorticoids, such as prednisone and prednisolone
•
Drugs that can decrease cortisol measurements include: Androgens Phenytoin
Aldosteronoma An aldosterone-producing adenoma of the adrenal gland accounts for up to 1.5% of hypersecreting adrenal incidentalomas. Initial biochemical screening consists of measuring plasma aldosterone and plasma renin activity. •
•
A ratio of plasma aldosterone to renin >20, with a suppressed renin level plus an elevated plasma aldosterone >15 ng/dL, is suggestive of the diagnosis; 24 h urine collection for aldosterone and potassium while on a high salt diet (or during saline loading) is then initiated.
Urinary aldosterone >12 ug/dL confirms the diagnosis; Urinary potassium >30 mEq/24 h confirms the diagnosis.
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Plasma aldosterone Aldosterone is a mineralocorticoid released by the adrenal glands that helps the body regulate blood pressure. It increases the reabsorption of sodium and water and the release of potassium in the kidneys. This action raises the blood pressure. • • •
Normal results are 2–15 ng/dL. Higher-than-normal levels of aldosterone may indicate primary hyperaldosteronism. Many medications can influence aldosterone levels, including: ACE inhibitors Calcium channel blockers Diuretics Heparin Lithium Nonsteroidal anti-inflammatory medications (NSAIDs) Propranolol
Plasma renin Renin is an enzyme that is released into the bloodstream by the kidney in response to decreasing sodium levels or low blood volume. Renin and aldosterone levels typically move in opposite directions in the normal regulatory cycle. • •
Normal values range from 1.9 to 3.7 ng/mL/h. Renin measurements are affected by salt intake, pregnancy, time of day, and body position.
Pheochromocytoma A pheochromocytoma can be seen in up to 5% of incidentally found hypersecreting adrenal lesions. In the classic presentation, patients are hypertensive and may have episodes of palpitations, headaches, tremors, sweating, or anxiety. This “classic” presentation occurs 40% of the time,
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while 10% of patients are found during screening evaluation, and 10% are found due to a hypertensive crisis. Almost 40% of patients with a pheochromocytoma are asymptomatic and are found as cases of incidentalomas. All patients with adrenal incidentalomas should be screened for a pheochromocytoma, because of their potential for life-threatening catecholamine release. Diagnostic evaluation of a pheochromocytoma consists of measuring catecholamines and metanephrines. Although the NIH State of the Science Statement suggests using plasma metanephrines as the primary screening test, many physicians use 24 h urine metanephrines because the high sensitivity and lower specificity of plasma metanephrines lead to a higher false positive rate and more unnecessary workups than with the higher specificity of 24 h urine metanephrines. • •
Normal levels for plasma-free metanephrines: <0.5 nmol/L Normal levels for 24 h urine metanephrines: Normotensive males: 44–126 ug/24 h Normotensive females: 30–180 ug/24 h Hypertensives: <400 ug/24 h
•
Measure plasma-fractionated metanephrines: Pro: simpler to perform than 24 h urine measurements Con: higher false positive rate
•
If abnormal plasma metanephrine levels are obtained, a 24 h urine measurement of fractionated catecholamines and total metanephrines should then be done to confirm the diagnosis.
Plasma-free metanephrines Epinephrine and norepinephrine are catecholamine hormones produced in the adrenal medulla that help regulate the flow and pressure of blood throughout the body and play important roles in the body’s response to stress. The catecholamines that the adrenal glands produce, and their metabolites, metanephrine and normetanephrine, are normally found in small fluctuating quantities in both the blood and urine. Metanephrines are the metabolites of epinephrine and norepinephrine.
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•
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Before testing, discontinue epinephrine and epinephrine-like drugs for at least one week before the test, stop using acetaminophen 48 h beforehand, and fast for 8–10 h prior to collection. It is especially important not to have any caffeine-containing food (soda, chocolate), coffee (including decaf), tobacco (smoking cigarettes or cigars), tea, or alcohol for at least 4 h before specimen collection. The plasma-free metanephrines test is very sensitive and has a high false positive rate (up to 18%).
Urine catecholamines/metanephrines This measures the total amount of catecholamines and metanephrines released in the urine over 24 h. Since the plasma hormone levels may fluctuate significantly during this period, the urine test may detect excess production that is missed with the blood test. •
If the patient has only moderately elevated plasma free metanephrines, then 24 h urine catecholamine testing and/or metanephrine testing should be done, to determine whether the free metanephrines are still elevated.
Studies have shown that if the measured plasma or 24 h urine metanephrine level is 1–2 times the upper limit of normal, there is a 30% chance that the patient has a pheochromocytoma. If the levels are less than one time the upper limit of normal, there is almost no chance that there is a pheochromocytoma. Lastly, if the levels are greater than two times the upper limit of normal, there is an almost 100% likelihood of a pheochromocytoma.
RADIOGRAPHIC ASSESSMENT Most patients have had their adrenal incidentaloma detected on CT scans and several characteristics should be noted on CT. •
Size — best predictor of malignant potential. The risk of primary adrenal cancer based on size is: <4 cm: less than 2–3% 4–6 cm: 7% >6 cm: 25%
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•
Homogeneity Adenomas — smooth, homogenous lesions Carcinomas — inhomogenous, with irregular margins and areas of necrosis, hemorrhage, or calcification
•
Invasiveness Adenomas — well-circumscribed lesions Carcinomas — may have evidence of local invasiveness
•
Attenuation values Adenomas — low attenuation lesions (<10 Hounsfield units) due to their abundant amount of intracellular lipid Carcinomas — usually >18 Hounsfield units
An MRI, specifically a T2-weighted MRI, may be a useful test for further characterizing the incidentaloma. • •
Normal T2 signal: suggestive of adenoma Bright T2 signal: a solid tumor that is T2-hyperintense is typically either carcinoma or pheochromocytoma
PET imaging is not recommended except in the case of a patient with known extra-adrenal malignancy. Adrenocortical Carcinoma These are rare tumors that are usually greater than 6 cm (>90% of the time) at the time of presentation. However, small cancers can occur and need to be part of the differential diagnosis of adrenal incidentalomas. Approximately half of adrenal cancers are functioning and produce symptoms of Cushing’s syndrome, virilization, or a mixed variety. However, assessing the risk of adrenocortical carcinoma is largely based on size.
Guidelines for Resection The NIH State of the Science statement recommends that all functional tumors and tumors over 6 cm should be resected. Tumors between 4 cm
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and 6 cm should be resected as long as the patient is healthy enough to tolerate the operation. However, many physicians use 3 cm and 5 cm as their size cutoffs, instead of 4 cm and 6 cm, because cross-sectional imaging underestimates tumor size by up to 25%. In cases of a negative biochemical workup and small tumor size, repeat imaging studies every six months for a year and a yearly biochemical workup for four years are recommended. Up to 22.8% of incidentalomas will grow and up to 9.5% will become functional over a 10-year followup period. Algorithm CT or MRI Incidentaloma Non-functioning Tumor
Functioning Tumor
Urine Metanephrines PAC:PRA 1 mg dex suppression
Pheo
Aldo
Cushing's
Non-functional/ non-malignant
ACC or Mets
ACC
Adrenalectomy
Adrenalectomy
3-5 cm
< 3 cm
young, healthy old, co-morbidities
Observe
> 5 cm
Observe Q 6 month imaging x 2 Q year hormonal testing x 4
SELECTED REFERENCES Cameron JL. Current Surgical Therapy, 9th Edn. Philadelphia: Mosby, Inc., 2008. Mazzuco TL, Bourdeau I, Lacroix A. Adrenal incidentalomas and subclinical Cushing’s syndrome: diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes 2009;16(3):203–210. Osella G, Terzolo M, Borretta G, et al. Endocrine evaluation of incidentally discovered adrenal masses (incidentalomas). J Clin Endocrinol Metab 1994;79(6):1532–1539. Stifelman MD, Fenig DM. Work-up of the functional adrenal mass. Curr Urol Rep 2005;6(1):63–71.
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Chapter III.A.2: Cushing’s Syndrome: Laboratory and Imaging Evaluation Geoffrey B. Thompson, MD and William F. Young, Jr., MD, MSc
INTRODUCTION Cushing’s syndrome (CS) is a disorder characterized by excessive circulating cortisol from either endogenous or exogenous sources, which can result in deleterious changes in virtually every organ system. Exogenous hypercortisolism is far more common than endogenous CS, but the focus of this chapter will be on the latter process. The incidence of endogenous CS is about two cases per 1,000,000 persons per year. Patients not cured by surgical intervention have a poor prognosis, with a standard mortality ratio up to five times that of normal individuals. The adult classification of endogenous hypercortisolism is depicted in Fig. 1. Adrenocorticotropin hormone (ACTH)–dependent causes account for 80% of all cases of endogenous CS, with the majority of these (85%) attributed to pituitary-dependent causes. Fifteen percent are due to ectopic production of ACTH or corticotropin-releasing hormone (CRH). The remaining 20% of cases of endogenous hypercortisolism are due to ACTH-independent causes; specifically, 10% of all cases are attributed to cortisol-secreting adrenal adenomas, 8% to adrenocortical carcinomas, and the remaining 2% are due to ACTH-independent macronodular adrenal hyperplasia (AIMAH), primary pigmented nodular adrenal disease (PPNAD) which can be associated with Carney complex, and true bilateral cortisol-secreting adenomas.
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Fig. 1 Cushing’s syndrome (adult classification). (With permission: Porterfield JR Jr, Young WF Jr, Thompson GB, et al. Surgery for Cushing’s syndrome: a historical review and recent ten-year experience. World J Surg 2008;32:659–677.)
CASE DETECTION FOR ENDOGENOUS HYPERCORTISOLISM: WHO SHOULD BE EVALUATED FOR CUSHING’S SYNDROME? Discriminating features of CS include: central obesity with varying combinations of facial rounding with plethora, increased supraclavicular and dorsal cervical fat pads, cutaneous wasting and ecchymoses, wide violaceous striae, proximal myopathy, increased lanugo facial hair, superficial fungal infections, and growth retardation in children. Patients with the so-called metabolic syndrome, which includes diabetes mellitus, hypertension, hyperlipidemia, and polycystic ovarian syndrome, should also be suspect. Patients with an incidentally discovered adrenal mass, patients with osteoporosis under the age of 65 years (especially when presenting with spontaneous rib fractures), and finally patients with hypogonadotrophic hypogonadism should be investigated further for biochemical evidence of CS.
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Fig. 2 Cushing’s syndrome (case finding). *May go straight to subtype evaluation of clinical assessment highly suggestive of pituitary Cushing’s. (With permission: Porterfield JR Jr, Young WF Jr, Thompson GB, et al. Surgery for Cushing’s syndrome: a historical review and recent ten-year experience. World J Surg 2008;32:659–677.)
Reviewing old photographs is particularly helpful in determining whether the patient’s appearance is highly suspicious for CS or simply the result of the normal aging process.
LABORATORY EVALUATION (FIG. 2) At Mayo Clinic, when hypercortisolism is suspected, our first test of choice is usually the measurement of free cortisol in a 24 h urine collection. We also quantify urine creatinine for complete collection quality control. The suspicion for CS is elevated when the 24 h urinary free cortisol is greater than twice the upper limit of the reference range (3.5–45 µg/24 h). Loss of diurnal variation in serum cortisol can be perturbed under many circumstances, including stress and hospitalization, and are thus less reliable than 24 h urine collections. Even for patients with known CS, approximately 10–15% will have one of four serial 24 h urinary free cortisol measurements in the normal range. All etiologies of CS can
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produce cortisol in a so-called episodic or cyclical fashion. Use of tandem mass spectrometry has avoided the falsely elevated 24 h urinary free cortisol caused by medications (e.g. carbamazepine). Other scenarios where the 24 h urinary free cortisol may be falsely elevated include severe illness, alcoholism, depression, obstructive sleep apnea, and excessive urine volume (e.g. >4 L/24 h). When the clinical picture is consistent with CS and the baseline 24 h urinary free cortisol exceeds five times the upper limit of the reference range (e.g. >300 µg/24 h), no additional studies are needed to confirm CS. An overnight 1mg dexamethasone suppression test is most useful for demonstrating autonomous cortisol secretion. The 8 a.m. plasma cortisol level in a healthy patient will be suppressed to below 5 µg/dL with this test. There are, however, many causes for cortisol nonsuppression with the overnight 1mg dexamethasone suppression test. They include: patient error, increased corticosteroid-binding globulins (CBGs) due to estrogen therapy or pregnancy, alcoholism, OSA, depression, panic attacks, obsessive–compulsive disorder, obesity, drugs that accelerate dexamethasone metabolism (such as anticonvulsants, primidone, and rifampin), renal failure, and stress. Another option is the 8 mg overnight dexamethasone suppression test. Normal patients should have an a.m. cortisol of nearly zero. Failure to suppress is considered positive and warrants a two-day, low-dose dexamethasone suppression test. The above-mentioned tests are most useful for demonstrating autonomous cortisol production in an adrenal incidentaloma. With equivocal findings and a 24 h urinary free cortisol excretion of less than 300 µg, hypercortisolism should be confirmed with the two-day, low-dose dexamethasone suppression test. Dexamethasone 0.5 mg is orally given every 6 h for 48 h. A 24 h urinary free cortisol, collected during the second day of suppression, ≥5 µg, is consistent with the diagnosis of CS. This test is approximately 79% sensitive and 74% specific, with an overall accuracy of 71%. It is most efficacious for ruling out CS in those patients for whom the index of suspicion for CS is low. However, some patients with mild pituitary-dependent CS may suppress with a low-dose dexamethasone suppression test. In an effort to correct the suppression with a low-dose dexamethasone suppression test observed in some patients with pituitary CS, the
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CRH dexamethasone suppression test was developed. A serum cortisol concentration >1.4 µg/dL at 15 min following corticotropin-releasing hormone administration is consistent with CS. Although it is purported to be highly accurate, false positive results have been seen in our clinic. Other diagnostic testing includes the use of late night plasma or salivary cortisol. A midnight, sleeping, serum cortisol concentration >1.8 µg/dL is 100% sensitive in patients with CS. Precision, however, usually requires hospitalization. Alternatively, measurement of salivary cortisol correlates well with serum cortisol levels. This is performed by giving the patient instructions to chew on a special cotton swab for 2 min, followed by placement in a specially designed plastic container. Salivary cortisol levels obtained at 11 p.m. >100 ng/dL are highly sensitive for CS. This test is becoming increasingly popular and may be used as a first-line screening test in some centers. No single test is satisfactory for case detection and confirmation of CS. Patients suspected of having endogenous hypercortisolism on clinical grounds should be evaluated with multiple tests for diagnostic confirmation. These would include, at a minimum, a 24 h urinary free cortisol, 11 p.m. salivary cortisol and, less often, the two-day low-dose dexamethasone suppression test or CRH dexamethasone suppression test.
SUBTYPE EVALUATION AND IMAGING (FIGS. 3 AND 4) With CS confirmed, subtype evaluation and localization are the appropriate next steps. Since 70% of patients with endogenous hypercortisolism have pituitary-dependent CS and 80% have ACTH-dependent CS, a plasma ACTH concentration is the first step in subtype evaluation. Normal plasma ACTH levels, when measured with an immunoradiometric assay (IRMA), are 10–60 pg/mL. Plasma ACTH levels <5 pg/mL indicate pituitary suppression by primary adrenal disease. ACTH levels in the 20–200 pg/mL range generally indicate pituitary-dependent disease, and ACTH levels in the 50 to >200 pg/mL range often represent patients with ectopic ACTH syndrome. When ACTH levels are less than 5 pg/mL, computerized crosssectional imaging with computed tomography (CT) or, less often, magnetic resonance imaging (MRI) of the adrenal glands will most often
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Fig. 3 Cushing’s syndrome (subtype evaluation). *TSS in appropriate clinical setting. † Chest abdomen. ‡Octreoscan, MIBG scan, FDG-PET. §Calcitonin, 5-HIAA, gastrin, metanephrines (plasma).
Fig. 4
Cushing’s syndrome (subtype evaluation).
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CT scan of cortisol-secreting adrenocortical adenoma.
delineate adrenal pathology. As with any high-resolution imaging, the presence of incidental findings is common. Five to ten percent of the population harbor adrenal nodules >1 cm. Typically, benign cortisolsecreting adrenal adenomas range from 2 to 6 cm in diameter and have a rather smooth, regular border with a homogenous appearance (Fig. 5). A homogenous adrenal lesion with <18 Hounsfield units (HU) on an unenhanced CT scan may be designated as a lipid-rich adenoma with a specificity of 80% and a sensitivity of 100%. Adrenocortical carcinomas are rarely seen below 5 cm in size but, when present, usually display a worrisome radiographic phenotype, consisting of a heterogenous mass with irregular borders, by CT. Other imaging characteristics of adrenocortical carcinomas include areas of necrosis, hemorrhage, calcifications, delayed or incomplete washout of intravenous contrast on CT, or bright areas on T2-weighted MRI sequences. Adrenocortical carcinomas may also manifest regional lymphadenopathy, venous thrombi, or direct invasion of contiguous structures, as well as distant metastases (lung, bone, or liver) (Fig. 6). The presence of high intracellular lipid content, characteristic of a benign adenoma, may be seen by axial, in-phase and out-of-phase, fast,
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Fig. 6 Adrenocortical carcinoma (left; MRI-T2 weight image), with (A) liver metastasis and (B) lung metastasis.
Fig. 7
PPNAD: “string of beads,” right adrenal. Somewhat larger nodule, left adrenal.
multiplanar spoiled, gradient-echo T1-weighted MR images (FMPSPGR). Benign adenomas also appear isotense relative to the liver in axial, fast, spin-echo, T2-weighted images. In patients with PPNAD, bilateral adrenal micronodularity (string-ofbeads appearance) is a characteristic on high-resolution CT (Fig. 7).
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Fig. 8 AIMAH: massively enlarged adrenals bilaterally. (With permission: Porterfield JR Jr, Young WF Jr, Thompson GB, et al. Surgery for Cushing’s syndrome: a historical review and recent ten-year experience. World J Surg 2008;32:659–677.)
The adrenal glands are usually normal in size. Once the diagnosis is made, the patient and family members must be screened for cardiac myxomas, a common cause of sudden death in those PPNAD patients with Carney complex. Genetic testing is available for the PRKAR1A mutations that can be seen in up to 40% of patients with Carney complex. In AIMAH, CT will demonstrate massive bilateral adrenal enlargement, which may be asymmetric, with nodules reaching 5 cm in size (Fig. 8). Research protocols are available to screen for abnormal adrenal expression and/or function of receptors, which include gastrointestinal polypeptide, interleukin-1, luteinizing hormone, vasopressin, and β-adrenergic receptors. Normal to moderately elevated ACTH-dependent levels confirm ACTH-dependent CS. The clinical presentation, however, cannot be underestimated in its predictive value. For example, a 35-year-old woman with an onset of CS over many years with classic signs and symptoms almost certainly has pituitary-dependent CS (>95% probability). In contrast, a 55-year-old man with a three-month history of fatigue, weight loss, marked skin pigmentation, hypokalemic alkalosis, glucose intolerance, and
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Fig. 9
MRI showing small hypodense ACTH-producing pituitary adenoma.
an ACTH level >100 pg/mL and 24 h urinary free cortisol >500–1000 µg, has ectopic ACTH syndrome until proven otherwise. Since 85% of patients with ACTH-dependent CS will have Cushing’s disease, a dedicated pituitary MRI with gadolinium enhancement is indicated in all patients (Fig. 9). If a hypodense and nonenhancing pituitary tumor larger than 5 mm is combined with a correct clinical scenario (female, indolent disease, urinary free cortisol <5-fold but >2-fold elevated), additional studies are usually not required before definitive treatment. Smaller (<5 mm) pituitary lesions occur in as many as 10–20% of normal individuals and are being detected with increasing frequency with each new generation MR scanner. Thus, normal pituitary scans or small lesions should be further studied with inferior petrosal sinus sampling, since 50% of patients with Cushing’s disease have a normal pituitary MRI. The risks associated with inferior petrosal sinus sampling are not trivial and include venous thrombosis, pulmonary embolism, cranial nerve palsy, and brain stem infarction, thus mandating the
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availability of an experienced interventional neuroradiologist. Inferior petrosal sinus sampling is technically successful in 85–99% of procedures at experienced centers and is considered the most important advance in subtype evaluation of CS in the past quarter-century. With ACTH-dependent CS, a negative pituitary MRI, and negative inferior petrosal sinus sampling, a search for an ectopic-ACTH-secreting tumor should ensue. In our recent 10-year review, we were successful in locating the primary tumor in only 65% of cases. Inferior petrosal sinus sampling can be avoided if the pituitary MRI is negative in the classic clinical setting of a male with rapid onset of CS, predominance of metabolic abnormalities, and very high cortisol/ACTH levels. CT and/or MRI of the neck, chest, abdomen, and pelvis should be performed. Somatostatin receptor imaging with 111In-DTPA-pentetreotide has not proven terribly accurate in localizing ectopic-ACTH-secreting tumors, which may remain occult for years, with sensitivities ranging from 30 to 80%. [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has added little to the diagnostic armamentarium for ectopicACTH-secreting tumors. It is hoped that the accuracy of PET will improve with the use of additional isotopes that include [11C]5-HTP, [11C]2-DOPA, but this has yet to be proven. In rare situations, biochemical markers may be of assistance, such as calcitonin, plasma and urinary fractionated metanephrines, gastrin, and urinary 5-hydroxyindoleacetic acid. However, when these markers are elevated, the source is usually readily apparent by conventional imaging.123I-metaiodobenzylguanidine (MIBG) scintigraphy may be helpful on occasion in localizing the rare ACTH-secreting or CRH-secreting pheochromocytoma. The most common sites for ectopic-ACTH- or CRH-secreting tumors include bronchial carcinoids, small cell carcinoma of the lung, thymic carcinoids, islet cell tumors of the pancreas, pheochromocytomas, other carcinoid tumors, and medullary thyroid carcinoma.
SELECTED REFERENCES Carroll T, Raff H, Findling JW. Late-night salivary cortisol measurement in the diagnosis of Cushing’s syndrome. Nat Clin Pract Endocrinol Metab 2008;4:344–350.
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Findling JW, Raff H. Diagnosis and differential diagnosis of Cushing’s syndrome. Endocrinol Metab Clin North Am 2001;30:729–747. Findling JW, Raff H. Cushing’s syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab 2006;91:3746–3753. Porterfield JR Jr, Thompson GB, Grant CS. Hypercortisolism. In: McGraw-Hill Manual of Endocrine Surgery (eds.) SY Morita, APB Dackiw, MA Zeiger. New York: McGraw-Hill Medical Publishing Group, 2009. Porterfield JR Jr, Thompson GB, Young WF Jr, et al. Surgery for Cushing’s syndrome: a historical review and recent ten-year experience. World J Surg 2008;32:659–677. Young WF Jr. The incidentally discovered adrenal mass. N Engl J Med 2007;356:601–610.
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Chapter III.A.3: Pheochromocytoma Goswin Y. Meyer-Rochow, MB, ChB, FRACS and Stan B. Sidhu, MB, BS, PhD, FRACS
INTRODUCTION Pheochromocytomas and extra-adrenal sympathetic paragangliomas (PGLs) are catecholamine-secreting neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or extra-adrenal sympathetic ganglia. Patients generally present with symptoms resulting from excessive production of the catecholamines dopamine, epinephrine or norepinephrine, although occasionally a tumor may be nonfunctioning or the patient may remain asymptomatic. Prior to embarking on laboratory or radiological investigations, it is essential that a thorough patient history and examination is performed, with a particular focus on symptoms, medications, prior history of pheochromocytoma-syndrome-associated tumors, family history and blood pressure, as the likelihood of a pheochromocytoma or a pheochromocytoma-associated familial syndrome based on clinical assessment will influence subsequent patient workup. For the purposes of this chapter adrenal pheochromocytomas and sympathetic PGLs will be collectively referred to as pheochromocytomas unless otherwise specified.
LABORATORY TESTING Overview The first step in establishing the diagnosis in a patient suspected to have a pheochromocytoma is the measurement of urinary or plasma catecholamines (dopamine, epinephrine and norepinephrine) and/or metanephrines (metanephrine and normetanephrine). The measurement of 299
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another catecholamine metabolite, vanillylmandelic acid (VMA), may also be included. A number of medications can interfere with the assay or affect catecholamine production or elimination and should ideally be stopped two weeks prior to biochemical testing. Normal reference ranges Normal reference ranges (Table 1) and cutoffs for the diagnosis of pheochromocytoma vary between laboratories, resulting in differing sensitivities and specificities. They may also differ depending on the assay or method used for measurement. High performance liquid chromatography (HPLC) appears to be the most sensitive and specific method for the measurement of fractionated catecholamines and metanephrines. For plasma blood collection an intravenous catheter should be inserted and the patient allowed to rest in a supine position for approximately
Table 1 Normal reference ranges and sensitivity/specificity for catecholamines, metanephrines and serum chromogranin A. Serum reference ranges
24 h urinary reference ranges Epinephrine: 0–20 µg/day Norepinephrine: 15–80 µg/day Dopamine: 65–400 µg/day Metanephrine: 26–230 µg/day Normetanephrine: 44–540 µg/day VMA: 2.0–7.9 mg/day
Epinephrine: 4–8 pg/mL Norepinephrine: 80–498 pg/mL Dopamine: <30 pg/mL Metanephrine: 18–112 pg/mL Normetanephrine: 12–61 pg/mL Serum chromogranin A: 33–105 ng/mL Investigation Urinary catecholamines Urinary metanephrines Plasma catecholamines Plasma metanephrines Urinary VMA Dopamine Serum chromogranin A
Sensitivity (%)
Specificity (%)
86 97 84 98 64 7 86
83 72 88 89 95 99 74
*Note that reference ranges are variable between different laboratories and values may be given in different units or in moles.
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30 min. A standing position or stress that result in higher catecholamine levels.
Diagnostic values Generally, measures at least twofold above the normal range are regarded as diagnostic whereas lower values should be repeated. Equivocal results should be further investigated by another method after excluding any pharmaceutical agents which may be affecting the biochemical testing results (Table 2).
Metanephrines Urinary and plasma fractionated metanephrines provide the highest sensitivity for the diagnosis of both sporadic and hereditary pheochromocytoma
Table 2
Pharmacological agents which may interfere with biochemical testing.
Increase measurements Acetaminophen (Tylenol) Aminophylline Beta adrenergic blockers Caffeine Calcium channel blockers Chloral hydrate Clonidine Disulfiram Erythromycin/tetracyclines Insulin Levodopa/methyldopa Lithium Methenamine Nicotinic acid (large doses) Nitroglycerin Quinidine Tricyclic antidepressants
Decrease measurements Clonidine Disulfiram Guanethidine Imipramine Monoamine oxidase inhibitors Phenothiazines Reserpine Salicylates
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but are less widely available than plasma or urinary catecholamine and VMA measures. Production of metanephrines by a pheochromocytoma is more constant and has a longer plasma half-life than the catecholamines, resulting in greater sensitivity. A negative test therefore reliably excludes the presence of a pheochromocytoma. Plasma metanephrines Advantages With the highest combination of both sensitivity and specificity where available, plasma metanephrines should be used as the initial investigation of choice for patients suspected of pheochromocytoma. They are particularly recommended for patients with a high pretest probability of disease such as pheochromocytoma-associated syndromes or predisposing germline mutations, and a prior history or family history of pheochromocytoma. Compliance issues which may occur with 24 urine measures are avoided. Limitations Less available than urine metanephrine or catecholamine measures and generally restricted to specialized centers. Urinary metanephrines Advantages Urinary metanephrines also have excellent sensitivity and therefore can reliably exclude the diagnosis of pheochromocytoma. They have greater availability than plasma metanephrines although they are generally also restricted to specialized institutions. Limitations Although urinary metanephrines have high sensitivity, they have an inferior specificity compared to both plasma metanephrines and
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urinary/plasma catecholamines and will therefore lead to a larger number of false positive results. They should thus be interpreted in combination with catecholamine or VMA measures to improve specificity. Catecholamines Catecholamine measures are still commonly used for the diagnosis of pheochromocytoma; however, there is now clear evidence that the sensitivity of fractionated urinary and plasma metanephrines is superior to that of catecholamine measures. Episodic secretion of catecholamines may not be detected, due to the rapid uptake and rate of metabolism of the catecholamines. Where metanephrine measures are not available, having two separate urine or plasma catecholamine measures as an initial investigation is reasonable, but the sensitivity and specificity can be further improved if done in combination with VMA. Plasma catecholamines Advantages Widely available, with reasonable sensitivity and good specificity. Not reliant on patient compliance with 24 h urine collection. Limitations If venesection protocols are not strictly adhered to (placement of IV and resting supine for 30 min prior to blood collection), catecholamine levels may be inappropriately raised. Have sensitivity inferior to that of metanephrine measures. Not sensitive enough to reliably exclude pheochromocytoma. Urinary catecholamines Advantages Widely available, with reasonable sensitivity and specificity. More likely to detect an intermittently secreting tumor than plasma catecholamines.
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Limitations Not sensitive enough to reliably exclude pheochromocytoma. Have inferior sensitivity compared to metanephrine measures. Vanillylmandelic Acid (VMA) Advantages Widely available and has the highest specificity for pheochromocytoma. Often used as an adjunct to urinary metanephrine and urinary or plasma catecholamine measures. Limitations Very poor sensitivity and therefore unreliable for the diagnosis of pheochromocytoma. Reliant on patient compliance with 24 h urine collection.
Provocation and Suppression Tests Due to the extremely high sensitivity of fractionated metanephrines, provocative testing with glucagon, histamine, metoclopramide or tyramine is no longer used as they have a comparatively low sensitivity for the detection of disease and may induce an adrenergic crisis. However, as a result of the high sensitivity and lower specificity of metanephrine and catecholamine measures, false positive results will occur. Clonidine suppression tests may still be useful when a false positive catecholamine or metanephrine result is suspected, but phentolamine suppression tests are no longer used due to poor sensitivity and specificity.
Clonidine suppression test Method After an overnight fast a baseline blood sample is drawn through an intravenous cannula after at least 30 min of supine rest. Oral clonidine (300 mg)
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is given and a second blood sample is taken 3 h after administration, with the patient remaining supine throughout the test. Interpretation A negative test is defined as a drop to below 50% from the baseline for total catecholamines and norepinephrine, or to below 40% from the baseline for normetanephrine. Plasma metanephrines and norepinephrine have been demonstrated to have higher sensitivity and specificity than the traditional measure of total catecholamines (Table 3). Chromogranin A (CgA) CgA may be used as an additional diagnostic biochemical test for pheochromocytoma. It has a sensitivity of 86% but poor diagnostic specificity. Advantages Secretion and measurement of CgA are not influenced by pharmacological agents which may interfere with biochemical testing for catecholamines or metanephrines. It is therefore useful as an adjunct to other biochemical tests for pheochromocytoma. Limitations Not sufficiently sensitive to reliably exclude pheochromocytoma and has poor specificity. Measurements are unreliable with renal impairment. May be elevated in patients taking proton pump inhibitors. Table 3 Sensitivity and specificity of catecholamines used for the clonidine suppression test. Biochemical test Total catecholamines Norepinephrines Metanephrines
Sensitivity (%)
Specificity (%)
62 85 96
66 78 67
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GENETIC TESTING Overview Germline mutations associated with the development of pheochromocytoma: • • • •
VHL (von Hippel–Lindau syndrome) RET [multiple endocrine neoplasia type 2 (MEN2)] NF1 (neurofibromatosis type 1) SDHB, SDHC, SDHD (succinate dehydrogenase subunits B, C, D)
NF1 is usually diagnosed based on clinical grounds. SDHC germline mutations are rare and associated with head–neck paragangliomas, and are therefore not recommended in the routine screening for pheochromocytoma. All have an autosomal dominant mode of inheritance with the exception of SDHD, which is a maternally expressed imprinted gene. Up to 25% of patients presenting with an apparently sporadic pheochromocytoma will have a germline mutation. This has led many experts in the field to suggest that all patients with pheochromocytoma should be offered genetic testing. A more cost-effective approach by selecting only patients at high risk (patient or family history of pheochromocytoma-syndrome-associated disease; age <35 years; multifocal, bilateral adrenal, extra-adrenal or malignant disease) has been suggested, with a demonstrated sensitivity of 91.8%.
Method for Genetic Testing Appropriate genetic counseling must be given prior to screening for germline mutations. Two patient blood specimens collected in EDTA tubes are submitted for blood leukocyte DNA analysis (the second tube for confirmation of an identified mutation). Exons from the gene of interest are amplified by the polymerase chain reaction. Relevant patient clinical details allow prioritizing of the most likely gene mutation based on the clinical phenotype. Prescreening for germline mutations may reduce the amount and therefore cost of DNA sequencing required.
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Prescreening for germline mutations This can be done using denaturing gradient gel electrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE), single-strand conformation polymorphism, conformation-sensitive gel electrophoresis (CSGE), heteroduplex analysis and denaturing high-performance liquid chromatography (DHPLC).
Advantages Cost-effective and rapid screening tools for germline mutations, particularly when screening family members of an index patient with a known germline mutation.
Limitations As a screening tool for germline mutations these tests have a sensitivity of 67–93%. Variant DNA sequences detected by these methods (including polymorphisms) need further evaluation by DNA sequencing analysis.
DNA sequencing analysis This determines the order of nucleotides in an amplified DNA fragment and is considered the gold standard for the screening and diagnosis of a germline mutation.
Advantages Rapid, reliable, with near-100% sensitivity and specificity.
Limitations Relatively expensive, particularly when all genes need testing. Limited to specialized centers. Will not detect large-scale deletions occasionally seen in VHL.
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Multiplex ligation-dependent probe analysis (MLPA) Used for the detection of large-scale deletions occasionally seen in VHL. Advantages Has near-100% sensitivity and specificity, and is a rapid and relatively inexpensive test.
Limitation Restricted to specialized centers.
Prioritization of Gene Testing Appropriate prioritization of genes to be tested based on the clinical phenotype can reduce the cost and time of genetic testing for pheochromocytoma-associated germline mutations. Relatives of patients with an identified germline mutation should have targeted genetic testing. •
•
•
VHL syndrome should be suspected in patients younger than 20 years of age, with bilateral adrenal tumors or tumors secreting norepinephrine/normetanephrine (without epinephrine/metanephrine), or when clinical features of VHL are present. The frequency of VHL germline mutations in patients with apparently sporadic pheochromocytoma is 2–9%. The risk of malignant disease is <10%. Less than 5% of VHL mutation carriers will have a large-scale deletion. SDHB mutations are associated with malignant and extra-adrenal disease; however, adrenal pheochromocytomas may also occur. Norepinephrine and normetanephrine secretion predominates. The frequency of SDHB germline mutations in patients with apparently sporadic pheochromocytoma is 2–7%. The risk of malignant disease is 34–70% RET-mutation-associated pheochromocytomas are usually adrenal and frequently bilateral. Extra-adrenal disease is rare. Epinephrine
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and metanephrine secretion predominates. A patient or family history of medullary thyroid cancer (MTC), hyperparathyroidism, mucosal neuromas and raised calcium or calcitonin with baseline blood tests are suggestive of MEN2. Most RET mutation carriers present with MTC as the first manifestation of MEN2; however, 9–27% will present with pheochromocytoma as the first manifestation of MEN2. The frequency of RET germline mutations in patients with apparently sporadic pheochromocytoma is 3–5%. Malignant disease is rare. SDHD mutations are generally associated with head and neck paragangliomas; however, adrenal and extra-adrenal disease will occasionally occur. The frequency of SDHD germline mutations in patients with apparently sporadic pheochromocytoma is 3–5%. Malignant disease is rare. In the absence of a patient or family history of head and neck paraganglioma, this is the least likely gene to contain a germline mutation in a patient with pheochromocytoma.
IMAGING EVALUATION Indications for imaging evaluation include evaluation of a biochemically confirmed pheochromocytoma and screening for patients with pheochromocytoma-associated germline mutations and patients with equivocal biochemical screening results. Imaging modalities for pheochromocytoma include computed tomography (CT), magnetic resonance imaging (MRI), metaiodobenzylguanidine (MIBG) or octreotide scintigraphy, and positron emission imaging (PET). Initial imaging is performed using either CT or MRI, depending on availability and institutional preference. CT Imaging This is able to detect lesions >1 cm in size. Pheochromocytomas typically have a homogenous appearance of soft tissue density (40–50 Hounsfield units) and uniform enhancement with IV contrast. Larger tumors may have regions of cystic necrosis, hemorrhage or calcification, resulting in a more heterogenous appearance. Unlike older contrast media, the newer nonionic contrast media do not pose a significant risk of hypertensive crisis and therefore α-adrenoceptor blockade is not required.
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Advantages A rapid and sensitive test with moderate cost. Readily available to most hospital institutions. Provides excellent anatomical detail of the tumor and surrounding structures. Sensitivity 90–95%. Limitations Cannot determine whether an identified lesion is functional, resulting in a relatively low specificity of 72%. MRI Similar sensitivity and specificity to CT imaging. The hypervascularity of pheochromocytomas gives an intermediate-to-high signal intensity with T2-weighted imaging.
Advantages No radiation exposure or IV contrast required and therefore the investigation of choice for pregnant women, children, annual screening examinations (for patients with high-risk germline mutations) and any patient with a contrast allergy. The greater resolution for different tissue types provides slighter superior sensitivity for extra-adrenal lesions compared with CT. Readily available to most hospital institutions.
Limitations Greater cost than for CT imaging. Slower than for CT imaging, particularly when full body imaging is required. MIBG Scintigraphy Due to the moderate specificity of CT and MRI, many specialists may choose to perform a further confirmatory test using MIBG imaging prior to surgical intervention. MIBG is a norepinephrine analog which accumulates
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in hyperfunctioning chromaffin tissue. 123I-MIBG has superior sensitivity compared to 131I-MIBG (90% vs. 77%), but is less stable and less widely available. Both have a specificity near 100%. MIBG single photon emission computed tomography (MIBG SPECT) or MIBG SPECT/CT will further improve the sensitivity over planar MIBG imaging.
Advantages MIBG scintigraphy is usually done routinely as a full body image, and is therefore a useful tool for the detection of multifocal or metastatic disease. Planar and MIBG SPECT can be done in most nuclear medical imaging facilities; however, SPECT/CT fusion imaging equipment is generally restricted to specialist centers.
Limitations Prior to MIBG imaging, oral iodine must be administered to avoid uptake of radioactive iodine by the thyroid gland. Nonfunctioning pheochromocytomas or pheochromocytomas producing only dopamine may not accumulate MIBG, in which case they will not be detectable by MIBG imaging.
Octreotide Scintigraphy Pheochromocytomas generally have a high density of somatostatin receptors. 111In-diethylenetriaminepentaacetic acid (DTPA)-octreotide and 121 I-DTPA-octreotide are radiolabeled analogs of somatostatin.
Advantages Particularly useful as an alternative agent for scintigraphy when MIBG imaging or PET imaging for a suspected pheochromocytoma is negative. Greater sensitivity compared to 123I-MIBG (87% vs. 57%) for the detection or monitoring of metastatic disease.
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Limitations Poorer sensitivity if used for the detection of benign pheochromocytomas.
PET Imaging PET imaging with 18F-fluorodopamine, 18F-fluorodopa, 18F-dihydroxyphenylalanine, 11C-hydroxyephedrine and 11C-epinephrine is highly specific for pheochromocytoma, because they depend on uptake into the tumor cells by norepinephrine transporters unique to chromaffin tissues. 18Ffluorodeoxyglucose has lower sensitivity and specificity than 123I-MIBG and is therefore not recommended as the initial agent of choice for the imaging of pheochromocytomas.
Advantages The tissue-specific agents have been demonstrated in several small studies to have remarkably high sensitivity and specificity for the diagnosis of pheochromocytoma. Limitations An expensive imaging modality with very limited availability and therefore generally used only when the previous imaging modalities have failed to localize a tumor or metastasis.
SELECTED REFERENCES Benn DE, Richardson AL, Marsh DJ, Robinson BG. Genetic testing in pheochromocytoma- and paraganglioma-associated syndromes. Ann NY Acad Sci 2006;1073:104–111. Brink I, et al. Imaging of pheochromocytoma and paraganglioma. Fam Cancer 2005;4:61–68. Eisenhofer G, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab 88: 2656–2666.
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Gimenez-Roqueplo AP, et al. Pheochromocytoma, new genes and screening strategies. Clin Endocrinol 2006;65:699–705. Havekes B, et al. Detection and treatment of pheochromocytomas and paragangliomas: current standing of MIBG scintigraphy and future role of PET imaging. Q J Nucl Med Mol Imaging 2008;52:419–429. Karagiannis A, et al. Pheochromocytoma: an update on genetics and management. Endocr Relat Cancer 2007;14:935–956. Lenders JW, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 2002;287:1427–1434. Peaston RT, Ball S. Biochemical detection of pheochromocytoma: why are we continuing to ignore the evidence? Ann Clin Biochem 2008;45:6–10. Rufini V, et al. Imaging of neuroendocrine tumors. Semin Nucl Med 2006;36:228–247.
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Chapter III.A.4: Evaluation and Diagnosis of Hyperaldosteronism Xavier M. Keutgen, MD, Rasa Zarnegar, MD, FACS and Thomas J. Fahey III, MD, FACS
INTRODUCTION Recent estimates suggest that 5–13% of patients with hypertension suffer from primary aldosteronism. Furthermore, the prevalence of primary hyperaldosteronism (PH) approaches 20% in patients with resistant hypertension. Aldosterone-producing adenoma (APA) and bilateral idiopathic hyperplasia (IHA) represent about 95% of all subtypes of primary aldosteronism. Only 1% of cases are caused by unilateral hyperplasia, 5% are caused by angiotensin II–responsive adenomas and less than 1% are caused by familial hyperaldosteronism type I (glucocorticoid-remediable hyperaldosteronism) and familial hyperaldosteronism type II. It has been well documented that patients with PH are at higher risk than other patients with hypertension for target organ damage of the heart and kidney. PH leads to an increase in the relative risk of stroke, myocardial infarction and atrial fibrillation, which seem to be due to an increase in arterial wall thickness and left ventricular wall thickness, as well as a reduction in diastolic function. PH also impacts renal function by proinflammatory and profibrotic effects throughout the kidney, as well as metabolic function through alteration in glucose homeostasis (decreased insulin receptor levels and affinity in subcutaneous tissues). These adverse effects of aldosterone on the cardiovascular and other systems should increase efforts by clinicians to identify PH in patients undergoing evaluation and treatment of hypertension.
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Classically, PH is characterized by hypertension, hypokalemia (in 9–37% of cases) and polyuria. In addition, patients may present with muscle weakness, polydipsia, headaches and fatigue. Additional electrolyte abnormalities can include hypernatremia and hypochloremic metabolic alkalosis. One should screen for hyperaldosteronism in patients with: • • • • • •
Hypokalemia and hypertension Treatment-resistant hypertension (three hypertensive drugs and poor control) Severe hypertension (≥160 mmHg systolic or ≥100 mmHg diastolic) Hypertension and incidental adrenal mass Onset of hypertension at a young age Workup for secondary hypertension evaluation (i.e. when testing for renovascular disease, pheochromocytoma)
In the past the diagnosis of PH was classically divided into three phases: case finding tests, confirmatory tests and subtype evaluation tests. However, in our experience, the combination of PAC/PRA ratio and CT imaging (if adrenal tumor >1 cm) alone is highly sensitive for the diagnosis of hyperaldosteronism, and confirmatory subtype tests are necessary only if any of those tests are equivocal.
DIAGNOSIS At our institution initial screening for PH consists of determining the PAC/PRA ratio in addition to a high resolution CT scan of the adrenals (Fig. 1). Plasma Aldosterone Concentration (PAC) to Plasma Renin Activity (PRA) Ratio This test is the most frequently used and is considered the standard screening test for determining PH biochemically. The PAC/PRA test should be measured in the morning (8 a.m.–10 a.m.) and may be performed while the patient is taking most antihypertensive medications and without postural stimulation. Mineralocorticoid receptor antagonists (i.e. spironolactone)
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Fig. 1 Algorithm for the diagnosis and treatment of primary aldosteronism. PAC, plasma aldosterone concentration; PRA, plasma renin activity; CT, computed tomography; MRI, magnetic resonance imaging.
and high dose amiloride should be discontinued at least six weeks prior to diagnostic testing, since they have been shown to interfere with the interpretation of the PAC/PRA ratio. Patients taking ACE inhibitors, angiotensin-receptor antagonists and diuretics could have falsely elevated PRA levels and therefore the detection of a PRA level or a low PAC/PRA ratio does not exclude the diagnosis of primary aldosteronism. However, suspicion for PH in those patients taking these medications should be high if the PRA level is undetectably low. Notably, hypokalemia reduces the secretion of aldosterone, and should be corrected to normal before performing any diagnostic/screening studies.
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PH should be suspected if: • •
The PAC is ≥15 ng/dL (or ≥416 pmol/L) and the PRA is <1.0 ng/mL/h; The PAC/PRA ratio is greater than 20. Secondary hyperaldosteronism (i.e. renal artery stenosis) should be suspected if:
•
Both PAC and PRA are increased and the PAC/PRA ratio is less than 10. Alternate sources of mineralocorticoid receptor agonism (i.e. hypercortisolism) should be suspected if:
•
Both PAC and PRA are suppressed.
The PAC/PRA ratio is considered a good screening tool, with a sensitivity ranging from 75 to 87% and a specificity ranging from 74 to 83%, respectively. Computed Tomography High resolution CT of the abdomen with thin slices (2.5 mm or less) and IV contrast is the imaging study of choice for most patients with confirmed PH based on an elevated PAC/PRA ratio. As a general rule, Aldosterone Producing Adenomas (APAs) are usually small hypodense nodules, measuring between 0.5 and 2 cm in diameter, and are readily visible on CT scan. Patients with APA tend to be younger (<50 years old), have more severe hypertension, more profound and frequent hypokalemia, and higher plasma (>25 ng/dL, > 694 pmol/L) and urinary aldosterone levels (>30 µg/24 h, > 83 nmol/dL). Patients fitting these descriptions are considered to have a high probability of APA, regardless of the CT findings. Studies have shown that up to 41% of patients with “high probability of APA” and normal adrenal CT scan prove to have unilateral aldosterone secretion. Idiopathic Hyperplasia (IHA) adrenal glands may be normal on CT or show nodular changes. Aldosterone-producing adrenal carcinomas are very rare and always above 4 cm in diameter and have an inhomogenous imaging phenotype on CT. In our experience CT imaging that indicates a unilateral unequivocal adrenal tumor >1 cm with a normal contralateral gland is consistent with
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adenoma. 98% of patients with unilateral adrenal tumors that underwent adrenalectomy had improvement in their hypertension, and 100% had resolution of their hypokalemia. Biochemical cure was achieved in over 95% of patients with a normalization of aldosterone levels postoperatively. Nevertheless, adrenal CT scan is not always accurate in distinguishing between APA and IHA, particularly for small adrenal lesions less than 1 cm in diameter. In addition, in some cases, CT may show normalappearing adrenals, minimal unilateral limb thickening, unilateral microadenomas or bilateral micro/macroadenomas, which are nonspecific findings and do not allow differentiation between APA and IHA. In those selected cases, additional testing is essential in order to differentiate between APA and IHA.
ADDITIONAL LABORATORY TESTS A PAC/PRA ratio >20 is highly sensitive and specific diagnostic laboratory test for PH. However, in borderline cases more extensive testing should be considered to confirm inappropriate aldosterone secretion. Confirmatory tests are based on the concept that aldosterone is secreted in an unregulated fashion in PH and therefore cannot be suppressed by the usual physiologic regulatory inputs. In a similar fashion, PRA is chronically and tonically suppressed and cannot be stimulated. There are several ways to measure aldosterone suppression, but the list of medications affecting the renin–angiotensin–aldosterone system axis is extensive (i.e. spironolactone, amiloride) and frequently falsifies the test results (Table 1). Notably, certain medications — like calcium channel blockers or α-adrenergic receptor blockers — do not interact with the measurement of aldosterone levels and therefore should be considered for primary treatment of hypertension in patients with suspected hyperaldosteronism, until the final diagnosis has been confirmed. In patients already receiving treatment with a mineralocorticoid receptor antagonist or high dose amiloride for hypertension, these agents should be discontinued at least six weeks prior to aldosterone level measurements. Keeping this in mind, several tests have been described to confirm the diagnosis of PH if necessary.
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Table 1 Effects of the main antihypertensives on the renin–angiotensin system following sustained treatment. Medication class
Plasma rennin activity
Aldosterone levels
Diuretics ACE I Angiotensin receptor blockers β blockers α blockers Direct vasodilators Central sympathetic agonists Dihydropyridine calcium channel blockers Non-dihydropyridine calcium channel blockers
↓ ↑ ↑ ↓ No effect No effect No effect ↑ or no effect
↑ ↓ ↓ ↓ No effect No effect No effect ↓
↑ or no effect
No effect
Measurement of PRA After Salt and Water In PH, PRA is less than 1 ng/mL/h and fails to rise above 2 ng/mL/h following salt and water depletion, furosemide administration or 4 h of erect posture. Captopril Suppression Test PRA and aldosterone levels are measured before and 2 h after administration of a single dose of captopril (25–50 mg). The test is considered positive if plasma aldosterone levels cannot be suppressed below 15 ng/dL. It has a sensitivity of 90–100% but a specificity of only 50–80%. Measurement of Serum Aldosterone Levels After three days of an unrestricted sodium diet and 1 h of full recumbency, healthy individuals have aldosterone levels of less than 15 ng/dL. When serum aldosterone is elevated above 22 ng/dL and renin is suppressed, the serum aldosterone test virtually confirms the diagnosis of PH. However, because aldosterone secretion is variable, the negative and the positive
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predictive value of a single random aldosterone level are limited. As many as 40% of patients with PH have serum aldosterone levels that remain within the reference range on repeat testing, as is typically the case in essential hypertension. Oral Sodium Loading Test After hypokalemia and hypertension are controlled, patients should receive a high sodium diet for three days, with a target sodium intake of 218 mmol of sodium (12.8 g of sodium chloride). On day 3, a 24 h urinary specimen is collected and aldosterone, creatinine and sodium levels are measured. To document adequate sodium repletion, the 24 h urinary sodium excretion should exceed 200 mmol. Urinary aldosterone excretion of more than 33 nmol/d in this setting is consistent with autonomous aldosterone secretion. Notably, potassium levels should be measured daily and replaced in those patients, since a high salt diet can cause kaliuresis and hypokalemia. Intravenous Salt Loading Test Another way of measuring aldosterone suppression is the intravenous infusion of 2 L of 0.9% sodium chloride solution over 4 h (intravenous saline infusion test). The patient’s blood pressure and heart rate are monitored during the infusion. At the completion of the infusion, blood is drawn and PAC levels are measured. Normal subjects show a suppression of PAC after volume expansion with isotonic saline (< 139 pmol/L, 5 ng/dL). Patients with primary aldosteronism do not suppress to less than 277 pmol/L (10 ng/dL). Notably, post-saline-infusion PAC values between 139 and 277 pmol/L (5 and 10 ng/dL) are indeterminate and can be seen in patients with IHA. Fludrocortisone Suppression Test Another less commonly used test is the fludrocortisone suppression test. Fludrocortisone acetate is administered orally for four days (0.1 mg every 6 h) in combination with sodium chloride tablets (2 g three times daily with food).
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Blood pressure, heart rate and serum potassium levels are monitored daily. On day 4 plasma aldosterone should be measured in the midmorning and the patients should be upright for at least 30 min prior to veinpuncture. Since patients with hyperaldosteronism are in a state of salt retention and excess sodium is lost in the urine, sodium loading with a sodium-retaining steroid will have no effect on plasma aldosterone (hence PAC <166 pmol/L or 6 ng/dL). Notably, increased QT dispersion on EKG and deterioration of left ventricular function have been reported during the fludrocortisone suppression test. Postural Stimulation Test APA is associated with an anomalous decrease in the aldosterone level with upright posture, in contrast to patients with IHA (in whom a renin–aldosterone-system-mediated increase in the aldosterone level occurs with upright posture). Moreover, a serum aldosterone surge is expected in patients with renin-responsive adenomas (RRAs) and low renin essential HTN. When abdominal CT and magnetic resonance imaging (MRI) scans are combined with postural stimulation, the positive predictive value of an abnormal postural test in predicting surgically correctable PH due to a single adenoma is 98%. The standard postural test protocol involves obtaining baseline values of serum aldosterone and PRA levels, as well as the same parameters 2 h after the assumption of an erect posture. Serum aldosterone levels typically rise in this setting at least 50% above the baseline in healthy persons, in persons with essential HTN, and in the subgroup of patients with PH who have either IHA or RRAs. Among patients with APA, the aldosterone levels typically do not rise or paradoxically fall with postural stimulation. The sensitivity and specificity of this test in the differential diagnosis of the main causes of PH have been reported to be as high as 80 and 85%, respectively. Furosemide (Lasix) Stimulation Test This test is often combined with the upright posture test. It typically involves oral administration of 40 mg of furosemide on the night before
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and the morning of the test. On the morning of the test, the patient remains standing upright for 2–3 h, then the PRA and serum aldosterone levels are assessed. Normally furosemide stimulates PRA within 4 h because of natriuresis and therefore produces an increase in the aldosterone level of at least 50% from the baseline in healthy individuals. Failure to do so is suggestive of PH. Diurnal Rhythm of Aldosterone The circadian rhythm of aldosterone secretion in healthy individuals parallels that of cortisol and is ACTH-dependent. The lowest values are observed around 11:30 p.m. to midnight, and the highest values occur early in the morning, around 7:30–8 a.m. (assuming a normal sleep–wake cycle). While this is preserved in patients with aldosteronomas, it is typically lost in patients with IHA. Dexamethasone Suppression Test This test is relevant only in the setting of possible familial hyperaldosteronism type 1 (GRA). In patients with PH, dexamethasone causes a transient reduction of plasma and urinary aldosterone levels, although not into the reference range. In the subset of patients with familial hyperaldosteronism type 1, small doses of dexamethasone (1–2 mg/d) induce full normalization in plasma and urinary aldosterone levels. This is invariably associated with improvement in hypertension in such patients. Other reports suggest a cutoff level for plasma aldosterone of less than 4 ng/dL and/or a relative plasma aldosterone suppression of greater than 80% of the baseline to make a diagnosis of familial hyperaldosteronism type 1 postdexamethasone challenge. Type 1 familial PH is associated with improvement in HTN using low dose dexamethasone. Type 2 familial PH is not dexamethasone-suppressible. Metoclopramide (Reglan) Test This is a promising noninvasive test for distinguishing between APA and IHA. It takes advantage of the differential expression of the
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dopamine receptors on the cell membrane of adrenocortical cells. Under normal conditions, dopamine causes tonic inhibition of aldosterone secretion in vivo. This response is retained in patients with APA and in patients with low renin hypertension, but not in patients with IAH. Following a 10 mg intravenous injection of metoclopramide, serum aldosterone levels increase significantly in patients with APA, but they remain either unchanged or paradoxically reduced in patients with IAH. Therapeutic Trial of Spironolactone (Aldactone) This procedure is no longer used as a diagnostic test for PH because easier and more rapid alternatives exist. The therapeutic trial involves spironolactone administered orally at a dose of 100 mg four times per day for five weeks. A positive test is characterized by a decrease in diastolic blood pressure of at least 20 mmHg. Angiotensin-II Infusion Test This test involves evaluating the response of PRA and serum aldosterone to a continuous angiotensin-II infusion. The response characteristics are similar to those observed in the postural tests, with an appropriate increase in the aldosterone level observed in IAH but not in aldosteronomas. It is less popular because of the need for continuous infusion and close hemodynamic monitoring.
ADDITIONAL IMAGING STUDIES There are three further imaging studies used for differentiation and diagnosis of PH: adrenal venous sampling, NP-59 scintigraphy and MRI. Selective Adrenal Venous Sampling Selective adrenal venous sampling (AVS) is considered the gold standard for differentiating unilateral from bilateral disease in patients with primary aldosteronism (Fig. 2).
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Fig. 2 Adrenal venous sampling in a 51-year-old man with biochemically proven aldosteronoma. The angiogram shows the catheter, which was placed in the right adrenal vein (arrow) via the inferior vena cava. The adrenal veins were opacified by gentle hand injection of contrast material, thus confirming correct placement for adrenal venous sampling. Cortrosyn-stimulated aldosterone levels were four times higher on the left than on the right. The patient’s symptoms resolved after left adrenalectomy.
In AVS, blood samples for cortisol and aldosterone are obtained from both adrenal veins, and from the inferior vena cava. This can be performed either with or without simultaneous cosyntropin infusion. The objectives of the procedure are to cannulate both adrenal veins and then to measure the ratio of the adrenal vein to IVC cortisol and aldosterone. This ratio is typically more than 3:1 without the use and 10:1 with the use of simultaneous cosyntropin infusion. Notably, the right adrenal vein is often difficult to cannulate because of its short length originating directly from the IVC. The left adrenal vein
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originates from the renal vein and has a larger length. Lateralization of an aldosteronoma or unilateral adrenal hyperplasia is confirmed if the ratio of the adrenal vein aldosterone to cortisol is at least four times higher on one side compared to the contralateral side. If the ratios are similar, bilateral hyperplasia should be considered. The test characteristics of AVS for detecting APA have been reported to be 95% sensitive and 100% specific. Complications occur in 2.5% of cases and include groin hematoma, adrenal hemorrhage or dissection of the adrenal vein. In our experience AVS has to be repeated in 6.9% of cases as a result of inadequate sampling. We also found that with unstimulated selective AVS for tumors <1 cm or equivocal adrenal glands, the failure to laterize and achieve 4:1 ratios was significant. In our experience cosyntropic infusion should also be used for the following reasons: minimizing stress-induced fluctuations in aldosterone secretion during nonsimultaneous AVS, maximizing the gradient in cortisol from adrenal vein to inferior vena cava and thus confirming successful sampling of the adrenal vein, and maximizing the secretion of aldosterone from an APA. We therefore use cosyntropin infusion routinely in our practice. 50 µg of cosyntropin per hour are infused intravenously 30 min before AVS and continued throughout the procedure. AVS is used at our institution only when CT or MRI is equivocal, i.e. adrenal tumor less than 1cm in diameter, minimal unilateral limb thickening, unilateral microadenomas or bilateral micro/macroadenomas. (6β-131I)Iodomethyl-19-Norcholesterol Scintigraphy (NP-59 Scintigraphy) The NP-59 scan is performed with dexamethasone suppression (1 mg q6 h, starting seven days before the NP-59 injection) and continued throughout the scanning period. Imaging starts on day 4 after the NP-59 injection and may continue daily through day 10. Only a few centers in the US use NP-59 scintigraphy, since it is not approved by the FDA, and takes several days for imaging and interpretation. It also has been shown to have poor tracer uptake in small (<1.5 cm in diameter) adrenal nodules. Studies reported a sensitivity of up to 78% and a specificity of up to 90% for NP-59 scintigraphy in diagnosing PH.
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MRI It is generally accepted that CT and MRI have comparable performances in the detection of aldosterone-producing adenoma. Sensitivity and specificity range from 83 to 92% and 80 to 92%, respectively, for MRI in the detection of PH. Many centers prefer CT to MRI, due to the lower costs and higher availability.
SELECTED REFERENCES Moo TA, Zarnegar R, Duh QY. Prediction of successful outcome in patients with primary aldosteronism. Curr Treat Options Oncol 2007;8(4):314–321. Young W. Minireview: primary aldosteronism — changing concepts in diagnosis and treatment. Endocrinology 2003;144(6):2208–2213. Young W. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol 2007;66(5):607–618. Young WF Jr, Klee GG. Primary aldosteronism: diagnostic evaluation. Endocrinol Metab Clin North Am 1988;17:367–395. Zarnegar R, Bloom AI, et al. Is adrenal venous sampling necessary in all patients with hyperaldosteronism before adrenalectomy? J Vasc Interv Radiol 2008;19(1):66–71. Zarnegar R, Young WF Jr, et al. The aldosteronoma resolution score: predicting complete resolution of hypertension after adrenalectomy for aldosteronoma. Ann Surg 2008;247(3):511–518.
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Chapter III.B.1: Laparoscopic Adrenalectomy Avital Harari, MD and Quan-Yang Duh, MD
LAPAROSCOPIC TRANSABDOMINAL APPROACH Laparoscopic adrenalectomy is the gold standard in the resection of benign, hyperfunctioning adrenal tumors. It has less operative and perioperative morbidity than open adrenalectomy. Useful instruments for laparoscopic transabdominal adrenalectomy include atraumatic graspers, scissors, hemostatic devices such as LigaSure or Harmonic Scalpel, a clip applier, rolled sponges (“cigarettes”), a suction instrument, a rigid fan retractor, and a 30°-angled 5 or 10 mm endoscope. A tray of instruments for use in open procedures should be available (including a vascular curved clamp) in case of conversion.
Right Positioning Initially the patient is placed supine for intubation and placement of a Foley catheter. The patient is then turned to a lateral decubitus position with the right side up, at an approximately 80° elevation. The patient is supported in this position using a bean bag and back supports. The patient is then positioned so that the 10th rib is located just above the break point in the table. The torso is then flexed at the lower ribcage in order to elevate the kidney and the adrenal gland and in order to open the subcostal space for trocar placement. The arms are propped up in a natural “hugging” position in front of the patient using arm rests and pillows. All pressure points are padded. The body is secured to the table with wide tape over the patient’s chest, hips, and knees. 329
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Operative approach Four dilating-type 10 mm trocars are placed 1–2 cm subcostally, evenly spaced, between the midclavicular and the anterior axillary line. The most medial trocar (port 1) is placed first, with the Veress needle technique. Open trocar placement may be used if there are significant intra-abdominal adhesions from a prior operation. Pneumoperitoneum is established at 15 mmHg. The three additional trocars are then placed under direct vision. The surgeon and the assistant both stand facing the patient’s abdomen. The assistant stands closer to the patient’s head and holds the liver retractor (port 1) and the laparoscope (port 2). The surgeon uses ports 3 and 4 for dissection. At the end of the procedure, we usually extract the specimen through the most lateral port site or the site of a port that was placed using an open technique.
Anatomical considerations For a right adrenalectomy, a rigid fan retractor is used to retract the liver anteriorly. The retraction should be gentle to avoid tearing the liver capsule and/or causing a subcapsular hematoma. This is especially a concern in Cushing’s patients and in those with large or fatty livers. Adrenal venous anomalies can confuse the surgeon and become the source of intraoperative hemorrhage. In 90% of patients, there is a short single right adrenal vein that drains anteriomedially into the lateroposterior border of the IVC. However, 5% of patients have an anomalous adrenal vein that drains into the right hepatic vein or, rarely, into the right renal vein. In addition, 5% of patients have multiple adrenal veins. Therefore, dissection of the medial and inferior aspects of the adrenal gland needs to be systematic, precise, and bloodless, so that possible venous anomalies can be recognized and vein injury avoided. The upper pole branch of the renal artery can be tortuous and adhere to the adrenal gland. This can be mistaken for the inferior adrenal artery. Injury to the superior branch of the renal artery will cause ischemia of the upper pole of the kidney and subsequently cause renin-dependent hypertension. Therefore, when the adrenal gland is separated from the renal hilum, the plane of dissection should be right on the adrenal capsule.
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In addition, since the precision of vascular dissection is most crucial in the medial and inferior borders as described above, we prefer to use the L-hook cautery, blunt tip dissector, and cigarette sponges in these areas. Key steps of the procedure Once the ports are placed, the liver is retracted anteriorly with a fan retractor. The lateral liver attachments, the triangular ligament, and other adhesions between the liver and the anterior surface of the adrenal gland are taken down with cautery. We call this the “open book technique” to remind the surgeon to open the working space widely so that the adrenal gland and the kidney are seen lateroposteriorly and the liver and the IVC are seen medioanteriorly. The next step is to mobilize the right adrenal gland along the medial border. It is best to begin dissection at the surperiomedial aspect of the adrenal gland, where it is easily separated from the liver. The adrenal gland is retracted laterally by the surgeon using a cigarette sponge on a grasper through port 4. Dissection is done through port 3 using the L-hook cautery. The superior and superiomedial aspects of the adrenal gland are dissected down to the posterior muscle while the adrenal gland is retracted laterally, creating a V shape working space. At this point, the superior adrenal artery or arteries are identified and can be taken by cautery, clips, or other vessel-sealing devices. The dissection proceeds from anatomically known to unknown areas, down the tip of the V, in a clockwise direction, around the right adrenal gland. The most crucial and delicate step is the dissection along the lateral border of the IVC to identify the right adrenal vein. The dissection around all borders of the adrenal vein will effectively lengthen the adrenal vein and will help to avoid injury to the middle adrenal arteries located posterior to the right adrenal vein. The vein is then ligated with three 10 mm clips and transected, leaving two clips on the IVC side and one on the adrenal side. After cutting the right adrenal vein, the adrenal gland is further retracted laterally, and the tissues posterior to the vein, including the middle adrenal arteries, are taken with cautery. The next step is to carefully dissect the adrenal gland off of the renal hilum. The adrenal gland is lifted superiorly, and the inferior border is
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dissected. In the renal hilar area, the inferior adrenal artery or arteries are identified as they branch off the superior branch of the renal artery. The inferior adrenal artery is usually larger than the superior or middle adrenal arteries and may need to be clipped. Before clipping and dividing the inferior adrenal artery, it is important to dissect it up to the lower border of the adrenal gland and to be certain that it is not the superior branch of the renal artery, which may loop toward the adrenal gland before continuing into the upper pole of the kidney. Once the adrenal gland is dissected off of the renal hilum, the periadrenal tissue is taken off the mediosuperior surface of the kidney to complete the clockwise circumferential dissection of the adrenal gland. Here we usually use LigaSure, Harmonic Scalpel, or other vessel-sealing devices, because the dissection is faster and less vascular. After freeing the adrenal gland, the adrenal fossa is irrigated and inspected for hemostasis and for possible residual adrenal tissue. The freed adrenal gland is placed in a 4′′ × 6′′ impermeable nylon bag. Softer bags may break during extraction of the specimen and risk tumor implantation. The nylon bag is brought out through the most lateral port. The specimen is usually extracted piecemeal (“morcellated”) from the bag using a pair of ring forceps, under visualization via the endoscope. If the pathological diagnosis of the tumor requires an intact capsule, a port site incision is extended for specimen extraction. Otherwise the port site incisions are closed with subcuticular sutures. No fascial closure is necessary when dilating-type trocars are used. Intraoperative problems Bleeding from injury to the IVC or an anomalous vein may require conversion to an open operation. This is best prevented by anticipating the possibility of multiple adrenal veins or an anomalous adrenal vein draining into the right hepatic vein. Precise vascular dissection along the medial border of the adrenal gland is thus very important. The surgeon’s urge to immediately cauterize or place a clip in an area of bleeding should be tempered until the source of bleeding is clearly identified. Most of the time, minor bleeding can be controlled by direct pressure with the cigarette sponge. This can be followed by suction if
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necessary. We rarely use irrigation to find a bleeding site, because it tends to prolong the bleeding and distort the anatomy. Multiple changes of fresh sponges allow excellent hemostasis. Removing old blood clots, which absorb light, and using fresh white sponges both improve the illumination and help identify the source of bleeding. Arterial bleeding is usually controlled easily by clips. Minor venous bleeding from the adrenal gland or the adrenal bed generally stops with direct pressure. Superficial bleeding from the liver can be stopped with cautery. Bleeding from the stump of the main adrenal vein or IVC can be first controlled by direct pressure and then either reclipped or sutured. Adding another port to improve exposure or for suctioning can be useful. Allowing the liver down (i.e. releasing liver retraction) can also aid in tamponade of small IVC injuries. Bleeding that is difficult to control will require conversion to open operation (using a subcostal incision with the patient remaining in the lateral position). Other problems may require conversion to open operation. The tumor may be too large to be dissected laparoscopically. It may be too adherent, which raises concern about malignancy and local invasion. In general, the dissected specimen should remain en bloc and include periadrenal tissue. Breaching the capsule or fracturing the tumor risks seeding and recurrence even if the tumor is not a cancer. Other intraoperative complications may include injuries to abdominal viscera and pleural tears. Operating on obese patients may also prove to be difficult, in which case an additional fifth trocar may be placed just inferiorly to the other four ports. Furthermore, if it is difficult to identify the adrenal gland amongst the perirenal fat, intraoperative laparoscopic ultrasound may be useful.
Left Positioning/operative approach The patient is positioned similarly to that of the right adrenalectomy, at an 80° lateral decubitus position with the left side up. Four trocars are placed subcostally from the midclavicular line to the anterior axillary line in a mirror image to what is described above for a right adrenalectomy.
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Anatomical considerations The left adrenal gland has two surgically significant anatomical differences compared to the right adrenal gland. The lower border of the left adrenal gland is closer to the renal hilum than the right adrenal gland, and the adrenal venous anatomy is distinct. The main left adrenal vein drains from the anterior surface of the gland inferiorly into the superior border of the left renal vein. The inferior phrenic vein starts from the diaphragm, running inferiorly and medially to the left adrenal gland. It usually joins the medial border of the left adrenal vein before it drains into the left renal vein. This junction can be high, near the adrenal gland, or low, near the renal vein. Very rarely, the inferior phrenic vein drains directly into the left renal vein without joining the left adrenal vein. This vein can be injured during dissection of the medial border of the left adrenal gland. When the left adrenal vein is elusive during adrenalectomy, it can be found in one of three ways. The superior approach first identifies the inferior phrenic vein and then traces it inferiorly and laterally to find where it joins the left adrenal vein. The inferior approach first identifies the left renal vein. The surgeon can then find the left adrenal vein where it drains into the superior border of the left renal vein. The third way is to use the splenic vein. After the spleen is rotated medially, the splenic vein is found running along the back of the pancreas. The imaginary straight line traced by the splenic vein medially on the pancreas and then laterally onto the adrenal will cross the left adrenal vein running vertically.
Key steps of the procedure After placing the four subcostal trocars as described in the right adrenalectomy section, the first step is to perform a medial visceral rotation of the spleen and the tail of the pancreas. The splenic flexure of the colon as well as the lateral attachments of the spleen to the abdominal wall may need to be dissected before inserting the most lateral trocar. After the splenic flexure is mobilized, the colon is retracted medially and inferiorly. The spleen is then mobilized by dissecting the lateral attachments. This will allow the surgeon to enter the avascular plane
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between the splenopancreatic block anteriorly and the adrenal/kidney block posteriorly (again “opening the book”). The lateral attachments are dissected up to the diaphragm far enough to see the greater curvature of the stomach and the left crus of the diaphragm. The splenopancreatic block is easily retracted medially, initially with a fan retractor. Subsequently, gravity alone will allow it to fall medially. The left adrenal gland is dissected in a counterclockwise direction, beginning at the superiomedial aspect of the adrenal gland. The upper pole adrenal vessels are taken and the dissection is continued down to the posterior muscle, again creating a V pointing inferiorly, dissecting from known to unknown. As one dissects the adrenal gland medially, Gerota’s fascia is entered. The middle adrenal arteries are usually small and can be taken with cautery or LigaSure. As the medial border of the adrenal gland is dissected, the inferior phrenic vein is found running mediosuperiorly to lateroinferiorly, crossing the plane of dissection. The inferior phrenic vein is dissected around where it is convenient, and cut. The distal end is traced down toward the left adrenal vein. The left adrenal vein is usually dissected at a point inferior to the junction with the inferior phrenic vein. The left renal vein is usually seen where the adrenal vein drains into it, but it is not dissected. The left adrenal vein is then clipped and divided, leaving two clips on the renal vein side. The inferior dissection is initiated by lifting the adrenal gland off of the renal hilum — similar to the technique used in right adrenalectomies. Again, the inferior adrenal artery is dissected carefully to avoid injuring the superior branch of the left renal artery. Once freed inferiorly, the adrenal gland is dissected off the medial and superior aspect of the upper pole of the kidney, usually with a vesselsealing device, and freed from the lateral and posterior attachments to the surrounding fat. The specimen is then placed in a 4′′ × 6′′ nylon bag and extracted through the most lateral port. The extraction methods and port closure technique are described in the right adrenalectomy section. Intraoperative problems Intraoperative complications are similar to those described for laparoscopic transabdominal right adrenalectomies. Those specific to left adrenalectomy
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include injuries to the spleen and tail of the pancreas. Injury to the splenic capsule may lead to splenectomy. Also, the tail of the pancreas can be confused with the adrenal gland during dissection. If there is difficulty finding the medial border of the left adrenal gland during dissection, the surgeon may be dissecting in the wrong plane (i.e. anteriorly instead of posteriorly to the tail of the pancreas). Another specific concern is that when the adrenal is dissected medially, it is important to be inside of Gerota’s fascia. If one enters the wrong plane, one could injure the splenic hilum and cause significant bleeding. A high splenic flexure of the colon increases the risk of colon injury during dissection. Bleeding can also occur from the inferior phrenic vein during medial dissection. It can be controlled with direct pressure followed by clips. The left adrenal gland tends to be encased in retroperitoneal fat in obese patients and sometimes it may be difficult to identify the boundary of the adrenal gland. Laparoscopic ultrasound can be used to delineate the anatomy, but the most reliable way to find the adrenal gland is to follow the vascular anatomy as described above. Contraindications (for both left and right adrenalectomies) Contraindications to the laparoscopic procedure include large tumor size (greater than 8–10 cm in diameter) and invasive cancer. A large left adrenal tumor is easier to remove laparoscopically than a large right adrenal tumor. This is because the presence of the liver on the right and the shorter right adrenal vein tend to limit the exposure for right-sided tumors. Laparoscopic resection for cancer is controversial because of the risk of breaching the capsule leading to local recurrence and tumor dissemination. Adrenal cancer is aggressive and particularly fragile or easy to fracture, in contrast to metastatic cancers to the adrenal glands, which can often be safely resected laparoscopically. In addition, patients with the following high risk factors are usually dealt with via the open approach since they are more likely to be malignant: feminizing and masculinizing tumors, tumors in patients with a family history of adrenal cancer, tumors in patients with SDHB mutations, and tumors that have mixed secretions.
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Other possible contraindications include bleeding disorders, cirrhosis, and severe cardiovascular or respiratory diseases which are general contraindications for laparoscopic surgery.
RETROPERITONEAL LAPAROSCOPIC APPROACH The retroperitoneal approach to laparoscopic adrenalectomy works well for small adrenal tumors. It is less likely to injure abdominal organs, since the dissection is limited to the retroperitoneum. It is particularly good for patients who have had previous abdominal operations and may have intraperitoneal adhesions. Positioning The same positioning is used for both unilateral (right or left) and bilateral retroperitoneal adrenalectomies. The patient is intubated and the Foley catheter is placed while the patient is supine on the stretcher. The patient is then flipped over to the prone position onto the surgical table, lying over two large bolsters that are situated under the chest and hips, allowing space for pannus to lie in between. The table is flexed to flatten the back and to expand the retroperitoneal space. The hips and knees are flexed with the lower legs on extension, horizontal to the floor. The patient’s face is protected with a mask. For small patients the body should be moved to the edge of the table on the side of the adrenalectomy. The arms are placed above the patient’s head and flexed at the elbows. All pressure points are padded. Operative Approaches The instruments/tools needed for this approach differ slightly from those of the transabdominal approach. Essential items are a 5 mm, 30° scope; 5 mm LigaSure (or a similar vessel-sealing device); two 5 mm, disposable, blunt entry ports; one 10 mm, donut-shaped, blunt balloon port; intraoperative ultrasound; and an Endocatch bag. For both unilateral and bilateral adrenalectomies, the patient’s back is prepped and draped from midribcage to just above the buttocks and as far laterally as possible. Ports are placed on the same side of the adrenal to
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be removed. The skin incisions are roughly placed in a horizontal line, 4–5 cm inferior to the inferior edge of rib 12. First, the central port (a 10 mm balloon port) is placed midway between the paraspinal muscle and the lateral edge of the patient. It is inserted with an open direct cut-down technique, using Metzenbaum scissors, aiming obliquely and entering the retroperitoneal space just under the rib. This opening is expanded by spreading with the Metzenbaum scissors as they are withdrawn. A 5 mm lateral port is placed as far laterally as possible. With a finger through the central incision, the surgeon feels and guides the entry of a blunt 5 mm port through the fascia. A similar technique is used to insert the medial port on the lateral edge of the paraspinal muscle. After inserting the 5 mm ports, the central 10 mm balloon port balloon is inserted and inflated. The retroperitoneum is insufflated to 18–20 mmHg CO2. The surgeon and the assistant both stand on the side of the adrenal to be removed. Anatomical Considerations Without external reference points, the retroperitoneal space can be disorienting initially, but with time the view becomes familiar. The space of dissection is bounded by peritoneum (laterally), paraspinous muscle (medially), kidney/adrenal/peritoneum (anteriorly), and the ribcage (posteriorly). The superior pole of the kidney is the major landmark and focus point for the dissection. The right adrenal vein drains from the medial side (i.e. paraspinous muscle side) of the adrenal gland into the vena cava. The left adrenal vein is joined by the phrenic vein, and drains the adrenal gland from the medial–inferior corner of the gland. There is often a tongue of adrenal tissue that extends inferior to the adrenal vein and should be dissected. To better understand these relationships, it is helpful to visualize the view of the adrenal veins from the lateral transabdominal approach as described above. Key Steps of the Procedure After port placement, a 30°, 5 mm laparoscope is inserted through the center port. A blunt instrument (a bowel grasper or a laparoscopic peanut)
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and a LigaSure are inserted through the two side ports, entering Gerota’s fascia. These are used to bluntly dissect the filmy tissue of the retroperitoneal space. The boundaries of the dissection are the peritoneum laterally, the perirenal fat anteriorly, and the paraspinous muscles medially. The diaphragm is at the apex of the retroperitoneal space. The perirenal fat is gently dissected to find the upper pole of the kidney. The upper pole of the kidney is dissected from laterally to medially, separating it from the inferior border of the adrenal gland. This allows the kidney to be rotated inferiorly and medially, allowing better visualization of the inferior adrenal border. This plane is relatively avascular. The adrenal gland can be dissected either before or after ligating the adrenal vein, but the superior attachment should be left to keep the adrenal gland suspended until nearly the end of the operation. The filmy attachments of the periadrenal fat to the peritoneum and paraspinous muscles are divided using a combination of blunt and sharp dissection. The periadrenal dissection usually begins laterosuperiorly, then proceeds laterally, then inferiorly, before dissecting and ligating the medial vessels. Medially, the dissection of the adrenal gland off of the renal hilum is facilitated by dissecting the attachments of the adrenal gland to the paraspinous muscles until halfway up the gland. This maneuver helps to uncover and define the inferior vena cava on the right side and the phrenic vein on the left. During this dissection, the adrenal arteries are encountered and can be divided with a vessel-sealing device. The adrenal vein is ligated using either clips or an energy-sealing device. On the left, the phrenic vein is usually preserved, but may be divided as needed. Before cutting the left adrenal vein, it is grasped next to the gland so that it can be subsequently used as a handle to retract the gland for final dissection of the superior attachment. An Endocatch bag is used to extract the gland. A high retroperitoneal pressure of 18–20 mmHg is maintained through the operation to keep the retroperitoneal space open and to tamponade minor bleeding. The pressure is lowered to 12 mmHg at the end of the dissection to check for bleeding. The middle port incision is closed with a figure-of-8 fascial stitch. Then, all three port sites are closed with subcuticular sutures.
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Intraoperative Problems Most of the areas of dissection in this operation are filmy and avascular. If the surgeon encounters bleeding or finds that he or she is dissecting through fat, it might indicate that the plane of dissection is incorrect. Most bleeding during dissection can usually be controlled by transiently increasing the insufflation pressure to 30 mmHg. Major bleeding may require conversion to open operation via a subcostal incision to enter the retroperitoneum. Elective conversion may be necessary, if the dissection is difficult or the anatomy is not clear. In such cases, the skin incisions can be closed and the patient flipped to the supine position to continue the procedure transabdominally. Contraindications Contraindications to laparoscopic retroperitoneal adrenalectomy are similar to those to laparoscopic transabdominal adrenalectomy. Those specific to this technique, however, include body mass index (BMI) >40 (a large pannus can make it difficult to create a large-enough retroperitoneal working space), large tumors (>6 cm), and large adrenocortical cancers.
SELECTED REFERENCES Novick A, et al. (eds.). Laparoscopic adrenalectomy. In: Operative Urology at the Cleveland Clinic (eds.) Novick AC, et al. Cleveland Clinic Foundation, p. 23. Strebel R, et al. Intraoperative complications of laparoscopic adrenalectomy. World J Urol 2008;26:555–560. van Heerden JA, Farley D. Adrenal surgery:tribute to a friend. Oper Tech Gen Surg 2002;4:277–345. Walz MK, et al. Posterior retroperitoneoscopic adrenalectomy: lessons learned within five years. World J Surg 2001;25(6):728–734. Walz MK, et al. Posterior retroperitoneoscopic adrenalectomy — results of 560 procedures in 520 patients. Surgery 2006;140(6):943–948. Yeh M, Duh Q. The adrenal glands. In: Sabiston Textbook of Surgery, 18th Edn. (eds.) CM Townsend, Jr., Beauchamp, et al. Elsevier, 2008, pp. 1024–1026.
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Chapter III.B.2: Preoperative and Perioperative Management of Adrenal Lesions
Tricia A. Moo-Young, MD and Richard A. Prinz, MD
OVERVIEW Approximately 15% of adrenal incidentalomas are functional. Functional tumors produce adrenally derived hormones independent of the hypothalamus–pituitary–adrenal axis. Prior to surgical resection, a biochemical workup is completed to determine if the adrenal mass is functional. A subclinical endocrinopathy can be present which can make preoperative and perioperative management of these patients challenging for the clinician and dangerous for the patient. Once a functional adrenal lesion is identified and the decision for surgical resection is made, preoperative optimization and perioperative monitoring and management are tailored to the specific endocrinopathy present. In this chapter, we will discuss the operative preparation and postoperative care of patients with pheochromocytoma (catecholamine excess), Conn’s syndrome (hyperaldosteronism), and Cushing’s syndrome (hypercortisolism). Lastly, because surgical resection can result in post-operative adrenal insufficiency, we will review the presentation and treatment of this condition.
PHEOCHROMOCYTOMA Preoperative Considerations Pheochromocytomas are rare neuroendocrine tumors, representing approximately 5% of all functional adrenal masses. They arise from
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catecholamine-producing chromaffin cells of the adrenal medulla. Ten percent of pheochromocytomas are located extra-adrenally. Most adrenal pheochromocytomas secrete norepinephrine, epinephrine, or a mixture of the two. Extra-adrenal pheochromocytomas secrete only norepinephrine because they lack phenylethanolamine-N-methyltransferase, which is the enzyme necessary for the conversion of norepinephrine to epinephrine. The release of high concentrations of catecholamines into the systemic circulation can cause episodes of either sustained or “paroxysmal” hypertensive crisis. Pheochromocytomas contain exceedingly high levels of catecholamines. The average norepinephrine content within a pheochromocytoma is 1.76 × 106 pg/g tissue and clinical studies have shown that these tumors release about 53% of their catecholamine content daily. This represents an excess of more than 1000 times normal plasma levels. In the preoperative period the main goal is to optimize the patient’s cardiovascular status and to minimize the chance of having a surgery-induced catecholamine “storm.” To achieve these goals it becomes important to (1) assess the patient’s cardiovascular status, (2) normalize the blood pressure and heart rate, and (3) restore the intravascular volume. Cardiovascular assessment Patients with pheochromocytomas often have cardiovascular sequelae that require preoperative evaluation. Assessment of a patient’s functional capacity begins with a thorough history. If indicated, appropriate diagnostic testing can be ordered. The most common cardiovascular disorder seen in pheochromocytoma patients is hypertrophic cardiomyopathy. Chronic exposure to catecholamine excess can lead to a dilated cardiomyopathy and associated ventricular failure. This is rare, because most patients come to medical attention before these long-term complications develop. At a minimum, all pheochromocytoma patients should have a 12-lead electrocardiogram prior to surgery. Electrocardiogram abnormalities are a common finding in patients with pheochromocytomas. Most of the findings are the result of the underlying myocardial hypertrophy and include elevated QRS amplitudes, abnormal R wave, ST segment changes, and T wave changes. Further cardiac workup is necessary only if the patient exhibits signs of decreased functional status or has other
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associated comorbidities, such as a history of myocardial infarction or congestive heart failure. Preoperative blockade Despite the lack of substantial scientific evidence, it is generally accepted that all patients with a biochemically active pheochromocytoma should receive α-adrenergic blockade prior to surgery. The objective of this strategy is to reduce the incidence and magnitude of intraoperative blood pressure fluctuations and development of arrhythmias. There is not a consensus for when adrenergic blockade should begin but at most institutions therapy is initiated at least 7–14 days prior to the operation. Normotensive patients can become hypertensive during surgery and thus should also be given α-adrenergic blockade preoperatively. Phenoxybenzamine, a long-acting noncompetitive α-adrenergic antagonist, is the most common agent used to achieve preoperative adrenergic blockade. The initial dose is usually 10 mg twice daily and is increased in increments of 10–20 mg every second or third day. A total daily dose of 1 mg/kg is usually sufficient for most patients. Adequately blocked patients should demonstrate evidence of the following criteria: (1) blood pressure no higher than 160/90 mmHg within the 24 h prior to surgery; (2) presence of orthostatic hypotension; (3) no ST–T wave changes on EKG for one week preoperatively; and (4) no more than one premature ventricular contraction every 5 min. Poor perioperative outcomes have been documented in patients who did not meet these criteria prior to undergoing surgical resection. Since most patients are now prepared in the outpatient setting, such strict criteria are rarely met. Presently most clinicians titrate the dose according to the patient’s orthostatically associated symptoms. Close monitoring of blood pressures during dose escalations is advised and initiation of or increases in dosages should be taken around bedtime so as to avoid the dangers of daytime presyncopal symptoms. As phenoxybenzamine doses are escalated most patients will experience a reflex tachycardia. This is best managed by adding a β-blocker such as propranolol. A β-blocker should never be administered prior to the use of an α-blocker. This is because β-blockade can cause severe vasoconstriction and hypertension due to inhibition of the
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vasodilator action of epinephrine. A cardioselective β1-blocker, such as atenolol or metoprolol, can be given in place of the nonselective β-blocker propranolol. Caution should still be exercised when using these agents, and again they should not be administered in the absence of appropriate α-blockade. Generally, combined α- and β-antagonists, such as labetalol, are not felt to be good first-line agents for achieving preoperative blockade, because these drugs have a fixed ratio of α- and β-blockers and thus do not allow fine-tuning to the individual patient and tumor-specific needs. Other α-adrenergic antagonists include prazosin, terazosin, and doxazosin. These agents have a shorter duration of action and decreased incidence of reflex tachycardia and postoperative hypotension. All of these agents still have the potential to produce severe postural hypotension. Calcium channel blockers are another option for preparing patients preoperatively. As a single agent they may be inferior to α-blockade and most clinicians do not use them as first-line therapy. Calcium channel blockers are felt by some to be appropriate under the following circumstances: (1) as an adjunct to α-blocking agents to minimize the need for escalating doses of phenoxybenzamine or to reduce catecholamineinduced coronary vasospasm; (2) as an alternative therapy in patients who cannot tolerate the side effects of phenoxybenzamine, and (3) to prevent α-blockade-induced sustained hypotension in patients with only paroxysmal hypertension. Agents that inhibit catecholamine synthesis, such as metyrosine, have been used by some to achieve appropriate preoperative hemodynamic stability. Their use requires treatment to begin a minimum of 1–3 weeks prior to surgery in order to achieve satisfactory intraoperative outcomes. Some studies comparing metyrosine in combination with α-blockers to α-blockers alone have shown significant intraoperative reductions in blood pressure lability, blood loss, and need for volume replacement during surgery. The main limitations of metyrosine are its lack of widespread availability and patient tolerance of associated side effects. If it is prescribed, patients must be educated about the drug’s potential to cause sedation, depression, galactorrhea, extrapyramidal side effects (i.e. parkinsonism), diarrhea, and crystalluria at higher doses. Metyrosine can be a useful alternative in patients who have very
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active tumors with difficult-to-treat symptoms that are refractory to standard α-adrenergic blockade. A summary of the various agents, their initial doses, and associated side effects is shown in Table 1. Volume repletion Normalization of the patient’s volume status preoperatively minimizes the occurrence of protracted hypotension or shock that results from sudden diffuse vasodilatation at the time of tumor removal. Preoperative hydration helps counteract the symptoms of orthostatic hypotension as phenoxybenzamine expands the intravascular space through blockade of α-receptors. If the patient requires inpatient admission, a continuous infusion of saline for a total dose of 1–2 liters is initiated just prior to the operation. For outpatients a high-salt diet and vigorous oral intake are used to assist with volume repletion. Neither strategy has been studied in a randomized controlled setting. Perioperative monitoring In addition to preoperative preparation of the patient, it is essential to involve an anesthesiologist experienced in the intraoperative management of patients with pheochromocytoma. Continuous arterial and central venous pressure monitoring is achieved through the use of radial artery and central line placement. Because even preoperative emotional stress and the induction of anesthesia can precipitate catecholamine release from the tumor, patients will often be given an anxiolytic prior to transfer to the operating room. During the procedure the anesthesiologist and surgeon must be in constant communication regarding the patients’ hemodynamic stability and the progress of the surgery. Manipulation of the gland will precipitate release of catecholamines, which can result in hypertensive surges. The anesthesiologist may require a “hands-off” of the gland to allow time for the administration of intravenous antihypertensives and to regain control of the patient’s hemodynamics. When the hypertension is not controlled, bleeding from numerous small vessels occurs, making the operation technically more challenging for the surgeon. Once vascular control of the gland is attained, the patient must be monitored for hypotension.
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Table 1 Commonly used drug classes in the preoperative blockade of pheochromocytoma patients. Drug class
Initial dosage
Indications for usage
Duration of effect
10 mg BID; raise in 10 mg increments every 2–3 days 2–5 mg BID or TID
First-line therapy, but limited by reflex tachycardia, postural hypotension First-line therapy, but also causes postural hypotension
3 days
20–80 mg TID
Treat reflex tachycardia of α-blockers Treat reflex tachycardia of α-blockers
8h
α-adrenoceptor antagonists Phenoxybenzamine
Prazosin
10 h
β-adrenoceptor antagonists* Propranolol (nonselective) Atenolol (β1-selective)
12.5–25 mg TID
24 h
Calcium channel blockers Amlodipine
10–20 mg daily
Alternative or adjunct to α-blockade, reduces need for higher doses of phenoxybenzamine, benefit for reduced catecholamine-induced coronary vasospasm
30–50 h
250 mg Q8–12 h; 1–3 weeks of treatment
Not widely available, extrapyramidal side effects, not yet tested in clinical studies
14–24 h
Catecholamine synthesis inhibition Metyrosine
*A β-blocker should never be used in the absence of an α-adrenoceptor blocker, because of the risk of unopposed epinephrine-induced vasoconstriction.
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This can usually be managed with fluid administration and the judicious use of vasopressors.
Postoperative Considerations Immediately following resection of a pheochromocytoma, the surgeon must be concerned about the development of hypotension and hypoglycemia. Hypotension can be a result of three situations occurring in isolation or in combination: (1) hypovolemia, (2) residual effects of the α-adrenergic blockade (phenoxybenzamine), and (3) hemorrhage. In the first 24–48 h following removal of the gland, an increase in venous capacitance from ongoing α-adrenergic blockade may blunt the patient’s vasconstrictive response to hypovolemic shock. Thus, the only signs of hemorrhage in a postoperative pheochromocytoma patient may be worsening tachycardia, decreased urine output, and altered mental status. Management of postoperative hypotension should start with intravenous fluid replacement. Pressors should not given until other causes of hypotension are excluded. That said, it is not uncommon for patients in the immediate postoperative period to need transient blood pressure support with vasoactive agents once the source of excess catecholamines has been removed. Hyperglycemia may be present preoperatively and intraoperatively as a result of catecholamine excess. The insulin-producing islet cells of the pancreas are under inhibitory control by α2-receptors. With catecholamine excess, patients can develop a relative hypoinsulinemia that leads to hyperglycemia. Postoperatively, patients may develop a profound hypoglycemia as a result of a rebound hyperinsulinemia that occurs with removal of the inhibitory catecholamine effect. Additionally, in these patients, liver glycogen stores may be severely depleted because catecholamines promote glycogen breakdown. Thus their ability to respond acutely to the hypoglycemia is impaired. It is unpredictable which patients will develop hypoglycemia, so pheochromocytoma patients are usually placed on a prophylactic dextrose infusion postoperatively.
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HYPERALDOSTERONISM Perioperative Considerations and Medical Management of Primary Hyperaldosteronism Bilateral idiopathic hyperplasia (60–70%) and aldosterone-producing adenomas (35%) are the two most common subtypes of hyperaldosteronism. The remaining subtypes — (unilateral adrenal hyperplasia (2%), carcinoma (<1%), familial hyperaldosteronism types I and II (<1%), and ectopic tumors) — are seen less frequently. Patients with aldosteroneproducing adenomas (APAs) are managed surgically, while those with bilateral idiopathic hyperplasia (BIH) are managed medically. Because of this, differentiating between these two disease processes is extremely important. APAs are usually unilateral, small, and benign, so laparoscopic removal of the entire gland is recommended. As mentioned in the previous section on pheochromocytomas, cardiac evaluation of these patients should be tailored to the duration of chronic hypertension and the associated comorbidities of the patient. Typically, aldosteronoma patients are younger and diseases associated with advanced age are less likely. Preoperative preparation of these patients includes correcting the associated hypokalemia and ensuring that the patient’s blood pressure is under reasonable control. The degree of hypokalemia in these patients can be profound (mean 2.9 mmol/L), and thus potassium levels should be checked in close proximity to the operation so that deficits can be replaced prior to surgery. Hypokalemia is associated with increased myocardial cell excitability and a higher risk of arrhythmias during anesthesia. It can be corrected with oral and/or intravenous potassium supplementation or with a mineralocorticoid receptor antagonist. Mineralocorticoid receptor blockers are first-line agents in both the preoperative preparation of patients with an aldosterone-producing adenoma and the medical management of those with bilateral idiopathic hyperplasia. Spironolactone, a potassium-sparing diuretic, is the most commonly used mineralocorticoid antagonist. Doses start at 25–50 mg per day and then can be titrated up to 800 mg per day based on the correction of hypokalemia and the need for only minimal potassium supplementation. Other agents include potassium canrenoate and eplerenone, both of which are metabolites of the parent drug, spironolactone. The benefit of
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these drugs is that they assist in controlling blood pressure while also correcting the hypokalemia. Spironolactone and its associated derivatives work by antagonizing aldosterone at the level of the mineralocorticoid receptor. The hypokalemia usually corrects quickly but the hypertension can take up to six weeks to resolve. Titration of the medications is done weekly and patients usually require doses between 400 and 800 mg daily. Eplerenone is typically started at doses of 25 mg and given twice daily, due to its shorter half-life. It has a 60% higher potency than spironolactone and a lower risk of side effects. It is, however, more expensive and currently clinical evidence supporting its efficacy or benefit when compared to spironolactone is lacking. In addition to the mineralocorticoid antagonists, patients with BIH are also managed with sodium channel antagonists. The two most commonly used are amiloride and triamterene. In hyperaldosteronism there is an upregulation of distal tubular sodium channels, which results in increased sodium resorption. Sodium channel antagonists reduce the resorption of sodium and promote a blood-pressure-lowering natriuresis. They are generally well tolerated in patients, mainly because they lack the sex steroid side effects of spironolactone. Other antihypertensives include calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, but these have been less well studied in the treatment of BIH. Postoperatively, aldosteronoma patients should have their potassium levels rechecked and their blood pressures closely monitored. All potassium supplementation should be withdrawn, mineralocorticoid antagonists discontinued, and antihypertensive therapy reduced if possible. The serum potassium levels correct quickly and thus postoperative fluids should not contain potassium. If not monitored appropriately, a rebound hyperkalemia can develop postoperatively because of chronic suppression of the renin–angiotensin–aldosterone axis. For this reason consensus statements have suggested placing patients on a high-salt diet postoperatively and monitoring weekly potassium levels for at least the first month following surgery. The blood pressure typically takes 1–6 months to normalize or show maximal improvement. Persistent hypertension, however, is not uncommon following surgery. Approximately one third of patients will achieve complete normalization of blood pressure
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and no longer require pharmacologic adjuncts. Predictors of which patients will have persistent hypertension postoperatively include having more than one first-degree relative with hypertension, use of more than two antihypertension agents, older age, renal dysfunction, and duration of hypertension.
CUSHING’S SYNDROME (HYPERCORTISOLISM) Perioperative Considerations Cushing’s syndrome can be the result of pituitary disease (>70%), adrenal adenoma (10%), ectopic-ACTH-secreting tumor (10%), adrenocortical carcinoma (8%), or adrenal hyperplasia (2%). Regardless of the source of hypercortisolism, there is an associated increased risk of mortality that is fourfold higher than for the general population. The systemic complications of hypercortisolism which account for this increased risk are collectively referred to as the “metabolic syndrome.” Patients will develop extensive central obesity, systemic hypertension, insulin resistance, hyperlipidemia, and a thrombotic diathesis. Cushing’s syndrome patients can have severe underlying cardiovascular and renal disease. Prior to the operation, patients should undergo a complete cardiovascular evaluation. The interpretation of a patient’s cardiovascular performance based upon their functional status is limited by the musculoskeletal disease that commonly occurs with chronic cortisol excess. If patients have activity limitations because of complications such as osteoporosis, alternative methods of evaluating their cardiovascular status should be initiated where appropriate. Often patients will be on several different diabetic or blood pressure medications at the time of diagnosis. These medications should be optimized prior to the operation. The integrity of tissue chronically exposed to elevated cortisol levels is diminished. Thus operative blood loss may be increased because blood vessels are fragile and easily torn. Anemia in a patient with known cardiovascular disease should be addressed preoperatively to help minimize the risk of cardiovascular complications. In the perioperative period, the avoidance of poor glycemic control and hypocortisolism are of primary concern. Plasma cortisol concentrations promptly decrease after the affected adrenal gland is
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removed, so intraoperative replacement therapy is necessary. The anesthesiologist will usually give an intravenous infusion of cortisol (100 mg) at the start of the case. In rare circumstances, hypercortisolism can be difficult to control and the patient’s medical condition will continue to deteriorate as a result. These patients and those felt medically unfit for surgery can be brought under control using steroid synthesis inhibitors. Examples of such agents are metyrapone, ketoconazole, mitotane, and etomidate. Metyrapone is a single-enzyme inhibitor that selectively blocks the 11 β-hydroxylase enzyme responsible for the conversion of 11-deoxycortisol to cortisol. It is effective in all forms of hypercortisolism and daily dosage ranges between 500 mg and 6 g. As result of its effects on cortisol production, ACTH can become severely elevated in these patients. Patients may display symptoms of mineralcorticoid excess and in women hirsutism may develop. Ketoconazole, mitotane, and etomidate are all multiple-enzyme inhibitors. The antifungal agent ketoconazole can cause gynecomastia when taken in high doses. This side effect is what led to the discovery of its properties of steroid synthesis inhibition. The synthesis of cortisol and testosterone is blocked by ketoconazole. The effectiveness of cortisol blockade is entirely dose-dependent and reversible. Recovery from steroid blockade takes place within 8–16 h of oral ingestion. It is generally well tolerated and safe for administration both in children and during pregnancy. Clearance of the drug occurs primarily through hepatic metabolism and thus should be used with caution with known liver dysfunction. Its ease of use and general tolerance by patients have made it the most widely used medication in the preoperative and long-term management of Cushing’s syndrome. Daily doses vary between 200 and 1200 mg, typically given in four divided doses. Mitotane, another multiple-enzyme inhibitor of cortisol, is a derivative of the insecticide DDT. Its effects on steroid biosynthesis were discovered in 1949, when dogs receiving the medication were noted to develop adrenal atrophy and severe adrenocortical insufficiency. Its exact mechanism of action is unclear. The primary action is thought to be its induction of mitochondrial degeneration and resultant adrenocortical atrophy and necrosis. This property is what makes mitotane superior to the other agents in the treatment of adrenocortical cancer. Mitotane is usually started at a daily dose of 1 g and then gradually
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increased to doses between 4 and 6 g daily. The most notable side effect of mitotane therapy is a propensity to cause severe adrenocortical insufficiency. During therapy patients are placed on high-dose glucocorticoid replacement and the drug levels should be closely monitored. Etomidate, a commonly used induction agent of general anesthesia, is a potent inhibitor of the 11-hydroxylase enzyme. It is the only steroid synthesis inhibitor that can be given parenterally. It is the treatment of choice for control of hypercortisolism in critically ill patients unable to take oral medications. The onset of action is very rapid (<1 min) and its half-life is only 3–5 h. The drug is administered as a continuous infusion with nonhypnotic doses ranging between 0.2 and 0.6 mg/kg/h. The infusion is titrated according to the decline in serum cortisol levels. Once the cortisol levels are brought within a physiologic range, some patients may require hydrocortisone supplementation to avoid the development of adrenal insufficiency. Etomidate has been used successfully to treat patients with acute physiologic decompensation as a result of Cushing’s syndrome. Patients presenting with acute peritonitis, a severe steroid psychosis, or eminent hepatic failure can often be acutely managed with etomidate until definitive therapy can be instituted. Associated side effects of the drug include mild hypotension, respiratory depression, nausea, and myoclonus. Postoperative Considerations Following their operation patients can develop adrenal insufficiency. A condition if left untreated can be rapidly fatal. Transient hypocortisolism and associated adrenal insufficiency occurs in approximately three quarters of patients postoperatively. Predicting which patients are at the highest risk of developing adrenal insufficiency is difficult and no clinical parameter has been found to be a reliable indicator. Among adrenalectomy patients, only those with overt or subclinical Cushing’s syndrome require steroid replacement. An exact algorithm for dosing and duration has not been established. A commonly used regimen involves giving patients 100 mg intravenous hydrocortisone every 8 h on postoperative day 1, followed by a three-day taper on oral prednisone to a maintenance dose of 5 mg daily. Some have stated that these doses are higher than necessary. For patients who have a unilateral adrenalectomy, steroids are tapered off
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over a course of six months to one year. During this period, patients are at the highest risk of perioperative infectious complications so they should be closely monitored for any signs or symptoms suggestive of a developing infection. Should an infection develop, patients will need appropriate stress dosing of their steroid medications, which can be tapered back to a maintenance dose once the infection has resolved. Because of the chronic steroid exposure and need for postoperative supplementation, Cushing’s syndrome patients may develop wound healing complications postoperatively. Although clinical evidence is lacking, prophylactic administration of vitamin A to these patients may counteract the catabolic effects of excess steroids on wound healing.
ADRENAL INSUFFICIENCY In patients who develop adrenal insufficiency (AI), early recognition and treatment are the two key factors in reducing morbidity and mortality. The hypothalamic–pituitary–adrenal (HPA) axis is an important part of the physiologic response to stress. AI can be either primary or secondary. Primary causes include infection, sepsis, trauma, or, most commonly, adrenalectomy. Secondary AI results from exogenous glucocorticoid administration. Postoperative AI occurs in patients who have undergone either a unilateral adrenalectomy for a cortisol-secreting adenoma or in patients who have undergone bilateral adrenalectomy. Patients undergoing bilateral total adrenalectomy will need lifelong glucocorticoid and mineralocorticoid replacement after the normal perioperative steroid taper. Among patients taking exogenous glucocorticoids for a specific medical condition, the risk of developing AI perioperatively or during an acute illness is directly correlated with the dose and duration of their therapy. In general, a patient who has taken ≥20 mg/day of prednisone for at least five days is at risk of developing AI and should get appropriate stress dosing of their steroids perioperatively or during an acute illness. If a patient has been on such a steroid regimen for more than one month, their HPA axis can remain suppressed for up to 6–12 months after therapy is stopped. In patients on doses of prednisone of 5 mg or less, the amount of HPA suppression is not as clinically important and perioperative stress may not be necessary.
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The presentation of AI is largely dependent on the health of the patient. In chronic AI, patients typically complain of chronic fatigue, vague abdominal pain, nausea, and hyperpigmentation of the skin. Patients with AI can have a deficiency of both glucocorticoid and mineralocorticoid production. These patients may have symptoms associated with electrolyte disturbances and orthostatic hypotension. Patients presenting in adrenal crisis secondary to surgery, trauma, or infection will exhibit signs of hypotension, shock, and will die if left untreated. Any patient with unexplained cardiovascular collapse refractory to medical or pharmacologic therapy should be suspected of having AI and empirically started on replacement corticosteroids. The presence of AI is first suspected by the presence of hyperkalemia, hypoglycemia, and refractory hypotension. The diagnosis is confirmed by performing either a high- or low-dose ACTH stimulation test. Which test is preferable is unclear. Although evidence suggests that the low-dose test is more sensitive, the studies supporting this were based on parameters validated only in high-dose testing. The test is done by administering either 250 µg (high dose) or 1 µg (low dose) of synthetic ACTH intravenously. Plasma cortisol levels are measured at 0, 30, and 60 min. A test is considered abnormal if the change from the baseline is <9 µg/dL or if there is an absolute value of less than 18 µg/dL at 30 or 60 min. Treatment for these patients can be challenging. The first step in preventing an adrenal crisis is appropriate patient education. All patients should wear a medicine alert bracelet identifying them as adrenally insufficient. Some clinicians advocate that patients carry a prefilled glucocorticoid syringe for intramuscular injection when illness supervenes and oral augmentation is not an option. Standard glucocorticoid replacement is usually given as a twice-daily dose of 5–7.5 mg of oral prednisone. The equivalent oral dosing of hydrocortisone is 15–25 mg daily. Hydrocortisone results in serum cortisol levels that are highly variable and it is not used routinely by most endocrinologists. Prednisolone and dexamethasone both have longer pharmacologic half-lives and can result in inappropriately high nighttime glucocorticoid activity. Table 2 lists some of the commonly used corticosteroids along with their relative potencies and equivalent doses. Assessing the adequacy of replacement dosing is not straightforward. At present there are no reliable clinical tests to measure the sufficiency of
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Corticosteroid Cortisone Hydrocortisone Prednisone Prednisolone Methylprednisolone Dexamethasone Fludrocortisone
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Equivalent doses of common corticosteroids. Relative corticosteroid activity
Relative mineralocorticoid activity
Equivalent dose (mg)
Plasma half-life (min)
0.8 1.0 4.0 4.0 5.0 25–30 10
0.8 0.0 0.8 0.8 0 0 125
25 20 5 5 4.0 0.75 –
30 90 60 200 180 100–300 200
steroid replacement. In the long-term setting, as with bilateral adrenalectomy, these patients should be followed by an endocrinologist trained in assessing the adequacy of both glucocorticoid and mineralcorticoid replacement. Measuring a random serum cortisol level without knowing the exact time of preceding glucocorticoid administration is not useful in monitoring the effectiveness of glucocorticoid replacement. More reliable is an assessment of the patient’s clinical history, need for stress–dose adjustments between followup visits, and measurement of blood pressure and weight at each checkup. The incidence of adrenal crisis in patients on chronic replacement is approximately 3.3 per replacement year. The risk of crisis is statistically higher in primary AI and female patients. Most episodes of adrenal crisis are precipitated by alterations in replacement dosing or by the patient or primary physician not providing a dose adjustment during times of stress. For major surgery, trauma, or other severe illnesses, patients should be given an intravenous dose of hydrocortisone 100–150 mg at presentation and maintained on an every 8 h interval until the acute level of stress resolves. Following this the patient can be placed on a standard steroid taper as described above.
SELECTED REFERENCES Akiba M, Kodama T, Ito Y, et al. Hypoglycemia induced by excessive rebound secretion of insulin after removal of pheochromocytoma. World J Surg 1990;14:317–322.
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Bravo E, Tagle R. Pheochromocytoma: state-of-the-art and future prospects. Endocr Res 2003;24:539–553. Coursin D, Wood K. Corticosteroid supplementation for adrenal insufficiency. JAMA 2002;287:236–240. Kinney M, Narr B, Warner M. Perioperative management of pheochromocytoma. J Cardiothorac Vasc Anesth 2002;16:359–369. Lenders J, Eisenhofer G, Mannelli M, Pacak K. Pheochromocytoma. Lancet 2005;366:665–675. Mitchell J, Barbosa G, Tsinberg M, et al. Unrecognized adrenal insufficiency in patients undergoing laparoscopic adrenalectomy. Surg Endosc 2009; 23:248–254. Mulatero P, Stowasser M, Loh K, et al. Increased diagnosis of primary aldosteronism including surgically correctable forms in centers from five continents. J Clin Endocrinol Metab 2004;89:1045–1050. NIH State-of-the-Science Statement on management of the clinically inapparent adrenal mass (“incidentaloma”). NIH Consens State Sci Statements 2002 Feb 4–6;19(2):1–23. Pacak K. Approach to the patient: preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metabol 2007;92:4069–4079. Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. Nat Clin Prac Endocrinol Metabol 2007;3:92–102. Roizen M, Schreider B, Hassan S. Anesthesia for patients with pheochromocytoma. Anesthesiol Clin North Am 1987;5:269–275. Rossi H, Kim A, Prinz RA. Primary hyperaldosteronism in the era of laparoscopic adrenalectomy. Am Surg 2002;68:253–256. Sawka A, Young W, Thompson G, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med 2001;135: 258–261. Schuttler J, Westhofen P, Kania U, et al. Quantitative assessment of catecholamine secretion as a rational principle of anesthesia management in pheochromocytoma surgery. Anasthesiol Intensivmed Notfallmed Schmerzther 1995;30: 341–349. Shupak R. Difficult anesthetic management during pheochromocytoma surgery. J Clin Anesth 1999;11:247–250. Wong K, Schafer P, Schultz J. Hypokalemia and anesthetic implications. Anesth Analg 1993;77:1238–1260.
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Chapter III.B.3: Adrenal Cortical Cancer Daniel T. Ruan, MD and Matthew A. Nehs, MD
DIAGNOSIS OF ADRENAL CORTICAL CANCER Presentation and Physical Exam Findings The diagnosis of adrenal cortical cancer (ACC) begins with a thorough history and physical exam. Patients will often manifest the signs and symptoms of hormonal hypersecretion, if it is a functional adrenal cancer, or large symptomatic masses if it is nonfunctional (Table 1). Since many of the signs and symptoms of functional ACC are nonspecific, a high index of suspicion will aid in the diagnosis of these tumors.
Demographics • • • •
Incidence: Approximately 1% of all adrenal tumors; one person per million in the United States Median age range: 40–50 years Bimodal age distribution (increased in patients <5 years old and again in the 4th–5th decades of life) Male:female ratio — approximately 1:1
Hereditary Tumor Syndromes Associated with ACC • • •
Li–Fraumeni Beckwith–Wiedemann Congenital adrenal hyperplasia
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Hormonal product Cortisol
Androgens Estrogen Aldosterone Mixed Nonfunctional
Physical exam findings with functional ACC tumors. Physical exam findings and clinical features
Percentage of ACC tumors
Truncal obesity, round face, thinning of the skin, cutaneous striae, hypertension, depression, anxiety, hirsutism, dysmenorrhea Cliteromegally, hirsutism, infertility, alopecia, deepening of the voice Gynecomastia, testicular atrophy, low sperm count Hypertension and hypokalemia Vary by hormonal product Painful mass
33%
25% 10% 3% Up to 35% 20–40%
Lab Evaluation In addition to physical exam findings, a full adrenal laboratory evaluation is helpful in establishing the diagnosis of ACC. It is also important to rule out pheochromocytoma when performing this evaluation. Glucocorticoids: Dexamethasone suppression test; 24 h urinary free cortisol; basal ACTH; basal cortisol Sex steroids: Androstenedione; testosterone; DHEAS; 17-OH-progesterone; 17 B estradiol Mineralacorticoid: Aldosterone/renin ratio; potassium Pheochromocytoma: Metanephrines; normetanephrines Imaging CT Adrenocortical cancers can appear heterogeneous with irregular borders. There are typically areas of hemorrhage and necrosis. Malignant radiographic features include invasion of adjacent structures, lymphadenopathy, metastasis (liver, lung, bones), and Hounsfield units >20.
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MRI Gadolinium persists with malignant tumors. This modality can be helpful in assessing invasion into the IVC and renal veins.
FDG-PET ACC has a high affinity for 18-FDG, and therefore PET can be used to detect adrenal tumors and metastases. Size Criteria • • •
One should suspect a malignancy for any tumor >6 cm; Tumors less than 3 cm are less likely to be malignant; Tumors 3–6 cm are more diagnostically challenging and require a thorough evaluation.
Pathology Pathologic features that suggest malignancy include size, weight, hemorrhage, necrosis, capsular invasion, and vascular invasion. Histologic features associated with malignant phenotypes can be used to assign a Weiss score to a given tumor. The presence of a feature is assigned a value of 1 and absence is assigned a value of 0. The sum of these variables is the Weiss score, and a value >3 is more likely to represent a malignancy. (1) (2) (3) (4) (5) (6) (7) (8) (9)
High nuclear grade Mitotic rate greater than 5 per 50 high-power fields Atypical mitotic figures Eosinophilic tumor cell cytoplasm Diffuse architecture present in 33% or more of the tumor Necrosis Invasion of venous structures Invasion of sinusoidal structures Capsular invasion
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PROGNOSTIC FACTORS AND DETERMINANTS OF RESECTABILITY Preoperative Clinical Risk Factors • • •
Older age Distant metastases Local invasion
Postoperative Pathologic Risk Factors • • •
Capsular extension or invasion Lymphovascular invasion Positive surgical margins
TNM staging is very similar to MacFarlane staging, as modified by Sullivan. The features of TNM staging and the corresponding 5-year survival are listed in Table 2. In the latter scheme, stage 1 includes tumors that are limited to the cortex and are less than 5 cm in size. In stage 2, the lesions are localized to the cortex, but are larger than 5 cm. As with TNM staging, stage 3 includes locally invasive primary tumors or the presence
Table 2 Stage I
II
III
IV
TNM staging of adrenocortical cancer. TNM features
5-year survival%
Primary tumor <5 cm without local invasion No regional lymph node metastases No distant metastases Primary tumor ≥5 cm without local invasion No regional lymph node metastases No distant metastases Primary tumor with local invasion Regional lymph node metastases No distant metastases Either of the following: Primary tumor with invasion into adjacent organs Positive distant metastases
33–66
20–58
18–24
<5
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of regional lymph node metastases. Stage 4 includes local organ invasion or distant metastases.
Determinants of Resectability In patients with ACC stage I–III, complete resection offers the greatest chance for cure. Favorable criteria include small tumor size, no lymphadenopathy or metastases, and no invasion into adjacent organs. Conversely, unfavorable criteria are large tumor size, locally advanced disease, and metastases. An ACC that encases the aorta and/or a major splanchnic vessel is unresectable. Debulking of tumors that cannot be completely resected in the setting of metastatic disease is a matter for debate. There does appear to be a benefit in controlling hormonal excess in this setting; however, an incomplete resection portends a poor prognosis.
OPERATIVE MANAGEMENT The essential surgical principles for adrenocortical cancer include obtaining wide exposure, achieving en bloc resection without tumor spillage, and achieving complete resection of the tumor which might require resection of nearby organs or the inferior vena cava. Open adrenalectomy is the preferred approach for ACC. Other options include the posterior retroperitoneal approach, the anterior retroperitoneal approach, and laparoscopic resection. These other options are usually not ideal, as ACC tumors are typically large with local invasion. The transabdominal approach facilitates maximum exposure and enables the resection of nearby structures if required. The transperitoneal approach can be achieved with a bilateral subcostal incision which can be extended through a partial sternotomy. The patient can also be placed in the lateral recumbent position, with the table flexed at the waist to maximize the distance between the costal margin and the iliac crest. A large flank incision is then created through a posterolateral incision. The rectus, external oblique, internal oblique, and transverse abdominal muscles are divided.
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Access to the right adrenal gland by the transabdominal route begins with a Kocher maneuver to expose the inferior vena cava. The size of the tumor, the extent of local invasion, and the relationship to the vena cava influence the operative approach. Ideally, the dissection begins along the superior aspect of the tumor, which may involve the liver. The dissection then proceeds along the medial border of the tumor, in the inferior direction, separating the lesion from the IVC. Suture ligation of the adrenal vein is a key step and often offers substantial tumor mobility. In patients with hypercortisolism, the vein can be friable. Caval invasion should be considered local extension of the tumor, and resection can often be achieved without patch repair. The final step of the operation includes separation of the attachments of the adrenal tumor to the kidney. Local invasion of the kidney requires nephrectomy. Careful attention to avoid ligation of a superior pole renal artery is needed to avoid devascularization and postoperative hypertension. The remaining lateral and posterior attachments are then easily divided with gentle medial and anterior retraction of the tumor. Access to the left adrenal gland by the transabdomninal approach begins with either mobilization of the splenic flexure or division of the gastrocolic ligament to enter the lesser sac. With the latter approach, the inferior border of the pancreas is dissected free and the pancreas is elevated to expose the adrenal gland and kidney. As with the approach described for the right adrenal gland, the tumor size and the extent of local invasion dictate the optimal approach to resection. Ideally, the dissection begins along the superior aspect of the tumor, freeing potential attachments to the spleen and exposing the diaphragm. It then proceeds along the medial border in the caudal direction, followed by careful dissection along the inferior border to free attachments to the kidney. The final steps involve the lateral and posterior attachments, which are the least dangerous regions of the dissection. Postoperative management for patients with autonomous cortical secretion includes a steroid taper to avoid adrenocortical insufficiency.
EVALUATION AND MANAGEMENT OF PATIENTS WITH METASTATIC DISEASE Complete surgical resection can produce curative outcomes; however, the majority of patients present with advanced disease that is not amenable to
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complete resection. The treatment goals for patients with advanced disease require individualization. Palliative interventions, including both local and systemic therapies, can extend survival and improve the patient’s quality of life. Preoperative evaluation must include a search for distant metastases. The most common sites of adrenocortical cancer metastases are the liver and lungs. Staging protocols include chest and abdominal CT, MRI, and FDG-PET scans. Patients with neurologic symptoms should have a head CT and patients with bone pain should undergo bone scanning.
Adjuvant Therapy While complete resection offers the best chance of cure, the overall survival for ACC remains poor (30–40%). Given the low five-year survival for ACC tumors, multiple adjuvant agents have been used, including hormonal and cytotoxic compounds; however, no adjuvant therapy has emerged as a major improvement in the mortality of the disease. Though no first-line agent has been established as adjuvant therapy, mitotane is the most widely used for this purpose.
Mitotane This is a pesticide analog (DDT). • • • • • • •
Acts as an adrenolytic agent (specific to the adrenal cortex) Causes necrosis of the adrenal cortex and inhibition of steroidogenic enzymes Only FDA-approved drug for treatment of ACC Dose-limiting toxicity (14–20 mg/L); slow to reach peak effect Very narrow therapeutic index (GI and neurotoxicity) Supplementation with long-acting glucocorticoids (prednisone, decadron) is necessary Used for palliation of functional tumors, with 80% of patients demonstrating decreased secretion of cortisol
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Other Hormonal Therapies • • • • •
Ketoconazole: inhibits p450 enzymes involved in adrenal steroid synthesis Metyrapone: inhibits adrenal 11b hydroxylase Aminoglutethimide: inhibits enzymatic conversion of cholesterol to pregnenolone Mifepristone: blocks progesterone and glucocorticoid receptors Etomidate: inhibits adrenal 11b hydroxylase
Chemotherapy Many chemotherapeutics have been used in ACC, including cisplatin, doxorubicin, etoposide, and 5-fluorouracil, with limited success. No good randomized control trials have evaluated these agents against ACC. A common combination chemotherapy protocol includes etoposide, doxorubicin, and cisplatin. Surgical Therapy Although local recurrence rates are higher in patients who undergo laparoscopic resection, laparoscopic adrenalectomy is appropriate for some patients with distant metastases who undergo palliative resection of the primary tumor. Palliative open resection can be beneficial to patients with severe pain from large tumors from mass effect. Debulking of functional ACC can palliate patients with severe symptoms from autonomous hormonal hypersecretion. Radiation Therapy Postoperative adjuvant radiotherapy has been used to prevent local recurrence; however, no randomized controlled trials have been performed to prove its efficacy, and ACC is a relatively radioresistant tumor. Tumor bed radiation can be considered in cases of incomplete resection or cases with local recurrence. Radiotherapy has also been useful in the palliative setting for symptomatic metastases, including boney metastases or those that cause local compressive symptoms.
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Targeted Therapy Early trials with targeted systemic therapy have been disappointing. Future molecular-targeted-based therapies are needed.
SELECTED REFERENCES Fassnacht M, Allolio B. Clinical review: adrenocortical carcinoma — clinical update. J Clin Endocrinol Metab 2006;91:2027–2037. Libe R, Fratticci A, Bertherat J. Adrenocortical cancer: pathophysiology and clinical management. Endocr Relat Cancer 2007;14:13–28. Phan AT. Adrenal cortical carcinoma — review of current knowledge and treatment practices. Hematol Oncol Clin N Am 2007;21:489–507. Soon P, McDonald K, Robinson B, et al. Molecular markers and the pathogenesis of adrenocortical cancer. Oncologist 2008;13:548–561. Sturgeon C, Shen W, Clark O, et al. Risk assessment in 457 adrenal cortical carcinomas: how much does tumor size predict the likelihood of malignancy? J Am Coll Surg 2006;202(3):423–430.
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Chapter IV.A.1: Evaluation of Carcinoid Tumors Katherine Heiden, MD and Mira Milas, MD
OVERVIEW Carcinoids are a rare neuroendocrine entity that arises from diverse anatomic regions containing chromaffin tissue. They can originate from the bronchopulmonary system, or the gastrointestinal system, where they are grouped into foregut (e.g. gastric), midgut (e.g. appendiceal), and hindgut (e.g. rectal) carcinoids. Although having a relatively slow growth rate, carcinoid tumors are considered malignancies and can be challenging to diagnose and manage, and can also be resistant to various treatment modalities. Pancreatic carcinoids are part of the foregut carcinoid family and represent some of the rarest of all tumors, accounting for <1% of all carcinoid tumor site distributions. Although the present handbook focuses on pancreatic tumors relevant to endocrine surgeons, the discussion of strategies to evaluate carcinoid tumors must have a broader context owing to the rarity of pancreatic carcinoids. The goal of this review article is to present the laboratory and imagining tools that are relevant to the evaluation of carcinoids. Whether addressing a rare pancreatic carcinoid or a more common entity such as an appendiceal carcinoid, clinical suspicion for the presence of this condition is critical and should precede the selection of diagnostic tools when possible. Clinical diagnosis is based on the recognition of symptoms of flushing and diarrhea, dramatic manifestations of carcinoid syndrome (hepatomegaly, flushing, diarrhea, and asthma), the severely sclerosing nature of bowel obstructions from carcinoid tumors, or the need to consider carcinoids with atypical and ambiguous clinical presentations. Pancreatic carcinoids are often
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diagnosed late in the disease process, with concurrent liver metastases, and absence of symptoms (flushing, diarrhea) in 25% of patients. They can be difficult to distinguish from other pancreatic neuroendocrine tumors and have a generally poor prognosis.
LABORATORY EVALUATION Multiple serum and urinary markers have been developed and tested with variable results in the evaluation of carcinoid tumors and carcinoid syndrome. The two most widely used laboratory measurements are 5-hydroxytryptamine (5-HIAA) and chromogranin A (CgA). Both have advantages and limitations, and the ideal marker remains to be identified. Both CgA and 5-HIAA levels should be measured at the time of diagnosis and be followed regularly in patients with a history of carcinoid tumor. Serotonin Metabolism Markers Carcinoid tumors preferentially metabolize tryptophan into serotonin precursors and derivatives, which include 5-hydroxytryptophan (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), resulting in elevated circulating levels of all of these substances (Fig. 1). Both serum and urine measurements of 5-HIAA are available. Although some believe that the urine measurement is most accurate, usage varies according to physician preference or ready availability. Serotonin itself can also be measured in blood, but it is not as routinely used for diagnostic purposes. Serotonin measurement and staining in the tumor is helpful, and for pancreatic carcinoids the immunocytochemical sensitivity for serotonin is 100%. Foregut carcinoids, like the pancreatic carcinoids, have a low serotonin content, midgut carcinoids have a high content, and hindgut tumors rarely contain serotonin. Twenty-four-hour urinary excretion of 5-HIAA is a useful measurement in patients with suspected carcinoid tumors, with a sensitivity of 80%. This test is performed on an outpatient basis and requires the patient to collect their urine over a 24 h period. The lab then analyzes the total amount of 5-HIAA in the urine collection. An abnormal value is defined as >10 mg/24 h. A random urine 5-HIAA test can be done with a urine
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Serotonin metabolism.
creatinine when 24 h collection is not feasible, but this measurement is not as accurate because 5-HIAA secretion can be intermittent and missed on a single time point test. Certain foods and medications can lead to increased serotonin production and resultant elevations in urinary 5-HIAA. They include bananas, avocados, pineapples, kiwis, tomatoes, nuts, caffeine, as well as Coumadin, Tylenol, fluorouracil, and various other, less common medications. Patients should be instructed to avoid these foods and medications before undergoing testing, usually just for a few days and on the day of testing. More recently, a fasting serum 5-HIAA test was developed that requires only a single blood test, obviating the need for 24 h urine collection with its inherent inconvenience and potential for collection errors. This sensitivity and specificity of this plasma test are 89% and 97%, respectively.
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5-HIAA is an effective marker for response to treatment (70% of patients will demonstrate a reduction in 5-HIAA levels with somatostatin therapy), as well as for disease recurrence. Chromogranin A Chromogranin A (CgA) is a general marker for all neuroendocrine tumors. It belongs to a family of intracellular proteins that are stored in secretory granules of neuroendocrine cells. It is released into the circulation, often resulting in elevated serum levels in patients with neuroendocrine tumors, which makes this a useful marker. CgA is both sensitive and specific to neuroendocrine tumors as a group, including pancreatic neuroendocrine tumors and carcinoids. The sensitivity and specificity of CgA to carcinoids are 80% and 95%, respectively. This test cannot, however, reliably differentiate among different types of neuroendocrine tumors, including carcinoids. False positive results have been correlated with hypertension, strenuous activity, and pregnancy. Normal levels of CgA are less than 39 ng/L, and the levels seen in patients with carcinoid tumors can range from just above normal to several thousand ng/L. Serum CgA is also useful as a prognostic indicator in patients with carcinoid tumors. Five-year survival is significantly improved in patients with low levels of CgA compared to patients with high levels. The quantitative value has been shown to correlate with tumor mass. CgA levels may not be affected by treatment with somatostatin, but will be dramatically reduced after a cytoreduction procedure. Other Biochemical Markers These include substance P, neurotensin, human chorionic gonadotropin alpha subunit, neuropeptide K, neuropeptide PP, adrenocorticotropin (ACTH), histamine, U-MelmAA, enkephalin, gastrin, glicentin, and the other pancreatic endocrine hormones, such as insulin, glucagon, VIP, and pancreatic polypeptide. None have the specificity or sensitivity to be useful diagnostic markers, and most in this category are produced only by midgut carcinoids.
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IMAGING EVALUATION Like many other solid tumors, carcinoid tumors may be visualized by standard CT or MRI; however, there are more sophisticated modalities available to help identify and localize carcinoids. Thorough imaging is helpful in diagnosis and important for staging. For pancreatic carcinoids specifically, CT scans or MRI, ERCP, and endoscopic ultrasound can be useful and be applied as they traditionally are in the evaluation of pancreatic masses. The modalities below are commented on in terms of practical relevance to carcinoids in general. Conventional Computed Tomography Cross-sectional imaging using an abdominal computed tomography (CT) scan is often the first test performed in the diagnosis of carcinoid tumors. While the overall sensitivity of a CT scan is relatively low (~50%), it can be especially useful for the identification of locally advanced disease, such as mesenteric lymphadenopathy, as well as metastatic disease in the liver. It also provides the basic survey of anatomy relevant to any subsequent surgical procedures.
OctreoScan A sensitive and specific test available for carcinoid tumors is the 111Inlabeled octreotide scan (OctreoScan). The sensitivity of detecting carcinoids is 80–90% for asymptomatic tumors, and greater than 90% for symptomatic tumors. However, recent data suggest that OctreoScan may not give additional information beyond CT scanning. It is useful for measuring response to somatostatin therapy and provides an effective means of monitoring for tumor recurrence. Hindgut carcinoids usually cannot be visualized by an OctreoScan. Ongoing therapy with somatostatin may confound the results of OctreoScan, due to octreotide receptor saturation. The best indications for using this imaging modality are (1) as a localization method in patients with abnormal 5-HIAA or CgA and disease not apparent with conventional imaging, (2) as a survey for widespread metastatic disease, or (3) when results would be expected to change the treatment strategy for the patient.
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Positron Emission Tomography Scan While a positron emission tomography (PET) scan is very useful for the diagnosis and localization of many tumors, its utility in carcinoid tumors is limited. It has been shown to have a low sensitivity and specificity to carcinoid tumors, possibly due to their relatively low metabolic rate compared to other solid tumors. There are several new neuroendocrinespecific tracers in the development for use in the PET scan that may improve the accuracy of PET in carcinoid tumors, but they are not clinically widely available yet. Other Nuclear Scintigraphy Modalities Radiolabeled metaiodobenzylguanidine (123I-MIBG) is concentrated by carcinoid tumors and has been studied alone or in combination with the CT scan for detection of carcinoids. The overall sensitivity of this modality is
Fig. 2
Algorithm for the evaluation of carcinoids.
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55–70% (less than for OctreoScan), but the specificity is high at 95%. It is more effective in imaging metastatic disease than the primary tumor, and may be valuable for imaging patients who are on long-acting octreotide.
SUMMARY The evaluation of carcinoids starts with the recognition of unique symptoms such as diarrhea and flushing, and then relies on biochemical markers of the disease process (5-HIAA and CgA) for confirmation of the diagnosis and imaging to localize the primary tumor and stage metastatic disease (Fig. 2).
SELECTED REFERENCES Modlin IM, Shapiro MD, Kidd M. An analysis of rare carcinoid tumors: clarifying these clinical conundrums. World J Surg 2005;29(1):92–101. Schirner II, Yao JC, Ajani JA. Carcinoid: a comprehensive review. Acta Oncol 2003;42:672–692. UpToDate. Online 17 Feb. 2009.
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Chapter IV.A.2: Evaluation of Insulinoma Jui-Yu Chen, MD, Yi-Fang Tsai, MD, Ling-Ming Tseng, MD and Chen-Hsen Lee, MD, FACS
INTRODUCTION Insulinomas are considered the most common functioning endocrine neoplasm of the pancreas, with an annual incidence of four cases per million population. Although 90% of insulinomas are benign in nature, they are still potentially fatal due to the risk of lethal hypoglycemia. The tumors are usually benign, small, single, well-circumscribed, and evenly distributed throughout the whole pancreas. Less than 10% of the tumors are associated with multiple endocrine neoplasia type 1 (MEN 1). The clinical presentation of this neoplasm depends on excessive production of insulin and proinsulin, and is characterized by the symptoms related to episodes of hypoglycemia that could be mistaken for a neuropsychiatric disorder. Hypoglycemic symptoms can be grouped into neuroglycopenia and catecholamine response from the autonomic nervous system. Typical clinical presentation from neurogylcopenia includes diplopia, blurred vision, confusion, abnormal behavior, amnesia and seizure, and even may progress to loss of consciousness, coma or permanent brain damage. Catecholamine response from the autonomic nervous system may result in sweating, weakness, tremor, nausea, hunger, feelings of warmth, palpitations and anxiety. The severity of symptoms generally has no relationship to the malignant potential of insulinomas. Diagnosis is confirmed in the setting of typical symptoms with biochemical confirmation, and exclusion of other causes of hypoglycemia. For definitive treatment of this rare disease, surgical resection remains the mainstay of management because of the unsatisfactory long term medical therapy. For the successful resection of insulinomas, preoperative 377
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localization studies are frequently employed and are expected to be helpful during the operations. Despite the evolution of diagnostic methods in recent years, tumor localization remains a challenge for clinicians and surgeons, mainly due to the relative rarity but also to variability in the choice of preoperative imaging and surgical approach to nonlocalized tumors. This chapter focuses on making and confirming a diagnosis, and localizing the tumor.
LABORATORY EVALUATION The diagnosis is suspected in patients with symptomatic fasting hypoglycemia. Patients with episodes of mental dysfunction while fasting have a high probability of insulinoma. An inappropriately elevated level of insulin in the presence of hypoglycemia is the key to diagnosis in insulinoma. The principles of the Whipple triad have remained important to this day: (1) Symptoms and signs of hypoglycemia (2) Concomitant plasma glucose level less than 45 mg/dL (3) Reversibility of symptoms with administration of glucose In addition to these criteria, the following diganostic tests allow more accurate diagnosis of insulinoma before surgical intervention. Glucose and Insulin Levels (Normal Glucose Level 60–95 mg/dL at Fasting; Normal Insulin Level Below 30 µU/mL) Failure in suppression of endogenous insulin secretion at the time of hypoglycemia is the hallmark of insulinoma. In patients with insulinoma, the circulating insulin level will be inappropriately high at the time of hypoglycemia. When the level of glucose drops to as low as 40 mg/dL, any measurable insulin is abnormal. Food is restricted after 6 p.m. on the preceding night, and a venous sample for plasma or blood sugar is obtained between 7 and 9 a.m. Samples should be drawn as early as possible, to avoid complications of hypoglycemia.
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Test interpretation A plasma insulin concentration of 6 µU/mL by radioimmunoassay (or 3 µU/mL by immunometric assay) when the plasma glucose concentration is below 45 mg/dL indicates excess of insulin and is consistent with insulinoma. Insulin–Glucose Ratio (Normal <0.4) The insulin–glucose (I/G) ratio means a relationship between these two values and helps in diagnosis of insulinoma. When the glucose level drops to 45 mg/dL, any measurable insulin is abnormal. The I/G ratio is diagnostic in some patients who have insulin levels within the normal limit when symptomatic hypoglycemia happens. Test interpretation In normal individuals the ratio is always less than 0.4, but in patients with insulinoma the serum insulin remains high and the ratio approaches 1.0 and may exceed that in some cases. 72 h Prolonged Fasting Test This test is the gold standard for establishing the diagnosis of insulinoma. In most reports, one-third of patients develop symptoms within 12 h, at least 80% within 24 h, 90% within 48 h, and 100% within 72 h. Serum glucose levels are checked at regular intervals, usually every 1–2 h, after the patient fasts for 72 h or until symptoms of hypoglycemia occur. Simultaneous insulin levels should be obtained with the onset of symptoms or if the glucose level is below 50 mg/dL. Test interpretation •
75% of insulinomas present with a glucose level that is less than 38 mg/dL within 24 h of fasting. In 25% of patients, the glucose level is less than 30 mg/dL.
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Other criteria are met:
Serum insulin levels of 10 µU/mL or more (normal <6 µU/mL) C-peptide levels exceeding 2.5 ng/mL (normal <2 ng/mL) Proinsulin levels greater than 25% (or up to 90%) that of immunoreactive insulin Screening for sulfonylurea negative In contrast, noninsulinoma pancreatogenic hypoglycemia syndrome (NIPHS) patients will often fail their 72 h fast, never developing hypoglycemia.
Measurement of Proinsulin and C-Peptide (Normal Proinsulin < 20% of Total Immunoreactive Insulin; Normal C-Peptide <1.2 ng/dL) Proinsulin, which is a biosynthetic precursor of insulin, is normally released into circulation in small amounts (between 5% and 22%) and cross-reacts in the insulin radioimmunoassay. Insulin is cleaved from proinsulin within beta cells of pancreas islets, and the peptide bridge, termed the “C-peptide,” is released by proteolytic conversion in equimolar amounts with insulin. In insulinoma, both proinsulin and C-peptide are elevated. Higher proinsulin levels of the total immunoreactive insulin also indicate an islet cell tumor. Test interpretation In patients with plasma glucose less than 45 mg/dL, a C-peptide level greater than 3.6 ng/dL (0.2 nmol/L) indicates diagnosis of insulinoma. For plasma proinsulin, patients with insulinoma present with a level greater than 5 pmol/L. C-peptide levels are elevated in endogenous hyperinsulinism and helpful in diabetic patients suspected to have an insulin-producing tumor. Patients with a high level of insulin after injection of insulin have low levels of C-peptide in the setting of hypoglycemia. Oral Glucose Tolerance Test Most often, the oral glucose tolerance test indicates diagnosis of diabetes. After an overnight fast, the patient ingests within 5 min 100 g
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(60 g/m2) of a standard glucose solution, and plasma or blood samples are obtained for glucose measurement at 0, 30, 60, 90, 120, 180, 240 and 300 min. In addition, plasma glucose should be obtained when the patient reports symptoms. The peak glucose level is reached by 1 h and less than 160 mg/dL. The normal serum fasting glucose level regained at 2 h. Test interpretation An exaggerated hypoglycemia status during which the glucose level may fall 20 mg/dL or more below fasting levels and remain low for several hours indicates diagnosis of insulinoma. Provocative Tests Stimulation tests are no longer recommended. The intravenous application of tolbutamide, glucagon or calcium can be hazardous by inducing prolonged and refractory hypoglycemia. Intravenous glucagon After an overnight fast, glucagon (1 mg) is infused within 30 s, and plasma if obtained for glucose and insulin levels at 0, 2, 5, 10, 15, 30, 45, 60, 90 and 120 min. As glucagon promotes acute insulin release and hepatic glycogeneolysis, it is helpful in assessing patients with hypoglycemia. Normally, a rapid rise in the serum glucose level occurs during the first hour, with a return to fasting glucose levels by 3 h. In insulinoma, there is a greater elevation of the glucose level, followed by severe hypoglycemia in elevation of insulin. Calcium infusion Intravenous administration of calcium at a concentration of 5 mg/kg/h has been recommended to cause inordinate insulin secretion to distinguish from normal individuals who have little or no increase in insulin levels. Hypoglycemia occurs within 2 h of calcium infusion.
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Intravenous tolbutamide After an overnight fast, tolbutamide (1 g) is infused within 30 s, and plasma if obtained for glucose and insulin levels at 0, 2, 5, 15, 30, 45, 60, 90, 120, 150 and 180 min. In normal individuals, the peak level of insulin usually occurs within 5 min, whereas the nadir for plasma glucose is within 15–30 min and is normally 50% of the level. The insulin and glucose have returned to the original levels by 90–120 min in normal individuals. Profound and protracted hypoglycemia associated with an inordinate release of insulin may occur after tolbutamide administration. Insulin Surrogates Insulin surrogates are measurable substances that indicate the presence of insulin, which is antilipolytic, antiketogenic and glycogenic. They include plasma b-hydroxybutyrate and the response of plasma glucose to intravenous glucagon at the end of the prolonged fast. They may be helpful in substantiating the diagnosis. Other Considerations A patient who is suspected to have insulinoma should be evaluated with MEN 1, which may include the following: • • •
Hyperprolactinemia due to a pituitary adenoma Hyperparathyroidism due to parathyroid hyperplasia Hypergastrinemia due to gastrinoma
IMAGING EVALUATION Overview Because of the small size (90% tumors are usually less than 2 cm in size), potential multiplicity, and possible throughout the whole of the pancreas, preoperative localization of tumors is essential in determining prognosis and appropriate surgical intervention. There are a variety of preoperative imaging modalities for the detection of insulinomas. However, no single imaging examination can localize tumors in all patients. Most experienced
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endocrine surgeons obtain one or more localization tests before treatment is performed. In choosing the localization technique, specific tumor characteristics need to be considered: • • • • •
Most insulinomas are vascular and are visualized in arterial phase imaging; Most tumors are intrapancreatic; 80–90% are solitary and 80% less than 2 cm in diameter; Distributed equally within the head, body and tail of the pancreas; Multiple tumors are found in only 8% of patients associated with MEN 1, and 2% of patients have diffuse islet cell hyperplasia, microadenomatosis or adult nesidioblastosis.
Preoperative Transabdominal Ultrasonography Transabdominal ultrasonography is one of the first imaging techniques available. It is performed with a frequency probe of 7.5–12 MHz and allows higher image resolution. Color-coded Doppler transabdominal ultrasonography allows imaging of adjacent vessels and aids in the investigation of the vascularity of lesions. Sensitivity Abdominal ultrasound has only a poor-to-moderate detection rate (9–66%). Especially, in tumors smaller than 1 cm in diameter, the sensitivity is less than 40%. Advantages Ultrasound is safe, rapid, noninvasive, relatively cheap and easily available. Liver metastases are also possibly detected by ultrasonography. Disadvantages and limitations The procedure is operator-dependent, limited by the small size of the tumor, and interfered with by other intra-abdominal organs. Tumors over the body and tail are difficult to localize.
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Endoscopic Ultrasonography (EUS) Endoscopic transgastric ultrasonography should be a first-line investigation in patients with biochemical evidence of insulinoma. EUS is performed with radial scanning of 360° and an ultrasonographic frequency of 7.5 MHz. The high spatial resolution of this technique enables the detection of very small lesions and their precise anatomical location. The availability of linear and curvilinear array EUS has broadened its applicability, with the ability to perform fine needle aspiration cytology (FNAC) of suspicious lesions. Sensitivity and advantages The sensitivity is 82–94%. Even 2 mm tumors can be detected. EUS is cost-effective, enables visualization of the pancreas with an accurate analysis of the relationship of the tumor to vital structures such as the biliary and pancreatic ducts, and can detect local metastases and invasion. FNAC can be performed along with EUS examination if necessary. Disadvantages and limitations The examination is invasive, due to the risk of upper gastrointestinal endoscopy. Cost, availability and expertise are other limitations. Besides, the limitations include poor evaluation of lesions in the distal body or pancreatic tail, inaccurate assessment of malignancy, poor identification of pedunculated or adjacent lesions and weak differentiation of larger homogenous tumors from surrounding parenchyma. Detection rates of 83–100% for head and body lesions are reported, compared with 37–60% for pancreatic tail lesions. Computed Tomography (CT) CT scanning is probably still the most widely used noninvasive technique for first-line localization of insulinoma. It can visualize the exact location of the tumor, and its relationship to vital structures and the presence of metastases.
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Insulinomas are highly vascular in the arterial phase. Contrastenhanced imaging can be used to aid detection. The approach recommended is biphasic or triphasic pancreatic imaging. The precontrast localizer image, and the images acquired in the initial phase and delayed phase, are obtained. Thin collimation imaging from 1.5 to 3.0 mm with multiplanar reconstruction is highly recommended. Standard oral contrast for preoperative assessment is unnecessary. Sensitivity Previous preoperative sequential CT scanning may localize as few as 35% of insulinomas (11–50%). With the development of rapid, spiral CT coupled with dynamic scanning after a bolus injection of a contrast medium, the sensitivities of detection of insulinomas are over 80%. CT at its early phase is most sensitive. Rapid injection of a high concentration contrast medium during the early phase enables the operator to capture the tumor blush. Advantages CT is a modality which is safe, noninvasive, only moderately expensive, readily available, simple to perform and operator-independent. Disadvantage and limitation The sensitivity of CT for detection of insulinoma is dependent on the size and location of the neoplasm. Small hyperattenuating tumors in the pancreatic head and neck can be confused with adjacent vessels. Magnetic Resonance Imaging (MRI) In previous studies, the use of fat-suppressed, T1-weighted imaging with spin echo after the administration of intravenous gadolinium has been suggested. Modern MRI systems now allow rapid triphasic, breath-held T1 rapid gadolinium-enhanced sequences to reduce motion artifacts and
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enable accurate assessment of the pancreas in the arterial and venous phases. Sensitivity and advantages Recent literature has reported that sensitivities can be over 90%, which is much higher than for early studies. MRI is safe, noninvasive and rapid. It enables accurate assessment of the tumor location in terms of resectability and major vessel involvement. Metastatic disease and lymphadenopathy may also be detected. Disadvantages and limitations The disadvantages are its cost, specific contraindications to MRI and more limited availability than for CT. In current practice, therefore, MRI is a second line investigation. Arteriography Most insulinomas are highly vascular tumors and produce a distinctive tumor blush on the images of angiography. Arteriography was regarded as the “gold standard” for insulinoma localization for more than two decades. At present, it could be considered as a first step before intraarterial calcium stimulation and venous sampling examination. Selective arteriography of the celiac axis and pancreatic arterial supply are performed for the technique by femoral puncture. Sensitivity The sensitivity is about 29–66%. With superselective arterial injections, magnification views and digital subtraction techniques, preoperative localization can be obtained in 75–80% of cases. Disadvantages and limitations Arteriography is known to be invasive, expensive, time-consuming, and carry a number of significant risks. Besides, considerable technical
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expertise is required to direct the catheter into branch arteries and interpret the significant imaging stains. Percutaneous Transhepatic Portal Venous Sampling (PTPVS) Transhepatic portal venous sampling is a means of regionalizing an insulinoma (pancreatic head, neck, body or tail). In an interventional suite, the portal venous system is reached through the liver parenchyma, and a catheter is passed through the portal vein into the splenic and superior mesenteric veins. Insulin levels of blood samples obtained from specific sites along these veins are measured. An insulin concentration that is two standard deviations higher than the baseline in the portal vein indicates that the insulinoma lies in the area drained by that particular vein. Sensitivity The sensitivity is from 70% to 95% in the hands of experienced practitioners. Disadvantages and limitations Transhepatic portal venous sampling is expensive, technically demanding, and only regionalizes the tumor. Most important of all, it is very invasive for the morbidity associated with percutaneously cannulating the portal vein through the liver, such as epigastric pain, transient hemobilia, hepatic hematoma, biliary leak and hemorrhage. Portal venous sampling is now considered obsolete as a routine investigation, because of a high complication rate (10%). Selective Arterial Calcium Stimulation with Hepatic Venous Sampling This test is a means of regionalizing an insulinoma due to the fact that calcium is a potent stimulant of insulin release from insulinoma. It is a modification of the selective arterial secretin injection developed by Imamura and Takahashi for regionalization of gastrinomas.
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This technique requires the placement of arterial and venous catheters by femoral puncture. The venous catheter is located in the right hepatic vein. Selective arteriography of the gastroduodenal, splenic common hepatic and superior mesenteric arteries is then performed. After this, calcium gluconate (5 ml bolus of 0.025 mEq/kg) in saline is injected into each artery, and blood samples (5 ml of blood) are taken from the hepatic veins at 0, 30, 60 and 120 s for the measurement of insulin levels. A twofold elevation of insulin in the 30 or 60 s sample indicates a positive test result and where the insulinoma is located. Positive test located Gastroduodenal or superior mesenteric artery Splenic artery Common hepatic artery
Possible region Head and neck region, uncinate process Body and tail region Occult hepatic metastases
Sensitivity and advantages The sensitivity is over 90%. At our institute, we could localize the region of insulinoma in every patient. Even if it is an invasive procedure, there is less morbidity than for PTPVS, because there is no need for hepatic puncture. It indicates the priority pancreatic region to explore, and saves the laborious work of whole-pancreas mobilization. Disadvantages and limitations Like arteriography, this test is a relatively invasive technique and is operatordependent, and it needs a higher level of expertise and a specialized facility compared to conventional arteriography. It is also a costly procedure. It regionalizes the lesion but cannot locate its specific site. Any suspected lesion found by palpation needs to be confirmed by an intraoperative test. Somatostatin Receptor Scintigraphy (SRS) Large numbers of somatostatin receptors (SS-Rs) are found on most endocrine pancreatic tumors. At least five different human SS-R subtypes
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have been cloned. Octreotide can bind with high affinity to SS-R subtype 2 (sst2) and sst5. In-111 octreotide study (indium-labeled octreotide scan) The SRS examinations are carried out after an intravenous bolus of 100–200 Mbq 111In-labeled pentetreotide. Planar images are recorded with a large field view gamma camera. All patients undergo anterior and posterior whole-body static scintigraphy. Planar images are obtained 4 and 24 h after injection of the radioligand. Single-photon emission computed tomography (SPECT) is performed and images are reconstructed and analyzed. Sensitivity and advantage The sensitivity of SRS is 46–63%, due to the low incidence of sst2 on insulinoma cells. Effective scanning that enables localization of both primary and metastatic insulinoma can be achieved. Disadvantages and limitations Insulinomas have a low density of somatostatin receptors, and express the somatostatin subtype 2 cell surface receptor in only 50% of tumors. Consequently, SRS has a limited role in the evaluation of primary insulinomas. Positron Emission Tomography (PET) PET plays only a limited role. It may detect the presence of a neuroendocrine tumor, and has a limited role in the evaluation of the operability of malignant lesions and the presence of metastatic disease. Benefits of Preoperative Localization Traditionally, intraoperative ultrasound imaging with manual palpation was the gold standard for localizing insulinoma with a sensitivity of over 80%. However, preoperative imaging enables more accurate surgery, may prevent
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the patient from receiving an unnecessary extended pancreatectomy and its associated morbidities, and facilitates the detection of metastases. Furthermore, it shortens the surgical time and decreases the incidence of potential intraoperative damage to major structures. Besides, there is a learning curve associated with the use of IOUS and introperative palpation. With the advance of minimally invasive surgery, the preoperative localization procedures become more important during the laparoscopic approach.
SELECTED REFERENCES Fajans SS, Vinik AI. Insulin-producing islet cell tumors. Endocrinol Metab Clin N Am 1989;18:45–74. Finlayson E, Clark O. Surgical treatment of insulinomas. Surg Clin N Am 2004;84(3):775–785. Grama D, Eriksson B, Mårtensson H, et al. Clinical characteristics, treatment and survival in patients with pancreatic tumors causing hormonal syndromes. World J Surg 1992;16:632–639. Grant CS. Insulinoma. In: Surgical Endocrinology (eds.) GM Doherty, B Skogseid. Lippincott Williams & Wilkins, 2001, pp. 347–353. Grant CS. Insulinoma. Best Pract Res Clin Gastroenterol 2005;19(5):783–798. McAuley G, Delaney H, Colville, et al. Multimodality preoperative imaging of pancreatic insulinoma. Clin Radiol 2005;60:1039–1050. Pasieka JL, McLeod MK, Thompson NW, Burney RE. Surgical approach to insulinomas; assessing the need for preoperative localization. Arch Surg 1992;127:442–447. Service FJ. Hypoglycemic disorders. New Engl J Med 1995;332:1144–1152. Tseng LM, Chen JY, Won JG, et al. The role of intra-arterial calcium stimulation test with hepatic venous sampling (IACS) in the management of occult insulinomas. Ann Surg Oncol 2007;14(7):2121–2127. van Heerden JA, Edis AJ. Insulinoma: diagnosis and management. Surg Rounds 1980;3:42–51. Wayne JD, Kaplan EL. Insulinomas. In: Textbook of Endocrine Surgery, 2nd Edn. (eds.) O Clark, et al. Saunders, 2005, pp. 717–724. Whipple AO, Franz VK. Adenoma of islet cells with hyperinsulinism. Am Surg 1935;101:1299–1335. Williams RH (ed.). Textbook of Endocrinology, 6th Edn. Philadelphia: Saunders, 1981, pp. 855–856.
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Chapter IV.A.3: Evaluation of Gastrinoma Adam S. Brinkman, MD and Clifford S. Cho, MD
INTRODUCTION In 1955, Zollinger and Ellison described a condition of unrelenting and potentially fatal upper gastrointestinal tract ulceration associated with gastric acid hypersecretion and non–beta islet cell tumors of the pancreas. Since their initial description, much has been learned about Zollinger– Ellison syndrome, or gastrinoma, with respect to its epidemiology and pathophysiology. These advances have permitted important refinements in the diagnostic evaluation of this complex disease.
PRESENTATION Gastrinoma is typically diagnosed between the ages of 20 and 50 years, and the male:female ratio is approximately 1.5:1. The most common symptoms of patients presenting with gastrinoma — abdominal pain, diarrhea, nausea/emesis, and gastrointestinal bleeding — are all referable to overproduction of gastrin, which results in acid hypersecretion by gastric parietal cells causing mucosal ulceration, inactivation of pancreatic digestive enzymes, and high volume throughput of fluid into the alimentary tract. Upper endoscopy will likely reveal evidence of gastric mucosal hypertrophy and large ulcers in either the duodenum or even the jejunum; indeed, identification of ulcers in multiple and/or atypical locations should alert the clinician to the possibility of gastrinoma. The most common clinical manifestations of gastrinoma are highlighted in Table 1. Approximately 80% of gastrinomas are located within the so-called “gastrinoma triangle,” the vertices of which consist of the junction of the cystic and common bile ducts, the junction of the second and third 391
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A. S. Brinkman and C. S. Cho Table 1 Common clinical manifestations of gastrinoma. Symptoms Abdominal pain (70%) Diarrhea (70%) Heartburn (40%) Nausea/emesis (30%) Gastrointestinal hemorrhage (25%) Weight loss (20%) Endoscopic signs Prominent gastric rugal folds (95%) Mucosal ulceration (70%)
Table 2
MEN-1 versus sporadic cases of gastrinoma.
Prevalence Most common tumor location Tumor number Tumor size Likelihood of malignancy Potential for surgical cure
MEN-1 gastrinoma
Sporadic gastrinoma
20% Second/third portion of duodenum Multiple <2 cm Low Low
80% Pancreatic Single >2 cm Common Common
portions of the duodenum, and the junction of the head and body of the pancreas. Approximately one-third of gastrinomas arise in a setting of multiple endocrine neoplasia 1 (MEN-1); indeed, approximately one-half of patients with MEN-1 will develop gastrinoma. Patients with MEN-1 typically present with multiple and benign gastrinomas, in contrast to those with sporadic gastrinomas, who generally present with single malignant tumors (Table 2). About a third of patients will have metastatic disease at the time of presentation; among these patients, the liver is the most common site of metastasis, followed by the axial skeleton.
DIAGNOSIS (FIG. 1) All patients with suspected gastrinoma should undergo measurement of a fasting serum gastrin, which is a simple blood test that is inexpensive and
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readily available in the clinic setting. Normal fasting gastrin levels are approximately 100 pg/mL; most patients with gastrinoma have fasting gastrin levels greater than 200 pg/mL, with some as high as 1000 pg/mL. Marked elevation of serum gastrin greater than 1000 pg/mL is more often associated with sporadic disease, extraduodenal tumor location, tumor size >2 cm, and metastatic disease. Serum gastrin levels are generally inversely proportional to gastric acid output; as a result, elevation of fasting gastrin levels can also be observed among patients with low acid production (Table 3). Because of their potentially confounding influence, Consideration of gastrinoma
Check fasting serum gastrin level
<200 pg/mL
200–1000 pg/mL
Evaluate other causes
Secretin stimulation test
Normal
Evaluate other causes
Fig. 1
Table 3
>1000 pg/mL
Localization studies
Abnormal
Localization studies
Algorithm for evaluation of hypergastrinemia.
Differential diagnosis for hypergastrinemia.
Gastrinoma Retained excluded antrum following antrectomy Gastric outlet obstruction Antral G-cell hyperplasia/hyperfunction Previous vagotomy Pernicious anemia Atropic gastritis Short gut syndrome Renal failure
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all histamine receptor type 2 (H2) blockers and proton pump inhibitor (PPI) medications should be discontinued for at least one and six days prior to measurement of serum gastrin levels, respectively. To distinguish gastrinoma from other causes of hypergastrinemia associated with low gastric acid output, the concomitant presence of elevated basal acid output can assist in the diagnosis of gastrinoma. In this test, a Levine gastric tube is advanced into the stomach and confirmation of placement is obtained using radiography. Once the tube is in position, a 12 h sample or a 30 min sample (two samples 15 min apart) is collected. A basal acid output test is considered elevated if the acid levels are greater than 15 mEq/h (or 5 mEq/h of H+ for patients on acid-suppressing medications). The practical utility of this test is obviously limited by its requirement of invasive gastrointestinal tract instrumentation. A more practical adjunct to serum gastrin measurement is the secretin stimulation test, which is often useful in the assessment of patients with mild-to-moderate hypergastrinemia of uncertain etiology. In patients without gastrinoma, intravenous infusion of exogenous secretin (0.4 µg/kg or 2 U/kg) will cause a reflexive decrease in gastrin production from gastric parietal cells. In contrast, secretin administration will cause a dramatic rise in gastrin levels measured at 1, 5, 10, 15, and 20 min post-infusion in patients with gastrinoma. For patients with gastrinoma, the peak rise in gastrin typically occurs 10 min after secretin infusion, and a secretin-induced increase in gastrin of at least 200 pg/mL above the baseline has a sensitivity of 83–93% for the detection of this disease. All acid-suppressing medications (H2, PPI, antacids) and any anticholinergic medications should be discontinued for at least 7 days and 12 h prior to testing, respectively. All patients suspected of having gastrinoma should also be evaluated for the possibility of MEN-1, as the treatment of gastrinoma in the setting of MEN-1 differs quite dramatically from that of sporadic cases. Testing for MEN-1 includes a thorough assessment of the personal and family history of multiple endocrine neoplasia, peptic ulcer disease, parathyroid disease, and pituitary disease. Physical examination and review of symptoms are directed toward signs and symptoms of hypercalcemia, and laboratory evaluation includes measurement of serum calcium, parathyroid hormone, prolactin, and fasting insulin levels. In addition, genetic screening for germline mutations is undertaken for high risk individuals
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or those with a family history of MEN-1. Patients who carry the MEN-1 mutation and who suffer from both primary hyperparathyroidism and gastrinoma should have their hyperparathyroidism addressed first (via subtotal parathyroidectomy), as persistent hypercalcemia can exacerbate the effects of hypergastrinemia.
LOCALIZATION Once the diagnosis of gastrinoma has been established, the next step of management involves localization of the tumor and evaluation for metastatic disease. While the majority of tumors reside within the gastrinoma triangle, 20% may occur elsewhere, necessitating comprehensive body imaging. Useful diagnostic modalities include somatostatin receptor scintigraphy, computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS), angiography, and selective venous sampling (Table 4). Somatostatin receptor scintigraphy is the modality of choice for identifying both primary and metastatic disease, and takes advantage of the biological fact that approximately 80% of gastrinomas express type 2 somatostatin receptors. Radiolabeled 111indium-pentetreotide, which has a high affinity for those receptors, is administered intravenously, and wholebody scintigraphy is performed between 4 and 24 h after injection. Notably, the patient must lie supine for 2–3 h while the images are obtained. Somatostatin receptor imaging has a sensitivity of approximately 85% and a specificity close to 100%, and there are no absolute contraindications to pentetreotide injection. Table 4 Sensitivities of preoperative localization modalities. Modality Somatostatin receptor scintigraphy CT MRI EUS Angiography
Sensitivity 80% 50% 50% 70% 60%
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Gastrinomas tend to be hypervascular; as a result, they often appear as briskly enhancing lesions on CT scans obtained after administration of intravenous contrast. Unfortunately, CT imaging has demonstrated relatively poor sensitivity for the detection of gastrinoma, particularly for extrapancreatic primary tumors and extrahepatic metastases. Gastrinomas located within the duodenal wall appear to be particularly resistant to detection by CT. When used in conjunction with somatostatin receptor scintigraphy, CT scans can allow excellent assessment of tumor size and anatomic relationships to neighboring structures. Similarly, MRI takes advantage of the hypervascularity of most gastrinomas. Furthermore, gastrinomas tend to display lower signal intensity on T1-weighted imaging and higher signal intensity on T2-weighted imaging compared with normal pancreatic tissue. However, like CT, MRI has generally exhibited suboptimal sensitivity in the detection of gastrinoma; this is again particularly evident in duodenal gastrinomas. In recent analyses, EUS has demonstrated sensitivities of detection comparable to those observed with somatostatin receptor imaging. EUS appears to be particularly useful for intrapancreatic primary tumors, but is limited in its ability to detect duodenal tumors. Like CT and MRI, angiography takes advantage of the hypervascularity of gastrinomas, and contrast administration into the gastroduodenal artery and inferior pancreaticoduodenal arteries has been shown to permit detection of gastrinomas with a sensitivity of 40–60%. This modality can also be utilized in conjunction with selective arterial administration of secretin followed by transhepatic portal venous sampling for gastrin, which has been shown to enhance sensitivity in small series. As a result of limitations on the sensitivity of these imaging techniques, approximately 20% of gastrinomas cannot be identified without operative exploration. For these patients, exploratory laparotomy with wide mobilization of the duodenal sweep and pancreatic head (the so-called “Kocher maneuver”), intraoperative ultrasonography, and anterolateral duodenotomy with transilluminated visualization and digital palpation of the duodenal wall are employed. When necessary, arterial stimulation and venous sampling can be performed intraoperatively, and this consists of injecting secretin into the hepatic, splenic, or superior mesenteric artery and measuring gastrin from the hepatic vein seconds after injection.
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Chapter IV.A.4: Evaluation of “Other” Neuroendocrine Tumors of the Pancreas Rachel Adams Greenup, MD, MPH, Tracy S. Wang, MD, MPH and Douglas B. Evans, MD
INTRODUCTION Pancreatic neuroendocrine (islet cell) tumors (PNETs) are most often non functioning but some may produce gastrin or insulin. The spectrum of PNETs includes rare tumors which are named for their secretory product and include glucagonoma, VIPoma, somatostatinoma, and PPoma. Overall, PNETs are extremely rare, representing 1–2% of all pancreatic neoplasms but being increasingly recognized as incidental findings on abdominal imaging (CT, MRI); however, when present, they are commonly associated with a clinical syndrome representative of the hormone they secrete. Nonfunctioning PNETs are often locally advanced or metastatic at the time of diagnosis, and clinical symptoms correlate with the extent of the tumor burden.
GLUCAGONOMA Clinical Presentation Glucagonomas constitute approximately 5% of clinically significant pancreatic endocrine tumors, but remain extremely rare, with an incidence of 1 per 20 million per year. Affected patients range from 40 to 70 years old; women are more commonly affected than men. Glucagonomas are occasionally seen in multiple endocrine neoplasia type 1 (MEN 1).
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Glucagon is important in glucose, fat, and protein metabolism through gluconeogenesis, glycogenolysis, ketogenesis, lipolysis, and catecholamine secretion. Glucagonomas arise from the alpha cells of the pancreas, and cause a syndrome classically described as the “4D” syndrome, which includes diabetes, dermatitis, deep vein thrombosis, and depression. The initial dermatologic findings (when present) may include erythematous plaques that start in the groin and migrate to the lower extremities, and bulla formation which progresses to epidermal shedding and crusting lesions; these are pathognomonic for glucagonoma and are described as necrolytic migratory erythema. Necrolytic migratory erythema is in part related to the amino acid depletion seen in patients, due to the high level of glucagon. The dermatologic findings exist in up to 70% of patients with glucagonomas. Diabetes is present in up to 75–95% of patients, and can be controlled with diet and oral hypoglycemic agents.
CLINICAL SYNDROME OF GLUCAGONOMA (THINK CATABOLISM!) • •
Diabetes (hyperglycemia) Dermatitis (“necrolytic migratory erythema”)
• • • • •
Face, groin, abdomen, lower extremities
Deep vein thrombosis Depression and neuropsychiatric syndromes Anemia (normochromic, normocytic anemia in 90% of patients) Weight loss Hypoaminoacidemia
Diagnosis Serum glucagon levels are elevated in patients with glucagonoma and often are greater than 500 pg/mL (normal: 50–100 pg/mL). Though other clinical conditions may cause mild elevation of serum glucagon levels, serum glucagon levels greater than 1000 pg/mL confirm the diagnosis of glucagonoma. Patients with clinical symptoms classic for glucagonoma and serum glucagon levels less than 1000 pg/mL should be further evaluated for a PET with CT or MRI imaging of the pancreas.
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Occasionally, glucagonoma patients will have tumor(s) which produce other hormones in addition to glucagon and will have the associated laboratory abnormalities (i.e. hypoglycemia syndrome or Zollinger–Ellison syndrome, with elevated gastrin levels). Approximately 20% of patients with glucagonoma will have elevated serum gastrin levels.
SERUM GLUCAGON LEVELS • • •
<500 pg/mL: unlikely glucagonoma. (Others causes: sepsis, pancreatitis, fasting, renal or hepatic failure.) 500–1000 pg/mL: possible glucagonoma; proceed with imaging. >1000 pg/mL: diagnostic of glucagonoma.
One-fifth of patients with glucagonoma will also have elevated serum gastrin levels. Localization A contrast-enhanced multidetector CT scan of the abdomen/pelvis should be the initial imaging study performed on a patient with a suspected glucagonoma. Most patients present with large tumors (>4 cm) and these are typically in the pancreatic body or tail, and can be identified on CT imaging. If CT imaging fails to identify a pancreatic tumor in a patient with presumed glucagonoma syndrome, endoscopic ultrasound (EUS) may be considered; however, this would be exceedingly unusual in the current era of high quality imaging. EUS has been successful in identification of nonfunctioning PNETs and gastrinomas too small to be seen on a CT scan, with a reported sensitivity of 82% and specificity of 92%. CT scans also allow the evaluation of potential metastatic disease in the liver. Once a glucagonoma is diagnosed, aggressive nutritional supplementation may be required in preparation for surgery.
VIPOMA Clinical Presentation The syndrome associated with tumor production of vasoactive intestinal peptide (VIPoma) is known by multiple names, including
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“Verner–Morrison syndrome,” “pancreatic cholera syndrome,” and “(watery diarrhea hypokalemia achlorhydria (WDHA).” VIPomas are extremely rare, with an estimated incidence of 0.2–0.5 per million per year, and they constitute 3–8% of all PNETs. In adults, they typically arise from the pancreas, but in children most VIPomas are neurogenic in origin and arise from extrapancreatic sites along the sympathetic chain, such as ganglioneuromas, ganglioneuroblastomas, neurofibromas, or the adrenal medulla. Women are affected more frequently than men, at a mean age of 48 years. VIPomas are found as part of MEN1 in 4% of patients, although somatic point mutations have been discovered at the MEN1 gene on chromosome 11 in patients with sporadic disease. Pancreatic islet cells secrete VIP, a hormone with high affinity for receptors within the intestinal lumen. When activated, the VIP receptors lead to the secretion of electrolytes and fluid into the intestinal lumen and increase intestinal motility, causing the clinical syndrome of watery diarrhea, hypokalemia, achlorhyrdia, and dehydration. Up to 70% of patients with VIPoma will have profuse watery diarrhea of more than 3 L daily. Diarrhea persists despite bowel rest or fasting. Patients with VIPomas also suffer from hyperglycemia, caused by hypokalemia and altered insulin sensitivity and hypercalcemia, due to dehydration, electrolyte imbalances, or hyperparathyroidism in those cases associated with MEN1. VIP also has a direct vasodilator effect that can lead to flushing. Death secondary to VIPoma may result from dehydration and renal failure, in addition to the development of metastatic disease, which is seen in at least 50% of patients.
Clinical Syndrome of VIPoma • • • • • •
Secretory diarrhea (0.5–15 L/day) Hypokalemia and hypochloremia Dehydration Vasodilation and flushing Bone resorption hypercalcemia Hyperglycemia
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Diagnosis Patients presenting with a clinical picture suspicious for VIPoma should undergo fasting serum VIP testing. Plasma VIP levels are typically 2–10fold above the upper limit of normal (200 pg/mL) and in most patients are greater than 1000 pg/mL. In some patients, serum peptide histadine may also be elevated because of cosecretion of peptide histidine methionine. Localization The majority of VIPomas will be easily identified on a CT scan, as they are usually greater than 3 cm in size, solitary, and located in the pancreas. Seventy-five percent of VIPomas arise within the pancreas, 20% are neurogenic (ganglioneuromas and neuroblastomas) in origin, and 5% arise in extrapancreatic sites and are nonneurogenic (duodenum and jejunum). If CT imaging fails to identify a VIPoma in which the suspicion remains high, somatostatin receptor scintigraphy can be used for further localization. Diagnosis of VIPomas should be followed by initiation of octreotide, a somatostatin analog, to correct the associated electrolyte abnormalities and volume depletion.
SOMATOSTATINOMA Clinical Presentation Somatostatinomas are rare neuroendocrine tumors of the pancreas or small intestine, most commonly found in the duodenum. The majority of them are sporadic (93%), though some are familial and are found in patients with MEN1, neurofibromatosis, or Von Hippel–Lindau syndrome. The patient age at presentation is typically in the early 50s, with an equal distribution among men and women. Somatostatinomas are often found incidentally on evaluation for abdominal pain. Most are functional and arise in the pancreas (56%), while nonfunctional tumors commonly exist in the duodenum and may present with biliary or intestinal obstruction. Periampullary somatostatinomas are often small tumors of the ampulla and may be seen in patients with
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neurofibromatosis. Somatostatin is released by pancreatic delta cells, and is a universal inhibitor of peptide release; the clinical findings on the somatostatinoma syndrome can be explained by this inhibition. Signs and symptoms include hyperglycemia or diabetes mellitus type 2 (suppression of insulin secretion), cholelithiasis (suppression of cholecystokinin secretion and inhibition of biliary motility), steatorrhea (decreased pancreatic exocrine and impaired fat absorption), and hypochlorhydria (suppression of gastrin and gastric acid secretion). Up to 75% of patients have metastatic disease at the time of presentation, and weight loss, anemia, and malaise may be present. Clinical Syndrome of Somatostatinoma • • • •
Steatorrhea Cholelithiasis Diabetes mellitus type 2 Hypochlorhydria
Diagnosis The diagnosis of a somatostatinoma is confirmed by the presence of the constellation of symptoms and fasting serum somatostatin levels greater than 14 mol/L, or at least three times the upper limit of normal. Up to onethird of somatostatinomas are associated with production of multiple hormones, including calcitonin. If serum levels fail to be elevated, both stimulation tests (calcium/pentagastrin, secretin, and tolbutamide) and inhibitory tests (diazoxide) have been described; however, pentagastrin is not currently approved for use in the United States. Localization Somatostatinomas are often large at the time of diagnosis (excluding those in the periampullary location), averaging 5 cm when located in the pancreas and 2–5 cm when located in the duodenum. Tumors located in the pancreas more often present with the syndrome, while duodenal tumors present with bleeding, obstruction, or jaundice. CT, MRI, celiac
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angiography, and ERCP have all been useful for the localization of somatostatinomas.
PPOMA Clinical Presentation Pancreatic-polypeptide-secreting tumors (PPomas) are usually considered nonfunctional neuroendocrine tumors of the pancreas, because they do not cause a clinical hormonal syndrome (despite high serum levels of PP). Up to 40% of PNETs are considered nonfunctional. Pure PPomas are extremely rare and constitute <1% of PNETs. Malignant PPomas may be associated with the MEN1 syndrome. The consistently presenting symptom of PPomas is abdominal pain requiring evaluation or, less commonly, pancreatitis. Diagnosis The diagnosis of PPomas may be made through elevated serum levels of PP; however, only 25% of patients with PPoma have this finding. Exercise and hypoglycemia can falsely elevate serum PP levels, and providers should therefore ensure that fasting levels are obtained. Alcohol abuse, renal failure, medullary thyroid cancer, certain medications, and renal failure can also be the cause of PP overproduction. PPomas are most commonly associated with VIPomas and glucagonomas. Localization PPomas are most frequently identified on CT imaging ordered for the initial evaluation of abdominal pain. On CT imaging, these tumors have a hypervascular appearance consistent with PNETs in general. MRI can also be used to identify tumors not detected by CT scans.
SELECTED REFERENCES Abood GJ, Go A, Malhotra D, Shoup M. The surgical and systemic management of neuroendocrine tumors of the pancreas. Surg Clin N Am 2009; 89:249–266.
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Bellows C, Haque S, Jaffe B. Pancreatic polypeptide islet cell tumor: case report and review of the literature. J Gastrointest Surg 1998;2:526–532. Ghaferi AA, Chojnacki KA, Long WD, et al. Pancreatic VIPomas: subject review and one institutional experience. J Gastrointest Surg 2008;12: 382–393. Kuo SC, Gananadha S, Scarlett CJ, et al. Sporadic pancreatic polypeptide secreting tumors (PPomas) of the pancreas. World J Surg 2008;32:1815–1822. Mansour JC, Chen H. Research review: pancreatic endocrine tumors. J Surg Res 2004;120:139–161. Nesi G, Marcucci T, Rubio CA, et al. Somatostatinoma: clinical-pathological features of three cases and literature review. J Gastroenterol Hepatol 2008;23: 521–526. O’Grady HL, Conlon KC. Pancreatic neuroendocrine tumors. EJSO 2008; 34:324–332. Peng SY, Li JT, Liu YB, et al. Diagnosis and treatment of VIPomas in China. Pancreas 2004;28:93–97. Yao JC, Rindi G, Evans DB. Pancreatic endocrine tumors. In: Cancer: Principles and Practice of Oncology, 8th Edn. (eds.) VT Devita Jr., TS Lawrence, SA Rosenberg. Lippincott Williams & Wilkins, 2008.
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Chapter IV.B.1: Clinical Management of Midgut Carcinoid Tumors Thomas W. T. Ho, MD and Janice L. Pasieka, MD, FRCSC, FACS
OVERVIEW Carcinoid tumors are a range of neuroendocrine tumors (NETs) derived from the neuroendocrine system cells widely distributed in the body. Coined by Oberndorfer in 1907, carcinoid tumors are characterized by their ability to produce peptides that cause characteristic hormonal syndromes. The term “neuroendocrine” derives from the phenotypical relationship to neural cells in the expression of peptides such as synaptophysin, neuron-specific enolase and chromogranin A (CgA). In 1963, Williams and Sandler proposed a classification which divided carcinoids into foregut, midgut and hindgut tumors, recognizing that tumors arising from each segment of the embryological gut varied in their morphological pattern and peptide production (Table 1). Over time, it became apparent that whilst this classification was useful for emphasizing the clinicopathological differences amongst the various gastroenteropancreatic (GEP) NETs, it was less helpful in predicting the biological behavior of each tumor. A new classification system was thus introduced by the WHO in 1980, and revised in 2000; it included not only the site of origin but also histological variations that were more predictive of their biological behavior. Using this system, tumors are classified into well-differentiated NETs, which show benign behavior or uncertain malignant potential; well-differentiated neuroendocrine carcinomas, which are characterized by low-grade malignancy; and poorly differentiated neuroendocrine carcinomas, of high-grade malignancy (Table 2). Nowadays the term “carcinoid” is preferentially used for tumors that arise in the small bowel or tumors that produce serotonin and cause carcinoid 405
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T. W. T. Ho and J. L. Pasieka Table 1
Williams–Sandler classification of NETs.
Williams–Sandler classification of NETs
Localization
Foregut carcinoids
Thymus Lung Stomach Duodenum Pancreas Jejunum/ileum Proximal colon Appendix Colon Rectum
Midgut carcinoids
Hindgut carcinoids
Table 2
WHO classification of NETs.
Well-differentiated neuroendocrine tumor Solid trabecular or glandular structure, Ki67 <2%, absence of cytological atypia, absence of angioinvasion Well-differentiated neuroendocrine carcinoma Well-differentiated, >2 cm, absence of low cytological atypia, absence of lymphovascular invasion, Ki67 <2%, presence of metastases Poorly differentiated neuroendocrine carcinoma Predominant solid structure with necrosis and cellular atypia, Ki67 >15%
syndrome. The remaining “carcinoid” tumors, termed “neuroendocrine tumors”, are classified by their degree of differentiation, and followed by their site of origin and the endocrinopathy if present.
MIDGUT SMALL BOWEL CARCINOIDS Although gastrointestinal NETs remain substantially rarer than adenocarcinomas, their incidence and prevalence have increased significantly over the last three decades. According to the most recent SEER database, the overall age-adjusted incidence of NETs is 5/100,000, compared with 1/100,000 30 years ago. Specifically, the age-adjusted incidence of small bowel carcinoids has increased by 460%, making it second only to NET
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of the lungs. Whether this is related to a biological increase in these tumors or a result of increased reporting and surveillance is not entirely clear. There is a slight male predominance. The prevalence in African Americans is greater than in whites and the other races (0.88/100,000 vs. 0.71/100,000 vs. 0.18/100,000). Regardless of race, the median age of diagnosis for small bowel carcinoids is 66 years. Presentation of Small Bowel Carcinoids The small bowel is the site of approximately 45% of NETs and is typically located in the terminal ileum, within 80 cm of the ileocecal valve. Arising in the submucosal layer, the primary tumor is typically small (diameter less than 1 cm), flat and fibrotic, making it difficult to identify during endoscopy or contrast imaging. One third of patients are found to have multicentric small bowel tumors. Mesenteric nodal metastasis is a frequent finding in small bowel carcinoids. These mesenteric metastases typically grow larger than the primary tumor and are characterized by marked mesenteric fibrosis from a desmoplastic reaction, leading eventually to kinking of the bowel. Up to 50% of patients therefore present as an emergency for small bowel obstruction. With time, the pronounced fibrosis may fix the mesentery to the retroperitoneum so that fibrous bands may also obstruct the duodenum. With progression, the mesenteric vessels become occluded and chronic ischemia of the bowel develops. Patients therefore present insidiously with chronic nonspecific abdominal pain and a history consistent with intermittent ischemia, making it difficult to diagnosis on initial presentation. For some, the significance of their chronic abdominal pain is brought to light only when the manifestations of carcinoid syndrome are noted. (See the sections “Carcinoid Syndrome” and “Carcinoid Heart Disease.”) (Table 3). Some patients do not manifest any obvious signs or symptoms: the diagnosis becomes apparent only on an incidental imaging study. Computer tomography (CT) findings of mesenteric mass with calcification and the radial “spoke and wheel” pattern are classical for regional disease arising form a small bowel carcinoid. On T2-weighted magnetic resonate imaging (MRI), the mesenteric mass typically appears as a hypointense stellate lesion. Similarly, NET liver metastases are multiple,
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T. W. T. Ho and J. L. Pasieka Table 3
Presentation of small bowel carcinoids.
Typical presentation of small bowel carcinoids
(1) Acute small bowel obstruction 50% (2) Chronic remitting abdominal pain (mean duration 54 months) (3) Incidental finding on imaging studies: Mesenteric mass 39% Liver metastases 31% (4) Carcinoid syndrome 20–30%
Unusual presentations
Spread to extra-abdominal sites may occasionally be the first manifestation of carcinoid tumors. The following are usually indicators of a poor prognosis: • • • • • • • • •
Axial skeleton (spine, ribs, skull) Lungs CNS Cervical (Virchow’s) lymph nodes Peripheral lymph nodes Ovaries Breasts Skin Myocardium
highly vascular lesions that are characteristically different in their appearance from a primary adenocarcinoma. These lesions usually demonstrate robust enhancement early in the arterial phase on CT imaging, becoming isodense with liver parenchyma during the portal venous phase. On MRI, the metastases appear hypointense on T1-weighted, and moderately or strongly hyperintense on T2-weighted unenhanced scans. Carcinoid Syndrome Carcinoid syndrome describes a constellation of symptoms related to the secretion of vasoactive peptides such as serotonin, histamine or tachykinins into the systemic circulation. There are four mechanisms by which it can occur: The most common mechanism by far is in the setting of liver metastasis whereby these peptides escape first pass metabolism in the liver and
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Liver metastasis Significant liver dysfunction without metastasis Significant tumor burden/high amine production Tumor draining directly into systemic circulation • Primary ovarian tumor or ovarian metastasis • Retroperitoneal metastasis • Peritoneal metastasis • Primary lung or lung metastasis • Primary rectal tumor
enter the systemic circulation directly. The classic symptoms include episodic cutaneous flushing (90%) and secretory diarrhea (70%) but lesser symptoms such as abdominal cramps, bronchial constriction and wheezing, myopathy and pellagra (niacin deficiency) may also be present. The carcinoid flush is divided into four categories, as a reflection of the duration, tumor burden and secretory product (Table 4). Management of carcinoid syndrome Attempts to control the symptoms and decrease the biochemical production should be made prior to any surgical intervention, and subsequently following any intervention. Somatostatin analogs have revolutionized the Table 4
Types of carcinoid flush.
Type 1
Diffuse, erythematous, affecting face, neck, upper chest
Lasts 1–5 min
Brought on by stress or tryptophan-rich foods
Type 2
Violaceous flush affecting face, neck, upper chest; facial telangiectasia
Lasts up to 2h
Patients stop noticing when flushing over time
Type 3
Dark purple residual discoloration, with thickening of the skin and telangiectasia on the face and upper torso; diffuse flush affecting the whole body
Lasts hours to days
Profuse lacrimation, swelling of salivary glands, hypotension, facial edema
Type 4
Bright red, patchy flushing (atypical carcinoid flush)
—
Mediated by histamine secretion (gastric NETs)
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treatment of carcinoid syndrome, demonstrating clinical improvement in up to 80% of patients and biochemical response in 70–90% of patients. Somatostatin analogs work by binding to somatostatin receptors (SSTRs), specifically SSTR-2 and SSTR-5, on the surface of carcinoid tumor cells, and inhibit the secretion of vasoactive substances. Currently, two somatostatin analogs (octreotide and lanreotide) are available commercially and have demonstrated equal efficacy (see “Adjuvant Therapy”) (Table 5). Carcinoid Heart Disease In 50–60% patients with carcinoid syndrome, exposure of the heart to high levels of serotonin and the other vasoactive agents leads to the development of right-sided valvular lesions characterized by plaquelike fibrous endocardial thickening. The right side of the heart is predominantly affected as the lungs are generally able to deactivate serotonin before it enters the left atrium. Because of retraction and fixation of the valves, tricuspid regurgitation is a near-universal finding. Involvement of the pulmonary valve is also common, leading to regurgitation and stenosis. Over time, symptoms of right-sided heart failure become apparent, such as edema, hepatomegaly, and fatigue with exertion. Historically, over one third of patients with small bowel carcinoid died of heart failure. Over the last two decades, the median survival has improved from 1.5 years to 4.4 years. The marked improvement in the mortality rates of patients with carcinoid heart disease has been attributed to the liberal use of somatostatin analogs and, more recently, the reintroduction of cardiac value replacement. A significant reduction in the perioperative mortality from cardiac surgery, now less than 10%, has resulted in a trend toward earlier surgical management of this complication in selected patients. Preoperative Assessment of Midgut Small Bowel Carcinoids All patients with NETs should be assessed in a multidisciplinary clinic devoted to these complex patients. Although surgery remains the first line and most effective treatment for these patients, most will require multimodality therapies. The diagnosis and preoperative assessment of
Initial therapy (Short-acting + one long-acting)
Analog type
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Somatostatin analog therapies.
Formulation
Parenteral form
Recommended initial dosing
Comments
Long-acting
Octreotide
Intramuscular depot
Long-acting
Lanreotide
Sandostatin LAR® Available in 10, 20, 30 mg Somatulin Autogel® Available in 60, 90, 120 mg
20 mg monthly Crossover period (2 wks) of short-acting octreotide needed 90 mg monthly No crossover period of shortacting octreotide needed
Subcutaneous depot
Can be titrated for breakthrough
Advantage of S/C injection: ideal for patients on anticoagulation or presence of significant muscle loss
Perioperative therapy Octreotide
Intravenous
100 µg
Omit if long-acting on board
Infusion (100 µg in 100 cc saline)
Octreotide
Intravenous
10–50 µg/h
Titrate to compensate for BP drop or cutaneous flush due to tumor manipulation
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Octreotide
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Clinical Management of Midgut Carcinoid Tumors
To initiate therapy: start with short-acting + one long-acting
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midgutsmall bowel carcinoids are listed below. In particular, an accurate assessment of the location and extent (staging) of the tumor, an assessment of the endocrinopathy, and a cardiac status are all crucial in preoperative planning. Biochemical diagnosis • •
•
24 Hour urinary 5-HIAA Plasma CgA Needed as tumor markers can be utilizied to assess therapeutic response High levels of u5-HIAA and/or CgA correlate with a poorer prognosis
Anatomical imaging •
• •
Contrast-enhanced CT: demonstrates mesenteric metastases in up to 70% of cases (seen as circumscribed mesenteric mass with radiating densities); retroperitoneal extension; relationship of tumor to main mesenteric vessels MRI: higher sensitivity than CT in demonstrating regional and liver metastases (80% vs. 77%) Both MRI and CT underestimate the extent of disease 32% of the time; liver 20% of the time and mesenteric disease 15%.
Functional imaging •
•
•
Somatostatin receptor scintigraphy (octreotide scan): high sensitivity (80–90%) in detecting metastatic spread, particularly in extra-abdominal sites. The sensitivity increases to 90% in the presence of carcinoid syndrome. Tumor avidity on this scan is predictive of tumor response to future octreotide therapy. MIBG scintigraphy: sensitivity of 60–70%; an alternative scan in the 10% of carcinoid tumors that do not take up octreotide; identifies patients who will benefit from MIBG therapy. 5HTP-PET: new imaging modality that utilizes the SSTR; has been shown to detect more lesions than CT or octreotide scanning in 58% of patients; benefit lies in patients with biochemical evidence of carcinoids or tumor recurrence but with negative conventional imaging workup.
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Cardiac assessment • • •
Cardiologist’s assessment EKG Transesophageal echocardiogram
Colonoscopy to evaluate for other colonic tumors •
Up to 15–25% of small bowel carcinoids exhibit a synchronous association with other tumors, typically colonic adenocarcinomas and less frequently small bowel lymphomas.
Surgical Management of Small Bowel Carcinoids Surgery is the only way to achieve a complete cure and remains the mainstay of treatment. Yet, in many patients, cure is not possible because of the presence of mesenteric disease in 80–90% of patients, liver metastasis in 60–80%, and peritoneal disease in up to 30% at the time of presentation. Broadly speaking, the goals of surgical intervention are: (1) Control of primary tumor and locoregional mesenteric disease (2) Cytoreduction of distant disease, primarily liver metastasis Control of primary tumor and locoregional mesenteric disease Resection of the primary tumor should be combined with adequate clearance of the regional mesenteric nodal disease. The rationale is: •
• •
Aggressive resection of the mesenteric disease is associated with better symptom relief and improved quality of life, and has been shown to increase the median survival to 7.9 years from 6.2 years when mesenteric disease was left behind. Effectively deals with the presenting problem of small bowel obstruction (SBO) and/or ischemic bowel. Diminishes the chance of progression of the SBO and/or bowel ischemia.
Even in the presence of distant metastasis, removal of the primary tumor and debulking regional disease remains important because: •
Alleviation of symptoms from a reduction of the tumor burden resulting in a decrease in the release of peptides provides excellent palliation.
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Most studies report a significant decrease in the rate of diarrheal episodes as well as a reduction in continuous and postprandial abdominal pain. However, carcinoid flush is not improved with surgery alone. A retrospective series demonstrated a greater progression-free survival of 56 months when the primary tumor was resected, compared with 25 months when unresected. In addition, overall survival was increased to 159 months from 47 months. It is postulated that the primary secretes propagating factors feeding into the liver metastases through the portal circulation. Intestinal bypass should be avoided, because the mesenteric disease continues to progress and ischemia will likely develop in the bypassed intestinal segment.
Ability to achieve adequate resection of the primary and regional disease depends on: (1) Acute versus planned procedure (2) Extent of the mesenteric disease Acute versus planned procedure •
•
•
In the acute setting (emergency surgery), extensive mesenteric resection should not be undertaken as appropriate assessment of the patient’s endocrinopathy, cardiac status and staging needs to be done in order to properly select patients for aggressive palliative surgery. Perform the surgery necessary to deal with the acute problem of SBO or ischemic bowel (i.e. limited bowel resection, temporarily defunctioning or bypassing the obstruction; assess intraoperative disease). Evaluate and treat the patient postoperatively for carcinoid syndrome and/or carcinoid heart disease. When these are adequately controlled, the patient is restaged and sent to centers of excellence for definitive surgical management.
Stage of mesenteric disease •
Arkerstrom’s stages of mesenteric involvement are predictive of surgical resectability.
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Stage 1 Stage 2
Mesenteric mass close to the intestine Mesenteric mass involving arterial branches near their origin from the SMA
Stage 3
Mesenteric mass extending along (but not encircling) the SMA trunk
Stage 4
Mesenteric mass extending behind or above the pancreas; encircling the SMA or involving the origin of proximal jejunal arteries
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Ileal resection to root of main arterial branch Ileal resection plus right hemicolectomy to include right colic and ileocolic arteries Attempt to dissect tumor free from SMA, then resect ischemic SB segment and right hemicolectomy Tumor not resectable, but may be able to debulk it to allow resection of obstructed or ischemic SB segment
Cytoreduction of distant metastatic disease •
• • •
•
Liver-directed cytoreduction includes primary surgical (formal hepatectomies or segmental resections), wedge resections, radiofrequency ablation (RFA) and hepatic artery ligation. Radiographic interventional approaches include hepatic chemoembolization (HCE), bland embolization and radionuclide therapies. Five-year survival of patients with hepatic resection has been increased to 75% from the historical figure of 35% for nonsurgical patients. Hepatic cytoreduction surgery has resulted in both biochemical and clinical responses in 65–95% of patients when at least 70% of the tumor burden in the liver was removed. Most patients require a multimodality approach to the liver disease (see chapter on management of metastatic NET).
Adjunctive Medical Therapy Somatostatin analogs Somatostatin analogs form the primary adjunctive treatment for midgut small bowel carcinoids. Studies have reported a symptomatic response
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in 50–75% and a biochemical response in 40–60% of patients. A true tumor response of greater than 50% reduction in tumor volume is rarely seen (15%). However, a recent randomized study reported partial responses and tumor stability in up to 50% of patients, suggesting that this treatment should also be offered to asymptomatic patients with progressive disease. The median response duration is 12 months, at which patients start to develop tachyphylaxis or loss of therapeutic effect. Newer somatostatin analogs such as SOM 230 which have a different binding affinity to the somatostatin receptors (mainly SSTR4 and SSTR5) may provide an alternative therapy once tachyphylaxis develops.
Interferon alpha Interferon (INF) alpha has been shown to inhibit protein and hormone synthesis in tumor cells, inhibit angiogenesis and stimulate the immune system by increasing natural killer cells. In addition, it upregulates the expression of somatostatin receptors and therefore may act synergistically with somatostatin analogs. However, the adverse effects of INF-α are more pronounced than with somatostatin analogs and have limited their use in some patients. A starting dose of 3 million IU three times weekly is usually well tolerated. Some studies have reported biochemical and clinical responses in about 50% of patients and disease stabilization in 35% but these excellent results have not been reproduced consistently.
Targeted/radionuclide therapies Somatostatin analogs By linking radionuclides such as 111indium, 90yttrium or 177lutetium to somatostatin analogs, which are taken up by 90% of tumor cells, carcinoid tumors can be specifically targeted with relative sparing of intervening nonneoplastic tissue. 111Indium, a gamma-emitter, showed some initial effect but the benefit appeared to be limited due to its poor penetration of tumor tissues. Recently, the somatostatin analogs Sandostatin (Novartis, Basel, Switzerland) and Lanreotide (Ipen, Berkshire, UK) have been
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coupled to a chelating agent (DOTA) which has allowed the formation of stable compounds when bound to the beta-emitter 90Y (yttrium) or 177Lu (lutetium). Both 90Y and 177Lu have been shown to display a greater therapeutic effect than 111indium. At present, the most effective therapy available, 177Lu-DOTA0Tyr3octreotate, has produced tumor responses in 35% and tumor stabilization up to 80% of patients. Its maximum tolerated dose is limited by renal and bone marrow toxicity.
mIBG Meta-iodobenzylguanidine (mIBG), which is taken up by 70% of NETs, has been successfully linked to the radionuclide 131I, a beta-emitter. Treatment with 131I-mIBG has yielded only a 30–40% biochemical response and a 15–20% tumor response at best. Patients, however, have reported a symptom response of 60–80%, and thus good palliation has been provided to these patients. Leukopenia and thrombocytopenia are the main significant side effects of this treatment. Myelosuppression in patients with extensive bone metastases has been reported. Some recent evidence suggests that radioisotopes in combination with concurrent chemotherapy may be more efficacious.
Chemotherapy Cytotoxic therapies are considered the first line therapy for the rare, poorly differentiated neuroendocrine carcinomas (high proliferation index, Ki67 >16%). The combination of etoposide and cisplatin has demonstrated a response rate of over 60%, albeit of short duration (median duration 2–6 months). In two randomized trials, the combination of 5-FU and streptozocin produced response rates of only 33% and 22%, with no evidence of improved survival. Most small bowel carcinoid tumors are well-differentiated, with a Ki67 index of less than 2%, and thus the use of systemic chemotherapy has not been shown to be beneficial to date. Preliminary data from targeted biological therapies have recently shown promise. Small phase II clinical trials with Bevacizumab (monoclonal
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antibody to vascular endothelial growth factor), Imatinib (plateletderived growth factor inhibitor), Temsirolimus (mTOR inhibitor) and tyrosine–kinase inhibitors have demonstrated tumor stabilization. In the future these compounds may prove to be an important adjunct for patients with metastatic small bowel carcinoids. External beam radiotherapy Local irradiation has limited value in midgut small bowel carcinoids. Its main application is for pain control of bone metastases. Followup and Prognosis After aggressive surgical intervention and the utilization of multimodality therapy, many patients remain symptom-free for extended periods. Since midgut small bowel carcinoids typically progress slowly, biochemical and radiographic recurrences become apparent after a median followup of five years. Any progression noted necessitates complete re-evaluation of surgical/cytoreduction options, increase or change in somatostatin analogs and consideration of chemotherapy. Re-evaluation of eligibility for radionuclide therapy should be done, as patients have been shown to change their tumor uptake over time. Survival for midgut small bowel carcinoids is dependent on the extent of disease, with the more significant adverse prognostic factors being the presence of liver metastases, carcinoid syndrome and carcinoid heart disease. Other poor prognostic factors include age >75, high urinary 5-HIAA levels and/or CgA, significant weight loss and presence of extraabdominal metastases. The overall median survival is 115 months.
Every 6 months for the first 2 years; every 12 months if disease is stable
Urinary 5-HIAA Plasma CgA Anatomical imaging
Annually
Octreotide scan or MIBG, depending on preoperative uptake Echocardiogram
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Survival probability (%) 5-year 10-year
Extent of disease Localized disease Regional disease Distant disease
65 70 55
50 45 30
An algorithm for the management of carcinoid tumors at our multidisciplinary NET clinic is shown in Fig. 1.
Biochemical Workup CT/ MRI Octreotide Scan MIBG Scan Echocardiogram
Assess Resectability
Cytoreductive Surgery Including Embolization
Complete Resection
Followed
Residual Disease or Nonresectable
Asymptomatic Radionuclide Therapy +/− Somatostaltin
Endocrinopathy α Somatostatin & Radionuclide Therapy
Tumor Response
Tumor Response
Disease Progression
Fig. 1
Algorithm for management of carcinoid tumors.
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APPENDICEAL CARCINOIDS Carcinoids of the appendix were for a long time thought to be the most common site in the gastrointestinal tract. This impression may have arisen from the fact that removal of the appendix is an operation of considerable frequency, rendering it available for frequent histopathological examination. The incidence of appendiceal carcinoids has since decreased to account for 8% of all GEP NETs reported in cancer registries. Most appendiceal carcinoids are diagnosed incidentally (1 in 300 appendectomies). Unlike the small bowel carcinoids, they express very different biological behavior: • • • •
Arise from subepithelial neuroendocrine cells; Exhibit excellent overall prognosis (five-year survival >98%); Carcinoid syndrome is rare (<2%); Τhe size of the primary is predictive of metastatic potential.
The risk of nodal metastasis for well-differentiated appendiceal carcinoids less than 1 cm is virtually zero, up to 10% for tumors 1–2 cm, and 30% for tumors greater than 2 cm. All appendiceal carcinoids should undergo a pathological review, which will look for pathological features that may indicate a more aggressive and potentially malignant tumor (Table 6). A prognosticating right hemicolectomy in patients at higher risk
Table 6 Tumor size <1 cm >2 cm 1–2 cm
Treatment of appendiceal carinoids. Treatment recommendation
Appendectomy (in the absence of aggressive features) Prognosticating right hemicolectomy Consider prognosticating right hemicolectomy in the presence of these aggressive features: • • • • • • •
Invasion into mesoappendix Lymphovascular invasion Serosal involvement Margin involvement Positive lymph nodes in appendectomy specimen High Ki67 index (>2%) Goblet cell (see GCC section)
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of metastases is helpful in sorting out which patients are cured (requiring no further followup) and which patients need to be followed as per the small bowel carcinoid guidelines. Fortunately, the majority of appendiceal tumors (90%) are less than 1 cm in size and are situated at the tip of the appendix (70%), and therefore are invariably cured with appendectomy alone. However, there is a considerable coincidence — 7 to as high as 48% — of further GI malignancies with appendiceal carcinoids and these patients should be offered a complete colonoscopy.
GOBLET CELL CARCINOIDS The goblet cell carcinoid (GCC) is a rare variant of the appendiceal carcinoid that has histological features of both adenocarcinoma and carcinoid tumor, and therefore warrants different considerations than the treatment outlined for appendiceal carcinoids. GCCs stain positively for synaptophysin, neuron-specific enolase, cytokeratin and chromogranin, which are all characteristics of carcinoid lineage, and produce mucin, which is a feature consistent with the adenocarcinoma cell line. GCCs display a spectrum of histologies, from the mixed endocrine–exocrine type to more of an adenocarcinoma phenotype of either signet ring cell or poorly differentiated adenocarcinoma. The more poorly differentiated the tumor and the higher the Ki67 index, the worse the prognosis. Because of the rarity of these lesions and the difficult and evolving histological classification, clear guides to treatment are hard to conclude from the literature. The clinical behavior of GCCs appears to be intermediate between the aggressive adenocarcinoma and the more indolent carcinoid. The mean age at presentation is 55 years, with a slight female predominance. Metastasis to distant sites at the time of diagnosis is common (50–63%), with ovaries being the most frequent site, followed by peritoneal disease. Liver metastasis and extra-abdominal disease are rare. Ten percent of patients with GCCs are found to have other primary malignancies. GCCs do not secrete the bioactive peptides, and therefore, unlike small bowel carcinoids, there are no reliable tumor markers for this disease. They do not routinely express somatostatin receptors and thus do not localize on octreotide scans; nor can radionuclide therapy be utilized. A recent
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meta-analysis found that T1 and T2 tumors rarely metastasize to lymph nodes, and therefore suggested that further resection for localized T1 and T2 disease is not necessary. It has also been shown that a right hemicolectomy does not change survival, nor does it decrease recurrence in patients with disease beyond the appendix (stages II–IV). This suggests that most patients have peritoneal or systemic disease at presentation. Therefore, a second look staging laparotomy is likely needed to adequately stage the patient and allow more advanced therapeutic options, such a peritoneal stripping and intraoperative chemotherapy. The median survival for GCCs is 47 months and the overall 5-year survival is 73–45%, depending on the histological classification. Peritoneal carcinomatosis is the most common disease-specific cause of death. For that reason many centers have adapted the approach of further resection combined with peritoneal stripping and intraoperative chemotherapy. Limited series have reported 10-year survival rates of 60% when peritoneal stripping was combined with intraoperative chemotherapy.
SELECTED REFERENCES Akerstrom G, Hellman P, Hessman O, et al. Management of midgut carcinoids. J Surg Oncol 2005;89:161–169. Boudereux P, et al. Consensus NANET guidelines in small bowel carcinoid. Pancreas 2010;39(6):753–766. Chambers A, Pasieka JL, et al. Role of imaging in the preoperative staging small bowel NET. J Am Coll Surg 2010;211:620–627. Kharow M, Gill G, Harrinton T, et al. Management of advanced NET in the hepatic metastases. J Clin Gastroenterol 2009;43:838–847. Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008;9:61–72. Pasieka JL. Carcinoid tumors. Surg Clin North Am 2009;89(5):1123–1137. Stinner B, Rothmund M. Neuroendocrine tumours (carcinoids) of the appendix. Best Pract Res Clin Gastroenterol 2005;19(5):729–738. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063–3072.
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Chapter IV.B.2: Clinical Management of Insulinoma David T. Hughes, MD, Gerard M. Doherty, MD and Paul G. Gauger, MD
PREOPERATIVE CONSIDERATIONS The majority of patients presenting with the clinical symptoms of insulinoma have solitary, small intrapancreatic tumors that can be treated by enucleation or limited pancreatic resection depending on location. Preoperative Planning • • • • •
Endoscopic ultrasound for primary localization (often well-defined and hypoechoic) (see other chapter on imaging and diagnosis) (Fig. 1) Abdominal CT to exclude metastatic disease or with MEN-1 (see other chapter on imaging and diagnosis) Splenectomy vaccines if planned or incidental splenectomy is likely Laparoscopic vs. open, based on preoperative localization studies, patient characteristics, and surgeon experience Preoperative admission during preoperative fasting for dextrose infusion and blood sugar monitoring if symptoms of nocturnal hypoglycemia are frequent or severe and NPO after midnight status is anticipated.
OPERATIVE PLANNING AND APPROACH The principles of surgical treatment center on intraoperative localization (usually by palpation and intraoperative ultrasound), followed by complete excision with either enucleation or limited pancreatic resection (Table 1). 423
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Fig. 1 Hypoechoic insulinoma with hypervascular appearance on Doppler ultrasound (largest arrow). The pancreatic duct is seen without flow, with a 2 mm margin (mediumsize arrow) between duct (smallest arrow) and tumor, which is important in determining whether enucleation or pancreatic resection will be required (Isla et al., 2009).
Table 1
Surgical options for insulinoma.
Enucleation Small tumors Benign Superficial Sporadic Solitary >2 mm separation from pancreatic duct No lymphadenopathy Pancreatic body or head
Pancreatic resection Large tumors Malignant, infiltrating or locally invading Deep MEN-1 Multifocal Duct involved or less than 2 mm separation Lymphadenopathy Distal pancreatic tail
Surgical Resection • • • •
Cure rates 75–98% for benign insulinomas Palliative resection of metastatic disease can improve symptoms and survival if a substantial proportion (≥90%) is removed Most benign tumors have pseudocapsule that allows for enucleation Options for excision
Enucleation Distal pancreatectomy Central pancreatectomy with pancreaticojejunostomy
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Pancreaticoduodenectomy (large malignant insulinomas or direct involvement of the main pancreatic duct)
Avoid splenectomy if possible because of increased risk of postoperative infectious complications Confirm removal with intraoperative frozen section Pancreatic drain placement important, given 18–33% fistula rate (a risk with either enucleation or resection)
INTRAOPERATIVE LOCALIZATION Open • • •
•
Tumors typically darker in color than surrounding parenchyma Bimanual palpation effective for about 90% of pancreatic body and tail lesions; fewer in head of pancreas Mobilize head (with Kocher maneuver) and tail (along superior and inferior margins) completely to facilitate palpation and intraoperative ultrasound (IOUS) IOUS to localize tumor and assess location of vessels and pancreatic duct
•
Insulinomas are typically hypoechoic, but can be isoechoic and difficult to discern from surrounding parenchyma
Doppler ultrasound
Insulinomas are often hypervascular Can help distinguish vessels from pancreatic duct
Laparoscopic • •
Ultrasound Primary modality for localization, due to limited tactile sense Addition of hand port for manual palpation can help with localization
OPERATIVE TECHNIQUE Open • •
Upper midline laparotomy or bilateral subcostal incision Assess for metastatic disease
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Bimanual palpation of pancreas after Kocher maneuver and mobilization of tail and body Intraoperative ultrasound Determination of resection technique — enucleation vs. resection Frozen section to confirm resection Placement of closed suction drainage
Laparoscopic •
Benefits
•
Instruments
•
Decreased length of stay Faster recovery Decreased wound complications/hernias Similar pancreatic fistula rates compared to open approach Conversion rate of 14%, primarily due to inability to localize lesion Advanced laparoscopy set 7.5–12 MHz laparoscopic ultrasound probe Ultrasonic scalpel or ligature device Liver or fan retractor for posterior stomach Endoscopic stapler for pancreatic resection Addition of hand port allows manual palpation
Port placement (Fig. 2)
POSTOPERATIVE MANAGEMENT Complications • •
Pancreatic fistula — 18% Diabetes — 4%
Prognosis • •
Nearly 100% survival at 10 years Recurrence rate of 5% at 10 years
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Fig. 2 Four ports typically used for a laparoscopic pancreatomy. The ultrasound is placed in the right sided port and the camera is placed at the umbilical.
•
Negative predictors of survival
Lymphovascular invasion Lymph node metastasis Presence of MEN-1 Microscopic positive margins are not usually predictive of future recurrence and occur in 1/3 of patients related to enucleation of tumor as operative strategy
SPECIAL CIRCUMSTANCES Failure to Localize (Occult Insulinoma) • • •
Most occult lesions are in head of pancreas Focus ultrasound exam on head of pancreas after Kocher maneuver if cannot localize in body or tail Extrapancreatic lesions are exceedingly rare and usually found in wall of duodenum
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• •
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Blind distal pancreatectomy not recommended, should close and confirm diagnosis, followed by selective arterial calcium stimulation with venous sampling to localize site of insulin hypersecretion Nesidioblastosis is a diagnosis of exclusion and incidence is <2% Treat medically or with subtotal pancreatectomy in severe cases Reoperative cases should have confirmation of diagnosis followed by preoperative localization with combination of EUS, CT, and venous sampling
MEN-1 • • • •
80% of patients have multifocal tumors distributed throughout pancreas Most of the tumors are nonfunctional; the insulin-producing tumors are generally isolated Treatment: extended distal pancreatectomy and enucleation of tumors in head with ultrasound guidance Patients who also have hypergastrinemia should have duodenotomy and resection of tumors from wall of duodenum, as well as peripancreatic lymph node dissection
Metastatic Disease • •
10% of patients at presentation Determination of malignancy
• • •
Lymphovascular invasion on final pathology Positive lymph nodes Evidence of distant metastasis
Recurrence rate 75% after initial resection Liver is most common site of metastasis Treatment options for palliative purposes
Chemotherapy (5-FU, dacarbazine, epirubicin) — 20–35% response rate (Table 2) Medical management of symptoms with diazoxide or octreotide Isolated liver metasectomy or hepatic artery chemoembolization
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Medications for the treatment of insulinoma. Dose
100–300 mg PO BID 100–300 mcg SQ TID
Effectiveness 50% 50% (often temporary)
Side effects Edema, weight gain, hirsutism, nausea Gallstones, bradycardia, diarrhea, nausea
MEDICAL MANAGEMENT Control of hypoglycemic symptoms in unresectable, recurrent, or metastatic disease is the primary goal of medical management. Dietary modifications, including avoidance of prolonged fasting, frequent snacking, and addition of complex carbohydrates, can mitigate some symptoms of hyperinsulinemia.
SELECTED REFERENCES Isla A, Arbuckle JD, Kekis PB, et al. Laparoscopic management of insulinomas. BJS 2009;96(2):185–190. Nikfarjam M, Warshaw AL, Axelrod L, et al. Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital. Ann Surg 2008;247(1):165–172.
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Chapter IV.B.3: Clinical Management of Gastrinoma Steven K. Libutti, MD, FACS
OVERVIEW Gastrinoma is a subset of pancreatic neuroendocrine tumors (PNETs), which are rare endocrine neoplasms that occur sporadically or as part of familial endocrine syndromes. These lesions are classified as APUDomas (amine precursor uptake and decarboxylation) and share cytochemical features with melanoma, pheochromocytoma, carcinoid tumors, and medullary thyroid carcinoma. The prevalence of gastrinoma is approximately 10 per million population. Gastrinomas may behave in a benign or malignant fashion and the percentage of gastrinomas that are actually malignant is unclear. No histologic criteria predict malignancy; therefore, malignancy can only be established by the presence of metastases. Approximately one half of patients have a malignantly behaving gastrinoma at the time of diagnosis and metastases are usually found in the peripancreatic lymph nodes and in the liver. Bone metastases have been reported in about 30% of patients with metastatic gastrinoma in the liver. A number of cases of extrapancreatic gastrinoma localized in lymph nodes have been described with no evidence of primary tumor, and some of these cases have apparently been cured by excision of lymph nodes, which suggests that the gastrinoma was not metastatic but originated as a primary tumor in the lymph node. While gastrinomas are commonly referred to as pancreatic neuroendocrine tumors, the proportion of gastrinomas found at surgery in the duodenum and in lymph nodes near the pancreatic head is greater than 50%, such that 65–90% of all gastrinomas found at surgery occur in the
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pancreatic head–duodenal area and not necessarily in the pancreas proper. This fact is critical in the localization of gastrinomas intraoperatively. In fact, sporadic duodenal gastrinoma can occur without involvement of the pancreas in 25–50% of patients operated on for ZES (Fig. 1). Gastrinomas may also occur in other intra-abdominal sites, such as the liver, stomach, jejunum, mesentery, common bile duct, and spleen. Primary tumor size, but not lymph node metastases, has been shown to be an important factor in predicting liver metastases. Liver metastases occurred in 4% of gastrinomas less than 1 cm in diameter, in 28% with tumors 1.1–2.9 cm, and in 61% greater than 3 cm. Duodenal gastrinomas have been found to be malignant with metastatic spread in 48–75% of cases. Because most duodenal gastrinomas are small (80% less than 1 cm) and most pancreatic gastrinomas are large (70% at least 3 cm), it remains unclear whether tumor size and location are independent predictors. Roughly 20% of patients with ZES have a familial form with evidence of MEN 1. MEN 1 is an autosomal dominant trait characterized by hyperplasia or tumors of multiple endocrine organs, with hyperparathyroidism
Fig. 1 This diagram shows the location of the primary gastrinoma in 57 evaluable patients with sporadic duodenal ZES who underwent an operation with intent to cure. The dashed lines indicate the first, second, and third/fourth portions of the duodenum.
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being the most common abnormality. Neuroendocrine tumors of the pancreas are the second most common, occurring in 82% of MEN 1 patients, with 57% having ZES and 25% insulinomas. Pituitary and adrenal adenomas are less common. Patients with MEN 1 with ZES differ from sporadic cases, in that they frequently present at a younger age; their tumors are almost always multiple and frequently small, and in some studies patients with MEN 1 have an increased survival rate compared with sporadic cases. Gastrinomas are more common in males (60%) than in females; the mean age at diagnosis is 45–50 years and approximately 20% have MEN 1. The most common presentation of patients with ZES is abdominal pain in 26%–58%, which usually cannot be differentiated from pain caused by other common acid-peptic disorders. However, in some studies a significant proportion of individuals (14–25%) have no peptic ulcer or abdominal pain at the time of diagnosis. Thirty-seven to 73% of patients have diarrhea as an initial symptom, and in 15–18% it is the only symptom. Esophageal symptoms, endoscopic abnormalities, or both, were present in 50–70% of patients. Although atypical or multiple ulcers strongly suggest the diagnosis, in 18–25% of patients no ulcers are present at the time of diagnosis. The diagnosis should be suspected on the basis of the clinical presentation and established in almost all patients by demonstrating elevated basal gastric acid secretion (BAO) and fasting hypergastrinemia. ZES should be suspected in the clinical setting of peptic ulcer with diarrhea, familial peptic ulcer, peptic ulcer in unusual locations, and recurrent or resistant peptic ulcer. It should be particularly suspected in patients with peptic ulcers that persist or recur despite treatment for Helicobacter pylori infection or with histamine H2-receptor antagonists, in patients with severe esophagitis, and in patients with duodenal ulcers without H. pylori. Surgical Management of Primary Gastrinomas Once the diagnosis of a gastrinoma has been made, a thorough assessment of the extent of disease should be carried out, including computed tomography of the chest, abdomen, and pelvis, as well as somatostatin receptor scintigraphy. If preoperative imaging fails to reveal evidence of metastatic disease, surgical management should be considered. The use of antisecretory
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and acid-reducing agents has dramatically altered the management of ZES patients, and the availability of these agents as well as their long duration of action has greatly simplified management because they can be taken once or twice per day. The role of surgery in the management of patients with ZES has therefore changed in its focus from managing the sequelae of acid hypersecretion to managing the long-term outcome for patients due to the malignant potential of the primary tumor. Total gastrectomy can now be reserved for very specific circumstances, such as when a patient does not have access to routine medical followup or cannot or will not take oral medications reliably. Parietal cell vagotomy in ZES patients, in whom no tumor was resected, decreased basal acid output by 66%. However, most patients still needed some antisecretory drug and therefore, at present, parietal cell vagotomy is not performed routinely. In patients with ZES and the MEN 1 syndrome, correction of hyperparathyroidism reduces the fasting serum gastrin concentration, increases the responsiveness to a given dose of antisecretory medication, or decreases the basal acid output. Therefore, in patients with ZES and MEN 1 with hyperparathyroidism, parathyroidectomy should be performed before any contemplated surgical procedure to control acid hypersecretion. The impact of surgical resection of the primary gastrinoma on overall survival in ZES patients has been extensively studied. In a number of reports, the 5-year survival rate for all patients with ZES was 62–87% and the 10-year survival rate was 47–77%. A comprehensive study reported long-term outcome in 151 consecutive ZES patients who underwent operation with curative intent. Among patients with sporadic gastrinoma, 34% were biochemically and radiographically free of disease at 10 years, compared to none with MEN 1 and ZES. The overall 10-year survival, however, was 94%. In another study from the same institution, a multivariate analysis of factors associated with long-term (>5 years) cure demonstrated that age, gender, duration of symptoms or disease, and severity of disease as reflected by the level of BAO, FSG, or SST did not predict outcome. Only a diagnosis of MEN 1 was inversely correlated with cure. In addition, the status of preoperative imaging studies (either positive or negative), tumor size, and number of tumors resected did not correlate with cure. However, a normal postoperative fasting serum gastrin (FSG) and secretin stimulation test (SST) did independently and significantly predict cure.
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Patients with sporadic gastrinoma arising in the duodenum enjoy similar results following resection. In a study of 63 patients with a gastrinoma in the duodenum who underwent surgery with curative intent, the diseasefree survival at 10 years was 60%, with a disease-specific survival of 100% (Fig. 2). The most important predictor of duration of disease-free survival was lymph node status. Since the resection of a gastrinoma results in an excellent prognosis and since there is evidence of the increased importance of the malignancy in determining survival, surgical resection of gastrinoma is offered for good-risk patients who have ZES. Surgical resection of gastrinoma may, in fact, alter the natural history of the disease. Only 3% of patients (3 of 98) with ZES undergoing tumor resection developed liver metastases during followup, whereas significantly more patients treated medically developed liver metastases (26%, or 6 of 26 patients; P < 0.003). While this data was not derived from a randomized study, the two groups did not differ in clinical or laboratory characteristics or time of followup [15.4 ± 1.5 years (no surgery) versus 14.0 ± 0.8 years (surgery) from onset]. The
Fig. 2 Kaplan–Meir plot of disease-specific and disease-free survival in patients with ZES who underwent the resection of a duodenal primary with curative intent.
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percentage of patients in whom gastrinoma can be identified and resected has increased with increasing experience in appreciation of the presence of small duodenal primary lesions. It is important, when contemplating a surgical resection with curative intent of a putative sporadic gastrinoma, to carefully establish the biochemical diagnosis and to rule out the presence of metastatic disease. A schematic for the approach to the ZES patient with a sporadic gastrinoma is shown in Fig. 3. The improvement in outcome following surgical exploration and resection with curative intent in most series is due to a number of factors. Because gastric acid hypersecretion can be managed in all patients with antisecretory agents, surgical exploration can be done electively and safely. Patients can be effectively screened, using an algorithm as outlined in Fig. 3, to eliminate occult metastatic or unresectable disease, thereby improving patient selection for potentially curative
Biochemical Diagnosis of Sproadic ZES
Negative
Angiography with Secretin Stimulation
SRS
Positive for metastases
Liver Metastases
Positive No distant Metastases
EUS
Limited/ ?Resectable
Diffuse
CT or MRI ± Angiogram
CT or US-guided Biopsy
Resection Surgery
Proton Pump Inhibitor Octreeotide Chemotherapy Embolization RFA
Fig. 3 A proposed algorithm for the approach to ruling out the presence of metastatic disease in a patient with sporadic ZES prior to a surgical resection of the primary with curative intent.
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surgery. Furthermore, the appreciation that small duodenal primary tumors are more frequent than previously appreciated has resulted in increased detection and resection of these frequently small lesions compared to earlier studies. A careful standardized surgical approach is critical to the detection and resection of a primary gastrinoma as well as any occult metastases to the lymph nodes or the liver. At laparotomy, the entire pancreas as well as the duodenum should be dissected and exposed. Intraoperative ultrasound (IOUS), duodenal transillumination via EGD, and routine duodenotomy should be performed. Palpation alone can identify 65% of duodenal gastrinomas, endoscopic transillumination an additional 20% of tumors, and duodenotomy an additional 15% of tumors not localized by other modalities (Fig. 4). Even small duodenal primaries can be detected with careful palpation through a duodenotomy (Fig. 5). For duodenal tumors, 71% are in the first part of the duodenum, 21% in the second part, and 8% in the third part. By employing this systematic approach, gastrinomas can be found in all patients undergoing operation. At laparotomy, if a gastrinoma is found as a solitary lesion in the liver, it should be removed, provided
Fig. 4 Palpation and inspection of the duodenum through a duodenotomy has increased the number of primary duodenal gastrinomas that can be detected and successfully resected. Here, the technique of palpation between the thumb and index finger through a longitudinal duodenotomy is demonstrated. Once the lesion is identified and resected, the duodenotomy is closed transversely in two layers.
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Fig. 5 Small duodenal gastrinomas can be identified using a combination of EGD transillumination, duodenotomy, and palpation.
that the resection can be performed safely. If gastrinoma is found in the pancreatic head, it should be enucleated if technically possible. If an extensive gastrinoma not amenable to eradication is found in the pancreatic head area, performing a pancreaticoduodenectomy (Whipple’s operation) for potential cure can be considered but is controversial because of the possible morbidity and mortality associated with this operation and the excellent long-term prognosis of these patients. Careful patient selection with consideration of comorbidities is important. If no gastrinoma is found at surgery, a blind distal pancreatectomy should not be performed as the majority of primary tumors are found in the pancreatic head or duodenum. In addition, ectopic gastrinoma can occur in a variety of other locations, including the small bowel mesentery, liver, common bile duct, and ovary. At surgery the use of IOUS is recommended to localize additional lesions, to confirm the significance of a palpated mass, and to establish the relationship between the tumor and the pancreatic duct. For either pancreatic or duodenal primaries, any abnormal or suspicious lymph nodes in that area should be excised. In some patients undergoing exploration, disease may be limited to one or more lymph nodes. Despite the inability to identify a primary site of disease in the duodenum or pancreas, long-term
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biochemical cures can be achieved with resection of the involved lymph nodes. In a recent study with a mean followup of 10.2 years, 10% of all 138 patients had only a lymph node containing gastrinoma resected and remained cured. No laboratory chemistries or lymph node characteristics at surgery were predictive of whether the lymph node was a primary tumor, supporting the conclusion that lymph nodes from the gastrinoma triangle should be routinely removed at operation. The role of surgery in the treatment of patients with ZES in the setting of MEN 1 is in evolution. Numerous studies have shown that in MEN 1 patients with ZES, 70–95% of primary tumors arise in the duodenum and 10–25% in the pancreas. Cure is not possible in patients with MEN 1 and ZES short of pancreaticoduodenectomy, because 30% of patients have more than 20 duodenal tumors and 86% of patients have positive lymph nodes. In 77 patients with MEN 1 and ZES, the only independent factor associated with the development of liver metastases was a greater-than-3 cm pancreatic primary tumor. However, operation with curative intent in 118 patients did not influence survival. Biochemical relapse occurs in over 95% of individuals within 3–5 years of surgery. Despite this recurrence rate, there is an excellent prognosis for patients with MEN 1 and ZES. The acid secretion can be completely controlled medically. Since there are multiple other pancreatic tumors seen routinely in MEN 1 patients, and since the morbidity of pancreaticoduodenectomy can be considerable, it is not routinely recommended. Our current recommendation is to operate on patients with MEN 1 and ZES when a tumor of at least 2.5 cm is seen on imaging studies. This policy is based on the observation that metastases to the liver correlated with tumor size. If the tumor is in the pancreatic head it is enucleated if possible, and in the pancreatic tail it is resected and a duodenal exploration is performed. The role of reoperation in ZES patients is important, because most patients with sporadic ZES undergoing operation and resection will have persistent or recurrent disease. In a series of 17 patients who had previously undergone an operation with curative intent, 18 reoperations were performed on the basis of biochemically documented recurrent disease and one or more positive imaging studies. In those undergoing reoperation, it was possible to identify and resect disease in 17 of 18 cases with
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biochemical cures in all, although median followup was short (34 months). Notably, the site of recurrent disease identified at reoperation was related to the initial operative findings. For example, for those patients who had lymph node disease resected initially, most had lesions identified in the duodenum at reoperation. In contrast, for those who had a primary duodenal or pancreatic lesion initially resected, the recurrence was commonly identified in regional lymph nodes. Because of the increase in potential risk associated with reoperation in this setting, consideration of reoperation should be made carefully.
MEDICAL MANAGEMENT OF PRIMARY GASTRINOMAS The approach to the treatment of patients with gastrinoma and ZES has undergone a profound evolution over the last 50 years. Initially, effective therapy consisted in aggressive surgery including total gastrectomy. The goal of surgery was to remove the organ responsible for acid hypersecretion in an attempt to manage the debilitating and often life-threatening sequelae of the ulcer disease. In the modern era, medical treatment of gastric acid hypersecretion is the mainstay of therapy. The H2 antagonists (cimetidine, ranitidine, famotidine) alone or in combination with anticholinergic agents (probanthine, isopropamide) and the substituted benzimidazole (omeprazole), which functions as an H+-K+ATPase inhibitor, have been used successfully in the long-term treatment of patients with ZES. The number of patients failing medical therapy varies greatly in different series: cimetidine (varying from 0% to 65%), ranitidine (varying from 0% to 40%), famotidine (0%), and omeprazole and lansoprazole (varying from 0% to 7.5%. Symptom relief does not adequately reflect the effectiveness of antisecretory therapy. Most studies have demonstrated that in order to assess the adequacy of antisecretory therapy, gastric acid secretion must be measured while the patient is taking medication. Patients with ZES often require higher doses of acid-reducing medications than patients with peptic ulcer disease or gastroesophageal reflux. The average doses for the treatment of ZES are 3.6 g/d for cimetidine, 1.2 g/d for ranitidine, 0.25 g/d for famotidine, 20–80 mg/d for omeprazole, and 30–120 mg/d for lansoprazole. The long-term use of
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these doses of H2 antagonists and omeprazole has proven not only effective but also safe. Some concerns have been raised regarding the long-term use of omeprazole. Female rats given omeprazole (or other potent inhibitors of gastric acid secretion) have developed proliferation of gastric enterochromaffin-like (ECL) cells and in some cases carcinoid tumors of the stomach. Omeprazole treatment for up to four years does not result in a significant increase in gastric ECL cells. While patients with MEN 1 may be predisposed to the development of gastric carcinoids with ZES, for patients with sporadic ZES the incidence of gastric carcinoids is very low (less than 1%). The gastric acid hypersecretion seen in ZES patients must be controlled because most patients will not be cured following surgical exploration. If acid hypersecretion is controlled, patients have an excellent quality of life; however, long-term prognosis is being increasingly determined by the malignant nature of the gastrinoma. As many as 90% of gastrinomas may be malignant and, therefore, it is important to consider surgical therapy directed at the primary and metastatic disease if feasible. Metastatic disease is often to the liver and can be managed with surgical resection, regional infusions, or radiofrequency ablation. For isolated liver metastases not amenable to these approaches without evidence of extrahepatic disease, a liver transplant may be considered based on the indolent nature of these tumors. Systemic therapies beyond those directed at the control of acid secretion have had limited utility. Somatostatin-receptor-directed therapies such as octreotide and radiolabeled octreotide have been used with variable results. Systemic chemotherapies such as cisplatin and adriamycin have also been tried with limited success. The mainstay of management remains surgical extirpation or debulking when possible and the use of acid-controlling medications to control symptoms.
SELECTED REFERENCES Libutti SK, Alexander HR Jr. Gastrinoma: sporadic and familial disease. Surg Oncol Clin N Am 2006;15(3):479–496. Norton JA, Alexander HR, Fraker DL, et al. Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases, or survival in
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patients with Zollinger–Ellison syndrome? Ann Surg 2004;239(5):617–625; discussion 626. Norton JA, Fraker DL, Alexander HR, et al. Surgery to cure the Zollinger–Ellison syndrome. N Engl J Med 1999;341(9):635–644. Norton JA, Fraker DL, Alexander HR, et al. Surgery increases survival in patients with gastrinoma. Ann Surg 2006;244(3):410–419. Zogakis TG, Gibril F, Libutti SK, et al. Management and outcome of patients with sporadic gastrinoma arising in the duodenum. Ann Surg 2003;238(1):42–48.
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Chapter IV.B.4: Clinical Management of Nonfunctional Neuroendocrine Tumors and Management of Metastatic Disease Jennifer Rabaglia, MD, Shelby Holt, MD and Fiemu Nwariaku, MD
OVERVIEW Pancreatic neuroendocrine tumors (PNETs) are a rare and heterogeneous group of tumors demonstrating a wide biological spectrum, with an estimated incidence of less than one case per 100,000 individuals annually in the United States. They account for 1–2% of all pancreatic neoplasms, although in the age of advanced imaging they are being diagnosed with increasing frequency. These tumors may be either functional or nonfunctional, based upon whether they result in detectable systemic hormone excess. According to several recent series, 40–70% of all PNETs are nonfunctional (nfPNETs). Since these tumors lack signs and symptoms of systemic hormonal excess, they commonly present with locally advanced disease, often mimicking the presentation of pancreatic adenocarcinoma. A large proportion of patients also present with metastatic disease, most commonly to the liver. Surgical intervention is the primary treatment, even in the setting of metastatic disease, although there are now many options for multimodal therapy as we continue to develop new advanced imaging and molecular targeting techniques.
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PREOPERATIVE EVALUATION Laboratory While there are no specific laboratory markers for the identification of PNETs, chromogranin A (CgA) is the most useful biochemical marker for the diagnosis and followup of nonfunctional tumors, with a sensitivity and specificity of 75% and 100%, respectively. CgA levels reflect tumor burden and correlate with disease progression and/or response to treatment. In addition, approximately 20–30% of nfPNET are associated with multiple endocrine neoplasia type 1 (MEN-1). Therefore, biochemical screening for MEN-1 is necessary, and is best accomplished by obtaining serum calcium, parathyroid hormone (PTH), prolactin, gastrin, and insulin levels, as well as genetic testing for Menin mutations. A positive genetic and biochemical screen can alter management significantly, especially with respect to intervention for functional gastrinomas. Parathyroid disease develops in over 90% of patients with MEN-1, and addressing this issue first can help ameliorate symptoms of Zollinger–Ellison syndrome in patients with concurrent gastrinoma.
Imaging Cross-sectional Conventional anatomic imaging (CT and/or MRI) is necessary for evaluating the extent of the primary tumor and to detect the presence of intra-abdominal metastases. Unlike pancreatic adenocarcinoma, nfPNETs appear characteristically hypervascular. In fact, the extent of tumor vascularity directly correlates with the degree of tumor differentiation. On dual phase spiral CT scanning with IV contrast, nfPNETs show moderateto-strong enhancement during both the arterial and portal phases (Fig. 1). Twenty percent of lesions also exhibit nodular or shell-like calcifications (Fig. 2). High signal intensity on T2-weighted images with homogeneous enhancement is the typical finding on MRI with IV gadolinium. Hepatic metastases show increased enhancement similar to the primary tumor using either modality.
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Fig. 1 Appearance of nfPNET on IV-contrast-enhanced CT. Note tumor enhancement with contrast.
Fig. 2
CT image of nfPNET. Precontrast. Note calcifications (arrow).
Scintigraphy Octreotide scanning is 80–90% sensitive and nearly 100% specific in detecting PNETs. It is most effective in detecting tumors with high concentrations of somatostatin receptors, whether they are functional or
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nonfunctional lesions. It plays an important role in the imaging workup, for several reasons: (1) it provides accurate localization of the primary tumor, especially with regard to small (<1 cm) tumors that are less often detected using cross-sectional imaging; (2) it can detect metastatic lesions even when they cannot be visualized on conventional imaging; and (3) it predicts which tumors are likely to respond to somatostatin analogs. Ultrasonography Though not always required for the localization of primary nfPNETs, endoscopic ultrasound (EUS) can be useful for determining the local extent of the tumor, including vascular invasion and regional lymph node involvement. This technique also facilitates biopsy, which is useful when the imaging diagnosis is equivocal. Intraoperative ultrasonography can be particularly useful for the localization of small (subcentimeter) or multiple tumors, and may aid in determining spatial relationships with respect to the pancreatic duct. Pathology Standard hematoxylin and eosin (H&E) staining of well-differentiated PNETs characteristically reveals nested or trabecular/glandular architecture. These tumors are predominantly composed of round-to-ovoid cells with eosinophilic granular cytoplasm and stippled (salt-and-pepper) nuclei. In contrast, poorly differentiated lesions consist of cell populations that are either larger and more heterogeneous in appearance, or densely packed “small round blue cells” that are characteristic of other aggressive small cell carcinomas (Figs. 3 and 4). Consistent with immunohistochemistry (IHC) performed on most neuroendocrine tumors, nfPNETs usually stain positive for CgA, synaptophysin and neuronal specific enolase, and many stain positive for pancreatic polypeptide. Most PNETs actually display multiple IHC markers, even if these hormones or peptides are not detectable at the systemic level. A few IHC markers may aid in prognostication, including the Ki-67 index, which predicts tumor differentiation, as well as cytokeratin 19, which is an independent marker for aggressive tumor
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Gross specimen (distal pancreatectomy) with tumor bisected.
Fig. 4 nfPNET histology/immunohistochemistry. Cellular nests with red/brown staining indicating tumor is positive for CgA (thin arrow). Also, note the extensive amyloid deposition (light pink; thick arrow).
behavior. The WHO classification of neuroendocrine tumors recognizes the following three categories: (1) well-differentiated neuroendocrine tumor — benign or unknown malignant potential; (2) well-differentiated neuroendocrine carcinoma — low grade malignant; and (3) poorly
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differentiated neuroendocrine carcinoma — high grade malignant. Although this represents a pathologic rather than clinical prognostication scheme, recent data suggest a significant disparity in five-year survival between the three WHO groups (approximately 90%, 40%, and <10%, respectively).
OPERATIVE MANAGEMENT OF nfPNETs Several principles influence the treatment and outcome of patients with nfPNETs: (1) the natural history of well-differentiated tumors is one of slow progression; (2) complete surgical resection is the only potentially curative treatment; (3) resection appears to improve survival (even in the setting of metastatic disease); (4) multiple treatment modalities are now available to provide effective control of hepatic and distant metastases. Therefore, aggressive surgically based treatment is favored, especially if the tumor burden can be completely resected, or greater-than-90% debulked. Despite improved survival rates with surgical intervention, the risk of recurrence remains high and recurrent disease most often manifests in the liver. The majority of nfPNETs arise in the pancreatic head, and thus resection of the primary tumor often involves pancreaticoduodenectomy. Lesions of the body or tail require distal pancreatectomy (most often with splenectomy). Total pancreatectomy may be required for large body lesions extending into the pancreatic head near the common bile duct. Enucleation is rarely an option for nfPNETs, given their large size and high rate of metastatic disease (approximately 75%) at presentation. Superior mesenteric vein (SMV) invasion should not be considered an absolute contraindication to surgery, as SMV resection and replacement with autologous vein can be performed with minimal morbidity in high volume centers. Given the frequency of nodal involvement, operative management should include inspection and removal of peripancreatic, periduodenal, and portal lymph nodes. Despite improved technology and increased experience with minimally invasive surgical techniques, the outcome data are limited with respect to laparoscopic resection of nfPNETs due to the rarity of these lesions.
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MANAGEMENT OF METASTATIC AND RECURRENT DISEASE Approach to Hepatic Metastases The presence of hepatic metastases is the most important prognostic indicator in patients with nfPNETs, and the extent of liver disease correlates with survival. Patients are evaluated for hepatic resection based on imaging findings (CT/MRI, octreotide scan), estimation of liver reserve, and patient comorbidities. Bilobar involvement with tumor does not necessarily preclude surgical resection; however, involvement of more than 75% of the liver is associated with a poor prognosis and is considered a contraindication to surgery. Overall, curative resection is possible in about 10% of patients, usually those with a solitary metastasis or disease confined to one lobe. Liver transplantation is the only potentially curative treatment for unresectable disease. Since complete curative resection of hepatic metastases is rarely an option, surgery often becomes one arm of a multipronged approach. Multiple therapeutic options exist for those patients in whom complete resection of liver disease cannot be achieved. Cytoreductive therapy is one such option, and is defined as complete removal or reduction of tumor volume by at least 90%. The goals of therapy are prolonged survival and palliation of symptoms. Cytoreductive therapy may be achieved through a multimodal approach, using a combination of various interventions, including hepatic resection, hepatic artery embolization, chemoembolization, radio frequency or cryoablation, peptide receptor radionuclide therapy, and targeted radiation with yttrium-90-labeled microspheres. Each procedure carries a slightly different therapeutic profile, and the modality or modalities chosen may be tailored to the individual patient. Hepatic artery embolization (HAE) is based on the principle that tumor cells are preferentially supplied via hepatic arterial flow while normal liver parenchyma is supported by the portal vein. It is a catheter-based technique employing intravascular coils or gel foam emboli to cause coagulation of the tumor arterial supply and thus focused tissue ischemia. The effect is temporary, as ischemic tumors develop collateral blood vessels over time. Symptomatic response can be seen in 40–80% of cases,
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whereas biochemical response is evident in slightly fewer patients. Contraindications include portal vein thrombosis, liver failure, biliary reconstruction, and poor functional status. HAE is generally well tolerated, and may be repeated PRN. Chemoembolization (CE) includes injection of a tumor arterial supply (targeted hepatic branches distal to the gastroduodenal artery) with an emulsion of doxorubicin or streptozocin dissolved in saline and iodized oil, followed by embolization with gelatin sponge particles. Like HAE, CE can be repeated PRN at 1–2-month intervals, and a minimum of two sessions is required to achieve the maximal response. This modality is advantageous in the setting of PNETs, as these tumors tend to be more chemosensitive than other hepatic malignancies, and the approach ensures excellent drug delivery at the tissue level. Several series have noted objective tumor response rates of 33–80% after repeated CE. Contraindications are similar to those for HAE, and postprocedure complications include ileus, portal vein thrombosis, hepatic abscess, hepatic fistula formation, encephalopathy, and renal insufficiency. Radio frequency ablation (RFA) and cryoablative therapy are thermal ablative techniques best applied in patients with limited focal or residual disease, or in combination with more extensive hepatic resection. RFA employs radio frequency waves to create intense heat, causing coagulative tissue necrosis. Care must be taken when treating lesions near large hepatic vessels. Conversely, cryoablation employs a thermal probe which applies repetitive freeze/thaw cycles to create tissue destruction via intracellular and extracellular ice crystal formation. These techniques are most effective when used in the setting of small (<4 cm) tumors that are less than or equal to five in number. Both modalities have shown good tumor response rates (as high as 87–96%) in multiple studies with response duration of up to 25 months, and may serve as useful adjuncts to surgery. Potential complications include hepatic abscess, hemorrhage, and bile leak. Radiation is now being utilized in a more focused fashion through a few innovative therapeutic modalities, including peptide receptor radiotherapy (PRRT) and microsphere radioembolization. Both techniques employ radiolabeled particles aimed at specific anatomic or molecular
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targets. PRRT uses radiolabeled somatostatin analogs to target somatostatin receptors, which exist in higher concentrations in most PNETs than in surrounding normal tissue. Thus, radiation is delivered to the target at a cellular level, avoiding the widespread damage typically caused by field irradiation. Radioembolization uses yttrium-90-labeled microspheres to deliver its dose of radiation through the tumor blood supply in much the same manner as CE, thus irradiating a very focused anatomic distribution.
Systemic Treatment Options Adjuvant therapy for malignant gastroenteropancreatic neuroendocrine tumors of all types remains a somewhat ill-defined area, but is gaining ground in the era of advanced molecularly based therapy. PNETs have proven more chemosensitive than their nonpancreatic counterparts, and for this reason patients with symptomatic, unresectable disease or disease progression after interventional options have been exhausted now have some reasonable options for systemic therapy. Somatostatin analogs, including octreotide and lanreotide, are quite effective in controlling symptoms associated with hormonal excess. Their effects on tumor growth are less dramatic, and their role in therapy for nonfunctional lesions is uncertain. However, with the application of PRRT, these agents may see renewed interest in this setting. Systemic chemotherapy for metastatic nfPNETs differs with respect to tumor differentiation. Traditional therapy for well-differentiated tumors typically includes a combination of streptozocin and either 5FU or doxorubicin, with reported response rates (actual tumor regression) of around 40–60%. Renal toxicity tends to be a limiting side effect. A combination of interventional techniques and systemic therapy generally achieves survival rates measured in years rather than months, although the five-year survival for these patients remains poor. With the failure of traditional chemotherapy agents, patients may now turn to newer drugs utilizing molecular targets, including bevacizumab (Avastin — vascular endothelial growth factor or VEGF inhibitor), sunitinib (Sutent — selective receptor tyrosine kinase inhibitor), and surafanib
Positive MEN-1 screen
Multimodality tx if applicable (RFA/cryo, HAE/CE) Resect primary tumor with resection or debulking of metastatic disease +/multimodality tx (RFA/cryo, HAE/CE) Well-differentiated
Poorly differentiated
Surveillance protocol
RD
Steptozocin systemic tx
PRRT, Y90 microspheres RD Clinical trial (RTK inhibitors, avastin, etc) RD=recurrent disease; Tx=therapy; CgA=chromogranin A; RTK=receptor tyrosine kinase; PRRT=peptide receptor radiotherapy; RFA=radio frequency ablation; HAE=hepatic artery embolization; CE=chemoembolization
Fig. 5
Management algorithm for nfPNETs.
Cisplatinum-based systemic chemotx
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Obtain: serum CgA, Ca++, PTH, prolactin, MENIN screen, CT or MRI with IV contrast octreotide scan
Positive CgA, octreotide scan or hypervascular tumor by CT/T2weighted MRI and Negative MEN-1 screen
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Suspected nfPNET
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(Raf kinase/VEGF inhibitor). Most of these agents remain limited to use in clinical trials, but early results seem promising, especially with respect to disease stabilization. Poorly differentiated tumors behave aggressively, and therefore respond better to a more aggressive systemic regimen, often including the combination of cisplatin and etoposide. They tend to be rapidly progressive and difficult to control, and treatment guidelines (i.e. when and in whom) for administration of chemotherapy remain poorly defined. Overall, despite advances in imaging, surgical technique, and molecular medicine, nonfunctional pancreatic neuroendocrine tumors still represent a diagnostic and therapeutic challenge. It is clear that surgeons play a central role in the care of these complex patients, and for this reason we have included a brief management algorithm (Fig. 5) to assist with basic decision-making. However, “best practices” in this setting remain somewhat ill-defined, and we look forward to a more complete understanding of these rare but interesting neoplasms.
SELECTED REFERENCES Abood GJ, Go A, Malhotra D, Shoup M. The surgical and systemic management of neuroendocrine tumors of the pancreas. Surg Clin N Am 2009;89: 249–266. Kaltsas GA, Papadogias D, Makras P, Grossman AB. Endocr Relat Cancer 2005;12:683–689. King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Am Cancer Soc 2008;113:921–929. Musunuru S, Chen H, Rajpal S, et al. Metastatic neuroendocrine hepatic tumors: resection improves survival. Arch Surg 2006;141:1000–1004. Norton JA, Kivlen M, Li M, et al. Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors. Arch Surg 2003; 138:859–866. Srirajaskanthan R, Toumpanakis C, Meyer T, Caplin ME. Future therapies for management of metastatic gastroenteropancreatic neuroendocrine tumours. Aliment Pharmacol Ther 2009;29:1143–1154.
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autograft failure 266, 269, 273 autotransplantation 265–268, 270–273 delayed 266, 268, 270, 271
5-hydroxytryptamine (5-HIAA) 370–373, 375 ACTH-independent macronodular adrenal hyperplasia (AIMAH) 287, 295 adrenal 277, 279–285, 341, 342, 348, 350–355 gland anatomy 333, 334, 336, 340 insufficiency 341, 352, 353 tumor 336 venous sampling 324, 325 adrenalectomy 329, 330, 333–335, 337, 340 laparoscopic 329, 330, 333, 335–338, 340 adrenal incidentaloma 279, 280, 284, 285 adrenocortical carcinoma (ACC) 294, 360, 361, 363 adjuvant therapy 363 radiation therapy 94, 98–100, 364 adrenocorticotropin hormone (ACTH) 287, 291, 295–297 adynamic bone disease 183, 184, 186, 191 antithyroglobulin antibodies 11, 12 anti-thyroid peroxidase antibodies (anti-TPO antibodies) 9, 10
beta-adrenergic blocker 113, 116 bone mineral density 147, 156 calcimimetic 187, 189 calciphylaxis 183, 187, 188 calcitonin 13, 63, 74, 75 calcium compound/replacement/ supplement 254–260 carcinoid 369, 370, 372, 374, 405–410, 412, 414, 416–421 appendiceal 421 midgut 405 syndrome 407–410, 412, 414, 418, 420 Carney complex 287, 295 catecholamine 299–304 central neck dissection 51, 53, 54 cervical block 173, 176 chemotherapy 98, 100 chromogranin A (CgA) 370, 372, 373, 375 chronic kidney disease (CKD) 179, 181, 184–186, 194 corticotropin-releasing hormone (CRH) 287, 291, 297 cortisol 287, 289–291, 293, 296, 297 455
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Index
Cushing’s syndrome 279, 280, 285, 287–289, 292, 295, 341, 350–353 diffuse B cell lymphoma 102 ectopic parathyroid gland 176 end stage renal disease (ESRD) 179–183, 188, 193, 203, 204 endoscopic ultrasonography (EUS) 384 fine needle aspiration biopsy (FNAB) 27, 29, 32, 34, 43–47 follicular lesion of undetermined significance 33 follicular neoplasm 33, 35, 79 follicular thyroid cancer 27, 31, 33, 35, 80 four-dimensional computed tomography (4D-CT) 161, 165, 166, 168, 169 gastrin 391–394, 396, 434 gastrinoma 391–396, 431–441 surgery 431, 434, 435, 437–440 genetic testing 225, 227, 228, 230, 232, 234, 237–239, 306, 308 glucagonoma 397–399 Graves’ disease 109, 111, 113, 114, 116–121 Hürthle cell carcinoma 33, 34, 36, 79, 80, 86 neoplasm 33, 34, 36, 79–81 hyperaldosteronism 281, 315, 316, 318, 319, 327, 341, 348, 349
hypercalcemia 148–154, 203–206, 208, 217, 219, 220 crisis 241, 243, 244, 245, 247 medical therapy 243, 245, 246 severe 241, 243, 247 treatment 243, 244, 247 hypercortisolism 287–291, 341, 350–352 hyperinsulinemia 429 hyperparathyroidism (HPT) 131, 132, 147–151, 153–155, 203–208, 211–214, 223, 224, 226–233, 237, 238, 265, 266, 268, 274 acute 241 familial 147, 154, 223 family screening 238 familial isolated HPT (FIHPT) 229–231 HPT-Jaw Tumor (HPT-JT) syndrome 231 primary 147, 151, 154, 155, 171–173, 177 secondary 151, 153, 154, 179–194 tertiary 151, 154, 203, 205 hyperthyroidism, extent of surgery 115 hypocalcemia 249, 251, 253, 254, 256–260 postoperative 131, 132 hypoglycemia 377–382
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hypoparathyroidism 252, 254, 257–259 hypothyroidism 138–142 insulinoma 377–382, 384–389, 423, 424, 427, 429 diagnosis 377–380, 382 enucleation 423–428 localization 378, 382–384, 386, 389, 390 intraoperative parathyroid hormone (ioPTH) 171, 173–175, 177
457
thyroid 106, 107 methimazole 109, 110, 112 mitotane 363 mucosa-associated lymphoid tissue (MALT) lymphoma 102, 103, 105 multiple endocrine neoplasia (MEN) syndrome 63 MEN1 223–227, 229–231, 234, 239, 377, 382, 383, 392, 394, 423, 424, 427, 428, 432–434, 439, 441, 444 MEN2A 227, 228, 235, 236, 306, 309
kidney transplant 203–205 levothyroxine 137–139 Lugol’s solution 113 magnetic resonance imaging (MRI) 161, 165, 166, 168 medullary thyroid cancer (MTC) 63, 65 familial 63, 64, 70, 71, 73, 74 metaiodobenzylguanidine (MIBG) 374 metanephrine 299, 300, 302–304, 308, 309 metastasis 358 hormonal therapies 364 lymph node involvement 49, 50–54 surgical indication 360–362, 364 surgical management 423–426, 428, 443, 448, 449, 453
neck hematoma 125–127, 129, 130 nerve injury 125, 126 neuroendocrine tumor (NET) 397, 401, 403, 406, 407, 415, 419, 431, 433 nonfunctional 443 pancreatic 443, 451, 453 neurofibromatosis type 1 (NF1) 306 octreotide 421
373, 375, 410–412, 418,
pancreas 397, 398, 400–403, 425–428 pancreatic neoplasm 443 pancreatic-polypeptide-secreting tumor (PPoma) 397, 403 papillary thyroid cancer (PTC) 27, 31, 33, 34, 37, 49–58, 60 paraganglioma 309
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parathyroid autotransplantation 265–268, 270–273 cryopreserved heterotopic parathyroid autotransplantation (CHPA) 265–267, 269, 270, 272, 273 gland 211, 212, 214, 217 reimplantation 269 storage 267–269 parathyroid carcinoma 147, 151, 155, 211, 212, 214–218, 220 parathyroid hormone (PTH) 203, 211–213, 218–220 parathyroidectomy complications of 250–253, 257–259 minimally invasive (MIP) 171, 173, 175–177 radioguided 167 subtotal 179, 189, 193, 194 total 179, 189, 190, 193, 194 parathyromatosis 217 phenoxybenzamine 343–347 pheochromocytoma 280, 282–285, 299–312, 341–347 plasma aldosterone concentration 316, 317 plasma renin activity 316, 317 Plummer’s disease 120 postoperative bleeding 130 potassium iodide (SSKI) 113, 114 primary pigmented nodular adrenal disease (PPNAD) 287, 294, 295 prolonged fasting test 379 propylthiouracil (PTU) 109, 110, 112, 114
Index
radioactive iodine (RAI) 54, 55, 59, 109, 113–115, 117, 119–123 radionuclide scanning 22 REarranged-during-Transfection (RET) 63, 64, 67, 69–73, 78 renal cell carcinoma 106, 107 reoperative neck surgery 218 secretin 394, 396 selective arterial calcium stimulation with hepatic venous sampling 387 sestamibi 163–165, 167, 168, 174 single-photon emission computed tomography (SPECT) sestamibi CT 163, 164, 168 somatostatin receptor scintigraphy (SRS) 388, 389 somatostatinoma 397, 401, 402 succinate dehydrogenase subunits B, C, D (SDHB, SDHC, SDHD) 306 technetium 163 thoracic duct leak 133 thyroglobulin 9, 11, 12, 50, 52 thyroid 15–25 cyst 47 imaging 15 lymphoma 101, 102, 104, 105 scanning 20, 22, 24, 25 storm 112, 114, 116, 121, 122 ultrasound 20, 27–29, 32, 34 thyroid cancer 89–93, 95–97, 99, 100 locally advanced 93–100 recurrent 49–51, 53, 54, 57–59 thyroid hormone 3–5, 11, 12 free T3 5, 8
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free T4 5, 6, 7, 9 replacement 137 total T3 8, 9 total T4 6, 7 thyroid nodule 27, 28, 30–32, 35–37, 39, 42–47 management 45 molecular testing 42, 46 thyroid stimulating hormone (TSH) 3, 4, 5, 7, 9, 10, 12 suppression 49, 56–59 thyroid stimulating immunoglobulin (TSI) 10 thyroidectomy 40, 42, 45–47, 91, 93–95, 97, 99, 138, 140 complications of 125, 129–131, 133–135, 249, 250, 252–254, 259, 260 total 49, 50, 54, 56
459
thyroxine 137–140 toxic adenoma 109, 111, 121 toxic multinodular goiter (TMG) 109, 111, 120 ultrasound 161–163, 165, 168, 169 cervical 52, 57, 58 intraoperative 423, 425, 426 vasoactive intestinal peptide tumor (VIPoma) 397, 399–401 von Hippel-Lindau (VHL) 306–308 Whipple triad 378 Zollinger-Ellison syndrome
391